Recent developments in peptide drug delivery to the brain.

Peptide-based therapeutics are highly water-soluble compounds that do not readily enter brain from blood owing to poor transport through the brain capillary endothelial wall, i.e., the blood-brain barrier (BBB). Strategies available for peptide drug delivery to brain include: (a) neurosurgical-based (intraventricular drug infusion, hyperosmotic opening of the BBB); (b) pharmacological-based (peptide lipidization, liposomes); and (c) physiological-based (biochemical opening of the BBB, chimeric peptides). Chimeric peptides are formed by the covalent coupling of a pharmaceutical peptide (that is normally not transported through the BBB) to a brain transport vector that undergoes absorptive-mediated or receptor-mediated transcytosis through the BBB. The most efficient brain transport vector known to date is a monoclonal antibody to the transferrin receptor, and this vector achieves a brain volume of distribution approximately 18-fold greater than the plasma space by 5 hr after a single intravenous injection of antibody. The chimeric peptides are formed generally with chemical-based linkers. However, avidin/biotin-based linkers allow for high yield coupling of drug to vector, and for the release of biologically-active peptide following cleavage of the chimeric peptide linker. These strategies may also be used for the delivery of antisense oligonucleotide-based therapeutics to brain. In conclusion, the development of efficacious neuropharmaceuticals in the future will require the development of both drug delivery and drug discovery strategies that operate in parallel.


Saturation analysis in receptor binding assays: an evaluation of six different calculation techniques.

Randomized errors to varying extents have been introduced in a constructed data set stimulating receptor binding saturation analyses. The parameters Bmax and Kd were then determined using six different evaluation techniques, four linear and two non-linear. It is concluded that a non-linear evaluation gives more reliable results, especially when errors are large. Furthermore, an inevitable correlation between Bmax and Kd regardless of evaluation technique results in possible misinterpretations of simultaneous changes in both parameters.


Active and passive electrical properties of isolated canine cardiac Purkinje fibers under conditions simulating ischaemia: effect of diltiazem.

The effect of a calcium channel blocker diltiazem on the electrical properties of canine Purkinje fibers superfused in a milieu similar to that occurring in acute myocardial ischaemia was studied. Action potential parameters, passive electrical properties, and conduction velocity were measured using conventional microelectrode techniques. Superfusion with glucose-free Tyrode's solution containing 9 mM K+, gassed with 100% N2 at pH = 6.5 ('ischemic solution') significantly reduced the maximal diastolic potential, action potential duration, maximal upstroke velocity, conduction velocity and length constant, while input resistance and longitudinal resistance were elevated and membrane resistance remained unchanged. Diltiazem (1 microM) alone reduced only the action potential duration, while all other parameters were unaffected. Pretreatment with diltiazem did not fully prevent the effects of ischemic superfusion; however, the ischaemia-induced decrease in length constant was not significant in the presence of diltiazem. In addition, the increase in longitudinal resistance during ischaemia was significantly reduced following diltiazem pretreatment. This decrease in longitudinal resistance may contribute to the improvement of ischaemia-induced conduction delay observed in intact animals and may be related to a reduction of ischaemia-induced increase in intracellular free Ca2+.


Effects of hydrocarbons on transformation and intercellular communication in Syrian hamster embryo cells.

The ability of 18 different hydrocarbons to induce and promote morphological transformation and to inhibit intercellular communication in primary Syrian hamster embryo cells in culture have been studied. The compounds were: the n-alkanes octane, nonane, decane, undecane, dodecane and tridecane; the iso-alkanes 2-methylheptane, 2-methyloctane and 2-methylnonane; the naphthenes 1,2-dimethylcyclohexane, 1,2,4-trimethylcyclohexane and tert-butylcyclohexane; the aromates 1,2-dimethylbenzene, 1,2,4-trimetylbenzene and tert-butylbenzene; and the alkenes 1-octene, 1-nonene and 1-decene. None of the hydrocarbons induced morphological transformation of Syrian hamster embryo cells. When the hydrocarbons were incubated together with benzo(a)pyrene, enhancement of the transformation frequency was observed for the naphthene 1,2-dimethylcyclohexane and the iso-alkanes 2-methylheptane and 2-methyloctane. None of the n-alkanes, alkenes or aromates enhanced the transformation frequency induced by benzo(a)pyrene. The alkane tridecane and the iso-alkanes 2-methyloctane and 2-methylnonane reduced intercellular communication in the primary Syrian hamster embryo cells.


Supersensitivity to the antinociceptive effect of a 5-HT1 receptor agonist after lesion of raphe-spinal serotonergic neurones.

The actions of the 5-hydroxytryptamine type-1B (5-HT1) receptor agonist 1(m-chlorophenyl)piperazine (mCPP) on response latencies in the tail-flick test and tail skin temperature were examined in mice after pretreatment with the 5-HT neurotoxin, 5,6-dihydroxytryptamine (5,6-DHT). All the compounds were given intrathecally. The level of 5-HT in spinal cord was reduced by 79% 4 days after intrathecal injection of 5,6-DHT (10 micrograms). There was a significant relationship between the tail-flick latency and tail skin temperature, and the reduced baseline tail-flick latencies induced by 5,6-DHT were non-significant after the change in skin temperature was taken into account. Intrathecal mCPP (5 micrograms) significantly increased the tail-flick latency and significantly reduced the tail skin temperature in 5,6-DHT pretreated animals when compared to control animals. These differences in tail-flick latencies could not be explained by alterations in skin temperature. The results provide evidence that neurotoxic lesion of descending 5-HT pathways induces supersensitivity to the antinociceptive effect of 5-HT1 receptor stimulation.


Effects of prostanoids and indomethacin on isolated smooth muscle from the human lower oesophagus.

Smooth muscle strips representing the longitudinal and the circular muscle layers of the oesophageal body and the oesophagogastric junction of the human oesophagus were mounted in organ baths and isometric tension recorded. Transmural field stimulation was applied to strips from both layers of the oesophageal body and to strips from the longitudinal muscle layer of the oesophagogastric junction. This resulted in contractions after cessation of the stimulus train in circular muscle, and in contractions during stimulation in longitudinal muscle preparations. Indomethacin lowered active tension in strips from the circular muscle layer of the oesophagogastric junction, and decreased responses to transmural field stimulation in all strips from the longitudinal muscle layer. The response to transmural field stimulation was increased in strips from the circular muscle layer of the oesophageal body, suggesting an inhibitory function of endogenous prostanoids in this muscle layer. Prostaglandin (PG) F2 alpha and the thromboxane A2 mimic U-46619 increased the responses to transmural field stimulation in all muscle types and the active tension in circular muscle from the oesophagogastric junction. PGE1 and PGE2 increased the responses to transmural field stimulation strips from the longitudinal muscle layer. In circular muscle strips from the oesophageal body responses to transmural field stimulation were inhibited. PGE1 decreased active tension in circular muscle strips from the oesophagogastric junction, whereas PGE2 produced inconsistent effects. These results suggest a role of prostanoids in the regulation of neuromuscular function in the human lower oesophagus. Moreover, exogenous prostaglandins may modulate oesophageal motor function.


Cytogenetic results from the U.S. Collaborative Study on CVS.

Cytogenetic data are presented for 11,473 chorionic villus sampling (CVS) procedures from nine centres in the U.S. NICHD collaborative study. A successful cytogenetic diagnosis was obtained in 99.7 per cent of cases, with data obtained from the direct method only (26 per cent), culture method only (42 per cent), or a combination of both (32 per cent). A total of 1.1 per cent of patients had a second CVS or amniocentesis procedure for reasons related to the cytogenetic diagnostic procedure, including laboratory failures (27 cases), maternal cell contamination (4 cases), or mosaic or ambiguous cytogenetic results (98 cases). There were no diagnostic errors involving trisomies for chromosomes 21, 18, and 13. For sex chromosome aneuploidies, one patient terminated her pregnancy on the basis of non-mosaic 47,XXX in the direct method prior to the availability of results from cultured cells. Subsequent analysis of the CVS cultures and fetal tissues showed only normal female cells. Other false-positive predictions involving non-mosaic aneuploidies (n = 13) were observed in the direct or culture method, but these cases involved rare aneuploidies: four cases of tetraploidy, two cases of trisomy 7, and one case each of trisomies 3, 8, 11, 15, 16, 20, and 22. This indicates that rare aneuploidies observed in the direct or culture method should be subjected to follow-up by amniocentesis. Two cases of unbalanced structural abnormalities detected in the direct method were not confirmed in cultured CVS or amniotic fluid. In addition, one structural rearrangement was misinterpreted as unbalanced from the direct method, leading to pregnancy termination prior to results from cultured cells showing a balanced, inherited translocation. False-negative results (n = 8) were observed only in the direct method, including one non-mosaic fetal abnormality (trisomy 18) detected by the culture method and seven cases of fetal mosaicism (all detected by the culture method). Mosaicism was observed in 0.8 per cent of all cases, while pseudomosaicism (including single trisomic cells) was observed in 1.6 per cent of cases. Mosaicism was observed with equal frequency in the direct and culture methods, but was confirmed as fetal mosaicism more often in cases from the culture method (24 per cent) than in cases from the direct method (10 per cent). The overall rate of maternal cell contamination was 1.8 per cent for the culture method, but there was only one case of incorrect sex prediction due to complete maternal cell contamination which resulted in the birth of a normal male.(ABSTRACT TRUNCATED AT 400 WORDS)


Chorionic mosaicism: association with fetal loss but not with adverse perinatal outcome.

Cytogenetic data from the United States NICHD collaborative study of chorionic villus sampling (CVS) were used to evaluate the clinical significance of chorionic mosaicism. The 10,754 patients with normal cytogenetic results were compared with 108 patients (1.0 per cent) with placental mosaicism and 181 patients (1.6 per cent) with pseudo-mosaicism. Of the pregnancies intended to continue, the pregnancy loss rate was significantly greater in patients with placental mosaicism than in the cytogenetically normal cohort (8.6 vs. 3.4 per cent, p less than 0.05). However, there was no difference in the frequencies of abruptio placenta, preterm labour or delivery, small-for-gestational-age newborns, pregnancy-induced hypertension, or neonates with Apgar scores less than 7.


First-trimester biochemical and molecular diagnoses using chorionic villi: high accuracy in the U.S. collaborative study.

The accuracy of biochemical and molecular prenatal diagnoses using chorionic villi as the fetal source was assessed by seven centres participating in the NICHD collaborative study on the safety and accuracy of chorionic villus sampling (CVS) and amniocentesis. Of 601 pregnancies studied, biochemical methods were used to determine the diagnosis in 283 fetuses at risk for 35 different metabolic disorders. Fifteen different lysosomal storage diseases accounted for 81 per cent of the biochemical prenatal diagnoses performed, with 57 per cent of these pregnancies at risk for Tay-Sachs disease. No errors were made in the biochemical diagnoses that predicted affected or unaffected fetuses. However, the diagnoses of certain disorders (e.g., mucopolysacchariodosis type IH, metachromatic leukodystrophy, and Krabbe disease) occasionally required confirmatory studies in cultured amniocytes because the enzyme results were inconclusive in direct and/or cultured villi or due to the presence of a pseudodeficiency allele. Of these, only the diagnosis of a fetus at risk for Krabbe disease remained inconclusive after special studies to discriminate between mutant and pseudo-deficiency alleles. Recombinant DNA techniques were used to predict the diagnosis of 318 fetuses at risk for 16 different disorders in which the defective disease gene could be detected either directly or by linkage analysis to a nearby polymorphic marker. Of these, 32 per cent were for haemoglobinopathies, 25 per cent for cystic fibrosis, 24 per cent for Duchenne or Becker muscular dystrophy, and 7 per cent for haemophilias. Pregnancies at risk for known disorders with specific molecular lesions (e.g., sickle cell disease) were accurately diagnosed in direct and/or cultured villi. Diagnoses requiring analyses with closely linked polymorphic markers were occasionally uniformative or inconclusive. Maternal contamination was not reported in any biochemical or molecular-based diagnosis. These studies document the high accuracy and rapidity of both biochemical and mutation-specific prenatal diagnoses with direct and cultured chorionic villi.


Risk factors associated with transcervical CVS losses.

Factors found to be associated with pregnancy loss after transcervical CVS were race (higher for non-white), history of spontaneous abortion, unplanned pregnancy, history of spotting or bleeding during the pregnancy prior to CVS, and placental position (higher for fundal or lateral locations). Whether the increase in loss risk is due to the factor, per se, or the factor plus the CVS cannot be determined due to the lack of appropriate control data.


The risk and efficacy of chorionic villus sampling in multiple gestations.

Chorionic villus sampling (CVS) in the first trimester of pregnancy provides a safe and effective method for the early prenatal diagnosis of cytogenetic abnormalities in multiple gestations. In this multicentre study involving 126 twin and 2 triplet gestations primarily at risk because of advanced maternal age, the overall success rate of obtaining an adequate villus sample from each fetus was 99.2 per cent. For women of advanced maternal age, the rate of combined losses of chromosomally normal fetuses due to spontaneous abortion, stillbirths, and neonatal deaths was 5.0 per cent, compared with a 4.0 per cent total loss rate following CVS in singleton pregnancies derived from the same population (Rhoads et al., 1989). There was a 100 per cent success rate in obtaining a cytogenetic analysis; a cytogenetic abnormality was present in five of the multiple gestations (3.9 per cent) and involved seven fetuses (2.7 per cent). There were no diagnostic errors and no cases of normal cytogenetic diagnosis followed by the birth of a cytogenetically abnormal newborn. Based on cases of XX/XY admixture, cell contamination derived either from maternal decidua or the other twin occurred in 6 of 256 samples (2.3 per cent), giving an overall estimate of the frequency of cell contamination of 4.6 per cent; these cases did not present a diagnostic problem. However, there were two cases (0.8 per cent) in which the fetal sex was incorrect, due either to complete maternal cell contamination or to the possibility that in error one twin was sampled twice.


Canadian multicenter randomized clinical trial of chorion villus sampling and amniocentesis. chromosome mosaicism in CVS and amniocentesis samples.

Data on 1040 chorionic villus and 969 amniotic fluid samples were collected from women studied in the Canadian Multicentre Randomized Clinical Trial of Chorion Villus Sampling and Amniocentesis. Cytogenetic results were obtained from 98.0 per cent of chorionic villus samples and from 99.9 per cent of amniotic fluid samples. Level I mosaicism (a single cell with an abnormal karyotype) occurred frequently in both chorionic villus and amniotic fluid samples and appeared to have no clinical significance. Level II mosaicism occurred in 0.9 per cent of CVS mesenchyme and 1.5 per cent of amniotic fluid cultures and in general was not perceived to be of sufficient concern to warrant cytogenetic follow-up studies. Level III mosaicism was reported in 18 CVS cases (15 cytotrophoblast, 1 mesenchyme, and 2 with both cell methods) and in one amniotic fluid case. In all cases but one (fetus with trisomy 18), level III mosaicism was confined to the placenta. Maternal cell contamination occurring with a frequency of 6.4 per cent in the mesenchyme analyses was a concern. This study supports the final report of the Canadian Multicentre Randomized Clinical Trial of Chorion Villus Sampling and Amniocentesis. Cytogenetic analysis of chorionic villus samples appears to be an acceptable alternative to the analysis of amniotic fluid samples. However, because of mosaicism and maternal cell contamination concerns, the examination of both cytotrophoblast preparations and mesenchyme cultures from chorionic villus samples is recommended.


Effect of ryanodine on mitochondrial respiration.

Ryanodine is a pharmacological agent that stimulates calcium leakage into the cytoplasm resulting in an increase in tension. In skeletal muscle, ryanodine acts primarily on the sarcoplasmic reticulum whereas in smooth muscle, the sites of action are less clear. Visually, the increase in tension is slow and the time course can be mimicked by mitochondrial poisoning and the resultant leak of mitochondrial calcium into the cytoplasm. Although it has been reported that ryanodine has no effect on calcium flow into or from mitochondria, the effect of ryanodine on mitochondrial oxidative function was not studied. In the current investigation direct measurements of the effect of ryanodine on mitochondrial oxygen utilization were made. The results demonstrate that ryanodine, even at high concentrations, has no effect (stimulatory or inhibitory) on mitochondrial oxidation.


Cytoprotective action of beraprost sodium against peroxide-induced damage in vascular endothelial cells.

Using a peroxide-injured endothelial cell model, beraprost sodium (beraprost) was tested in relation to the action to protect against the damage of vascular endothelial cells employing the viability of the cells and change in lipid peroxides as the indicators. At a concentration of 1-3 mumol/l or higher, beraprost significantly inhibited the decrease in viability of the cells and the increase in lipid peroxides level caused by t-butyl hydroperoxide or 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid. When similar tests were conducted with prostaglandin I2, its inhibiting action was equal to or slightly weaker than that of beraprost unlike PGE1 and PGD2. This action of beraprost in inhibiting cell damage caused by peroxides suggests that beraprost may be useful for protecting cells from damage due to ischemic diseases.


Potassium channel activators cromakalim and celikalim (WAY-120,491) fail to decrease myocardial infarct size in the anesthetized canine.

The cardioprotective effects of the K channel activator drugs celikalim (WAY-120,491) and cromakalim were studied in a canine model of myocardial infarction consisting of 90 min of ischemia and 5 h of reperfusion. Intracoronary infusion of cromakalim and celikalim at 0.2 microgram/kg/min beginning 10 min before occlusion of the left circumflex coronary artery and continuing throughout the duration of the reperfusion period appeared to exacerbate ischemic injury. Infarct size (percent of risk area) was 27.7 +/- 5.6% in vehicle control animals (n = 5), 40.3 +/- 6.2% for cromakalim (n = 5) and 55.7 +/- 6.4% (p less than 0.05 vs. vehicle) for celikalim-treated animals (n = 5). When these compounds were administered intravenously, using doses shown to increase total coronary flow in nonoccluded control animals, no exacerbation of ischemic injury was observed. Anatomic infarct size was 32.8 +/- 7.1% for vehicle animals (n = 5) and 32.6 +/- 13.3 and 30.9 +/- 9.8% for cromakalim- (n = 6) and celikalim-treated (n = 5) animals, respectively. Intravenous diltiazem decreased myocardial infarct size to 16.3 +/- 7.3% (n = 5) of area at risk (p = NS vs. vehicle). The anatomic area at risk was similar in all three treatment groups, and no significant differences in rate-pressure product were observed. Results of this study suggest that K-channel-activating drugs such as cromakalim and celikalim may not be effective agents in the acute therapeutic management of myocardial ischemic injury.


Cardiovascular effects of acetaldehyde in pithed rats.

The influence of acetaldehyde (30 mg/kg i.v.) on blood pressure and heart rate in anesthetized and pithed rats was studied. In anesthetized rats we observed a small increase, and a subsequent considerable decrease in mean blood pressure. The latter did not occur in pithed rats. Stimulation of the circulatory system in anesthetized and in pithed rats was completely abolished by administration of phentolamine or reserpine. Both in anesthetized and in pithed rats acetaldehyde caused an increase in heart rate which was inhibited in animals treated earlier with propranolol or reserpine. Our results demonstrated that besides its peripheral action, acetaldehyde exerts central effects which cause severe hypotension.


Cytosol-free calcium concentration in single bladder smooth muscle cells from normal and diabetic rats.

The effect of diabetes mellitus on intracellular calcium concentration was measured in single rat bladder smooth muscle cells using the fluorescent calcium indicator dye fura-2 AM. Techniques were developed for isolation and short-term culture of rat bladder smooth muscle cells. Cytosol-free calcium concentrations were measured at rest and during carbachol stimulation. Peak intracellular calcium concentration, rate of increase in intracellular calcium concentration and the integral of accumulation of intracellular calcium were determined. The techniques used to isolate and culture bladder smooth muscle cells produced live, physiologically responsive cells. Resting intracellular free calcium levels and were similar in control and diabetic cells. Both control and diabetic cells responded to carbachol stimulation. No significant differences between these cells were noted in peak calcium concentrations, rate of response or integral of response, but standard errors were large. Two patterns of intracellular response to carbachol stimulation were identified, and may explain the large variability in intracellular calcium response to carbachol stimulation.


Vomeronasal and/or olfactory mediation of ultrasonic calling and scent marking by female golden hamsters.

The role of the olfactory and vomeronasal systems in mediating odor-stimulated ultrasonic calling, flank marking, and vaginal marking by female hamsters was investigated by selective lesions of either system. Removal of the vomeronasal organ resulted in reduced frequencies of ultrasonic calling by estrous and nonestrous females in response to conspecific odors but it had no influence on either scent marking behavior during the same tests. When tested immediately after separation from a male, ultrasonic calling was not reduced by vomeronasal removal, indicating that such surgery does not cause deficits in calling ability and that the vomeronasal organ specifically mediates odor-stimulated calling. Zinc sulfate treatment of the olfactory mucosa led to reduction in the frequency of ultrasonic calling, flank marking, and vaginal marking in response to conspecific odors. Females' ability to discover buried food was also impaired by this treatment. Thus, the stimulation of both scent marking behaviors due to the perception of conspecific odors appears to be mediated primarily by the olfactory system, whereas stimulation of ultrasonic calling is mediated by both olfactory and vomeronasal systems.


Sex difference in blood pressure of spontaneously hypertensive rats influenced by perinatal NaCl exposure.

Our prior study showed that the basal blood pressure level and pressor response to peripheral angiotensin II of adult Sprague-Dawley rats were enhanced by perinatal exposure to a high NaCl diet. The purpose of the present study was to assess further the relationship between NaCl-sensitivity of blood pressure and perinatal NaCl exposure. We tested the hypothesis that the basal blood pressure level and pressor responses to angiotensin II could be increased by perinatal exposure to high NaCl in NaCl-resistant spontaneously hypertensive rats (SHR-R). Adult female SHR-R were maintained on a diet containing either basal 1% or high 8% NaCl throughout pregnancy and lactation. The offspring were continued on these same diets to 30 days postpartum. Thereafter, all offspring were maintained on a diet containing 1% NaCl. After being adapted to restraint, systolic blood pressure was measured indirectly by the tail-cuff procedure when the rats were 30, 44, and 58 days of age. Subsequently, baseline mean arterial pressure (MAP) and pressor responses to intravenous administration of angiotensin II (20, 40, 80, and 120 ng/kg body weight) were obtained from the catheterized femoral artery in conscious unrestrained rats. The MAP levels of adult female SHR-R exposed perinatally to 8% NaCl were significantly greater than those of females exposed to 1% NaCl. This elevated blood pressure was accompanied by an elevation in plasma osmolality. Perinatal exposure to 8% NaCl did not raise the blood pressure and plasma osmolality levels of adult male SHR-R, but did enhance pressor responses to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)


Diet-induced thermogenesis and cumulative food intake curves as a function of familiarity with food and dietary restraint in humans.

Cumulative food intake curves and diet-induced thermogenesis were recorded in women during four-course solid-food lunches, consisting of familiar and unfamiliar food, offered in ad lib or restricted portions, in order to assess a possible relation between eating behaviour on the one hand and a reflection of internal processes and subject characteristics on the other. The subjects were characterized as normal weight restrained, normal weight unrestrained, and overweight restrained. A negative relation was found between degree of restraint and deceleration of the cumulative food intake curve during the ad lib courses of any menu, and between degree of restraint and diet-induced thermogenesis (p less than 0.001). Consequently, a positive relation was found between deceleration of the cumulative food intake curves during the ad lib courses of any menu and diet-induced thermogenesis (p less than 0.001). Diet-induced thermogenesis during the first serving of a meal consisting of unfamiliar food was significantly higher in all groups than during the other two times, when meals consisting of more familiar food were served (+0.98%; 0.71%, p less than 0.05).


Social separation and reunion affects immune system in juvenile rhesus monkeys.

Removal of juvenile rhesus monkeys from their natal social group to indoor individual caging resulted in increased basal cortisol secretion and significant decrements in the frequency of lymphoid subpopulations. Fourteen juvenile rhesus monkeys, which had never been removed from the group, were studied. Baseline immune and cortisol measurements were obtained before seven of the subjects were removed from social housing to standard individual cages. The remaining seven subjects, matched for age, sex, weight, and rank, remained in the social group throughout the study serving as controls. Blood samples were taken 24 hours after removal of the test subjects from the group and at specific intervals thereafter through 11 weeks. At 24 hours after the separation test subjects showed a significant increase in basal cortisol levels (40%) and a significant decrease in several immune parameters, with absolute numbers of total T cells declining 72 +/- 12%. Significant group differences in immune parameters persisted through 11 weeks. Eighteen weeks following removal, the test subjects were returned to the group which produced a cortisol rise in both test and controls at the 24-hour postreturn sample. Although there were no group differences in the frequency of lymphoid subsets 24 hours after return, some test subjects showed marked decrements which were inversely related to cortisol and were predicted by behavioral events. These data demonstrate that the removal of naive juvenile rhesus monkeys from their natal social group to individual indoor caging is a potent psychosocial stressor and that the behavioral interactions which characterize the return of the individual subjects to the natal group may predict physiological response.


Postnatal deficiency of omega-3 fatty acids in monkeys: fluid intake and urine concentration.

Previous studies demonstrated increased fluid intake in rhesus monkeys exposed to combined prenatal and long-term postnatal (PRE+POST) dietary deficiency of omega-3 fatty acids. Here we determined the effect of dietary deficiency in omega-3 fatty acids occurring only prenatally (PRE) or only postnatally (POST). Water intake over 24 hours, water intake in 15-minute tests, and excretion of combined urine and feces over 24 hours were all about twice as great in POST as in PRE monkeys. Neither group preferred or avoided salt solutions compared to water in two-bottle tests. Serum electrolytes, total protein, and glucose were within the normal range, and both groups concentrated urine when deprived of water. Levels of all omega-3 fatty acids in red blood cells were greatly depressed in POST monkeys, while levels of omega-6 fatty acids were elevated or unchanged. These results confirm the effects of PRE+POST deficiency on fluid intake and demonstrate that postnatal deficiency by itself is sufficient for the effects.


Prostaglandins E2 and D2 have little effect on rabbit sleep.

Prostaglandins (PGs) are hypothesized to be involved in sleep regulation; PGE2 and PGD2 are major PGs in the hypothalamus of many species and are proposed to reciprocally promote wakefulness and sleep respectively. PGD2 and PGE2 are also major PGs in rabbit cerebrospinal fluid, yet their effects on rabbit sleep have not heretofore been systematically investigated. We report here that a bolus injection of PGE2 into a lateral cerebral ventricle induces dose-dependent fevers and transient sleep responses in rabbits. PGE2 induces a suppression of sleep of 24 min duration. In contrast, PGD2, across a wide range of doses (0.25-500 nmol) failed to alter sleep; however, at the highest dose it induced fever. We conclude that if PGs are involved in sleep regulation, a chronic stimulation of their production by other sleep factors is necessary.


Cocaine-exposed newborns show an exaggerated sucking response to sucrose.

The sucking responses of 16 newborn infants exposed to cocaine just prior to birth and 16 control newborns were recorded when offered a fluidless sucrose-flavored nipple and a comparable nonsweet nipple. Cocaine-exposed infants showed a significantly greater preference for sweet taste: Compared with control infants, the cocaine group sucked more frequently when offered the sweet nipple and less frequently when presented with the nonsweet nipple. This heightened response to sweet stimulation might reflect (i) a coping mechanism for the perinatal distress of intrauterine cocaine-exposure since sweet taste appears to alleviate distress via an opioid mechanism; and/or (ii) altered dopaminergic activity in a common neuronal pathway that mediates the rewarding aspects of both cocaine and sweet taste.


The effects of anticholinergic drugs on delayed time discrimination performance in rats.

To investigate the effects of the muscarinic antagonist scopolamine and the nicotinic antagonist mecamylamine on time discrimination and short-term memory, rats were trained on a delayed conditional time discrimination task until performance stabilized. In a two-lever operant chamber, pressing one lever was correct after the presentation of a stimulus light for 2 seconds (SD short); and pressing the other lever was correct after presentation of a stimulus light for 8 seconds (SD long). Scopolamine (0.06 mg, 0.25 mg, and 1.0 mg/kg) attenuated performance in a dose-dependent manner. Furthermore, the drug decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimuli and the presentation of the response levers), and increased response delay (time from opportunity to lever press to actual lever press). Performance attenuating effects of mecamylamine in the time discrimination task did not appear unless high doses (8 mg/kg) of the drug were given. With increasing delays between 0 and 8 seconds, animals injected with saline developed a bias towards reporting the occurrence of the SD long, independent of the actual stimulus presented. A reversal of this bias was seen in animals injected with scopolamine; they more often reported the occurrence of the SD short. Our results support a role for muscarinic receptors in discrimination learning, attention, and time estimation.


Reactivity to written mental arithmetic: effects of exercise lay-off and habituation.

The present study examined (i) the effects of exercise lay-off on heart rate (HR) and subjective response to mental stress in 24 individuals highly committed to exercise, and (ii) psychophysiological reactivity to a challenging written mental arithmetic with subjectively controlled difficulty level. Subjects were tested on two occasions one week apart. Exercise withdrawal did not influence psychophysiological stress response. Second exposure to the mental arithmetic resulted in significantly lower HR response, due to habituation; higher pretask resting HR, due to anticipation of performance; and later onset in HR recovery. No changes in task performance and subjective measures were observed from session one to session two, indicating that habituation is rather a physiological than behavioral phenomenon. While these findings do not strengthen the link between exercise and stress response, they demonstrate the significant mediatory roles of habituation and anticipation in laboratory studies employing a test-retest design.


A system for studying the microstructure of ingestive behavior in mice.

A system for long-term monitoring of mouse eating and drinking behavior with 6-s resolution is described. The apparatus utilizes infrared beams to monitor activity at a single feeding port and electronic contact detector circuitry to record individual licks at two drinking ports. Eight SWR/J mice were monitored using this system and data from the last day of testing with food and water were analyzed. Mice ate an average of 4.54 +/- 0.40 g of powdered food and drank an average of 5.81 +/- 0.65 ml of water. Mice had an average of 36.25 +/- 3.96 food bouts and 32.25 +/- 7.56 water bouts lasting 3.00 +/- 0.48 and 0.88 +/- 0.35 min, respectively. Information regarding the temporal association between eating and drinking and the circadian patterns of ingestion was provided, utilizing customized software that augments the system. Important implications for the use of mice in ingestion pattern research are discussed.


Motor abnormalities in lurcher mutant mice.

Lurcher mutants had deficits in equilibrium in the coat-hanger and grid tests but not the wooden beam test. Although the mutants had less hole-pokes when confronted with small holes in most conditions, they had more hole-pokes with larger holes, demonstrating perseverative behavior. There was no decrease in rearing responses. These results indicate that in spite of cerebellar degeneration and ataxia, lurcher mutants are not impaired in all tests measuring motor function.


Neonatal catecholaminergic influence on behaviour and sexual hormones.

There is evidence of a sexually dimorphic effect of serotonin administration during the critical period of sexual differentiation on gonadal hormone secretion in adulthood. To investigate the possible involvement of catecholamines on these mechanisms, we have injected dopamine or noradrenaline intraventricularly into neonatal male and female rats to examine the influence, during the critical period, of this single treatment on the adulthood. Gonadal sex hormone contents, sexually dimorphic behaviours, and catecholaminergic distribution in hypothalamic and extrahypothalamic areas were studied. Both catecholaminergic treatments in females resulted in a reduced striatal dopaminergic activity and an increase in the hypothalamic noradrenergic ratio, while a reduction in the open field activity occurred in the same groups. These results suggest the possible involvement of striatal dopamine and hypothalamic noradrenaline in the differentiation of exploratory activity in females. A reduction in copulatory behaviour was shown in adults of both sexes after neonatal dopaminergic administration, but gonadal hormone levels were not affected in the same way. This indicates the existence of different facets of sexual differentiation, with striatal dopamine and hypothalamic noradrenaline playing important roles in neurobehavioural differentiation.


Foraging for macronutrients: effects of protein availability and abundance.

A laboratory simulation of foraging required rats to search for opportunities to obtain meals of pure-macronutrient foods (separate sources of carbohydrate, fat, and protein). Reductions in protein availability (increases in the cost of procuring protein meals) and reductions in protein abundance (decreases in the likelihood of encountering protein meal opportunities) were examined in separate phases. Rats foraged selectively, composing high-fat, adequate-protein diets; they tended to alternate between protein and nonprotein meals when protein was accessible. When protein became less available or relatively less abundant, meal patterns changed, and the proportional intake of protein fell. The tactic of shifting relative nutrient intake was used to a greater extent than the tactic of increasing foraging behavior. The foraging constraints revealed a flexible nutritional strategy that balanced responses to internal and external demands.


Somatosensory control of the onset and retention of maternal responsiveness in primiparous Sprague-Dawley rats.

The role of perioral and ventral-trunk somatosensory stimulation from pups mediating the initial expression of maternal behavior and its long-term retention 8 days later, was investigated. Six groups of female rats were permitted to physically interact with four 1-5-day-old foster pups for 1 h, 36 h after Cesarean delivery on gestation day 21. Prior to this maternal experience, dams were subjected to: reduced cutaneous rostral snout sensitivity (anaptia) by injection of lidocaine into the mystacial pads; reduced ventral-trunk sensations by occlusion of the entire ventrum with a full spandex jacket; both manipulations; or control manipulations. Additional groups of females not receiving a maternal experience (inexperienced) also received the somatosensory deprivation or control manipulations. During retention testing, rats in the singly manipulated experienced groups exhibited reduced latencies to become maternal in comparison to their inexperienced counterparts (approximately 3 days vs. 8 days). However, rats previously rendered both anaptic and ventrally-occluded responded like inexperienced rats in showing a long latency to become maternal (8 days). Thus, reduction of either perioral or ventral somatosensory contact from pups did not block the maternal experience effect, but reduction of both of these inputs did.


Choice behavior of fornix-damaged rats in radial maze error-free situations and subsequent learning.

Fornix-damaged, sham-operated, and control rats were placed in a radial eight-arm maze for fixed series of runs with either a 0% or a 100% reinforcement schedule in order to study their choice behavior independently from any learning problem. Subsequently, the ability to learn the radial maze task was examined as a function of the exploratory patterns developed in each error-free situation. The results showed that the continuous absence or presence of food in the radial maze induced two distinct models of exploration in sham-operated and control rats: choice alternation in the absence of food and perseveration in the presence of food. Conversely, this dichotomy did not occur in fornix-damaged rats that run approximately the same number of paths in both error-free situations, but made fewer different path choices in the 0% reinforcement condition and more different path choices in the 100% reinforcement condition than controls. When submitted to the radial maze task, a positive transfer was observed in all groups from the error-free situation in which the rats run more different paths: from the 0% reinforcement situation for controls and from the 100% reinforcement situation for the lesioned rats. These data indicate that damaging the septo-hippocampal pathway modifies spontaneous choice behavior through a different response to specific reinforcement programs but does not prevent the memorization and the transfer of information from error-free to learning situations.


Control of ventilation in androgenized hypogonadal male rats.

We have previously shown that subcutaneous administration of aspartic acid (a dicarboxylic acidic amino acid) at a dose of 580 mg/kg causes long lasting depression of ventilation in adult intact and postpubertally castrated male rats, but not in intact female rats. The purpose of the present study was to determine if hypogonadism induced by perinatal administration of testosterone propionate (TP) will alter ventilation, oxygen consumption, and the ventilatory response to aspartic acid and to hypercapnia in adult males. TP treatment resulted in adult males who had lower body, prostate, heart, and testes weights than those of control male rats. Ventilation in air and oxygen consumption were comparable between the two groups as was the ventilatory response to aspartic acid. In contrast, TP-treated rats exhibited a significantly decreased ventilatory response to hypercapnia due predominantly to lower tidal volumes compared to control animals. Aspartic acid treatment did not affect oxygen consumption in either group. Thus, TP treatment results in the development of adult male rats who, although hypogonadal, retain a male-like ventilatory response to aspartic acid, but whose response to hypercapnia is more like that of hypogonadal men and rats.


Thermoregulatory responses of rhesus monkeys during spaceflight.

This study examines the activity, axillary temperature (T(ax)), and ankle skin temperature (Tsk) of two male Rhesus monkeys exposed to microgravity in space. The animals were flown on a Soviet biosatellite mission (COSMOS 1514). Measurements on the flight animals, as well as synchronous flight controls, were performed in the Soviet Union. Additional control studies were performed in the United States to examine the possible role of metabolic heat production in the T(ax) response observed during the spaceflight. All monkeys were exposed to a 24-h light-dark cycle (LD 16:8) throughout these studies. During weightlessness, T(ax) in both flight animals was lower than on earth. The largest difference (0.75 degree C) occurred during the night. There was a reduction in mean heart rate and Tsk during flight. This suggests a reduction in both heat loss and metabolic rate during spaceflight. Although the circadian rhythms in all variables were present during flight, some differences were noted. For example, the amplitude of the rhythms in Tsk and activity were attenuated. Furthermore, the T(ax) and activity rhythms did not have precise 24.0 hour periods and may have been externally desynchronized from the 24-h LD cycle. These data suggest a weakening of the coupling between the internal circadian pacemaker and the external LD synchronizer.


The single-item meal as a measure of binge-eating behavior in patients with bulimia nervosa.

To determine whether the characteristics of binge eating could be observed in a single-item meal, in a laboratory, patients with bulimia nervosa and controls ate two single-item meals and two multiple-item meals. When they were instructed to binge eat, the patients ate significantly more and for a longer time on both single- and multiple-item meals than did controls. When they were instructed not to binge, intakes of the two groups did not differ. Controls, but not most of the patients, showed deceleration in their eating rate when they were asked to binge. Intakes of the single- and multiple-item meals were significantly correlated for the patients under both sets of instructions. These results are consistent with previous reports in indicating that patients with bulimia nervosa eat differently from controls and suggest that a single-item meal can be used to examine the characteristics of binge eating in patients with bulimia nervosa.


The effects of amphetamine on body weight and energy expenditure.

Although there is evidence suggesting that, in addition to suppressing food consumption, amphetamine reduces body weight by increasing energy expenditure, there is little consistency among the few studies examining that factor. In this experiment, the effect of amphetamine on daily energy consumption, within-day body weights, and hourly measures of metabolic rate (MR) and respiration quotient (RQ) were assessed. Daytime drug injections decreased total energy consumption, produced biphasic changes over time in MR, and persistently lowered RQ values. In contrast, nighttime injections of drug had little effect on energy consumption and MR but did reduce RQ for the first 4 postinjection hours. These effects show that amphetamine effects interact with the circadian organization of behavior and suggest that rodent studies of anorectic agents have more relevance for humans if drugs are given during the night, when rats are normally awake and eating. From this study, it seems clear that amphetamine reduces body weight by altering metabolic rate and fat metabolism in rats when the drug is given during the day.


The circadian rhythm of body temperature.

This paper reviews the literature on the circadian rhythm of body temperature (CRT). The review starts with a brief discussion of methodological procedures followed by the description of known patterns of oscillation in body temperature, including ultradian and infradian rhythms. Special sections are devoted to issues of species differences, development and aging, and the relationships between the CRT and the circadian rhythm of locomotor activity, between the CRT and the thermoregulatory system, and between the CRT and states of disease. A section on the nervous control of the CRT is followed by summary and conclusions.


Oral habituation in rat pups is in the brainstem.

We have previously demonstrated a decremental, oral, experienced-based control of ingestion in rat pups that is potent, diet-specific, and long lasting. This control of ingestion is revealed in the decreases in mouthing responses of rat pups to repeated oral stimulation, a phenomenon that is well described as oral habituation. The present study examined the neural basis for oral habituation by examining the responses of decerebrate 10-day-old rat pups to repeated, brief infusions of a sucrose solution. Like neurologically intact pups, decerebrate pups showed distinct decreases in mouthing responses following a series of oral infusions. Thus, oral habituation is present in the hindbrain. Although intact pups demonstrated sensitization by showing increased responding to the first few stimulus presentations, decerebrates failed to show a sensitization to the stimulation. These results suggest that while the brainstem alone is sufficient for the expression of oral habituation, the forebrain also influences oral responsivity in intact animals.


The effect of feeding on defecation behaviour in pigs.

The effect of eating on defecation behaviour was investigated in four 20-30 kg pigs. Rectal distention stimulation was performed pre- and postprandially at 10 cm from the anus with a 5 cm latex balloon. Volume was increased in steps of 10 ml up to 200 ml of air or until balloon defecation. Dependent measures were volume, rectal pressure, determined with a solid state pressure transducer inside the balloon probe, rectal compliance, and an index of distention induced contractile activity. The volume and pressure required to elicit defecation was significantly lower after feeding (p less than 0.01). Distention induced contractile activity was significantly increased near defecation threshold, but pre- and postprandial conditions were not different. There was no difference in rectal compliance pre- and postprandially. These results suggest that eating lowers defecation threshold in terms of distention volume and rectal pressure, and that these changes are not dependent on altered rectal compliance or changes in distention induced motor activity.


A microwave-transparent operant chamber for rats.

To study the operant behavior of rats in a microwave field, an operant chamber equipped with a response lever, stimulus lights, and a feeder was constructed using polycarbonate and fiber optic material. The chamber was connected to a personal computer located outside of the microwave chamber to program the schedules of reinforcement and to collect data. The operant chamber did not interfere with the microwave field and kept the subject's body parallel to the E-field for maximum absorption.


Yohimbine reduces neuropathology induced by ketamine/xylazine anesthesia.

Ketamine, an NMDA receptor antagonist, is commonly used in combination with xylazine, an alpha 2-adrenergic receptor agonist, to induce surgical anesthesia in birds and other vertebrates. Problems associated with this anesthetic combination include impaired thermoregulation, compounded by the inability to feed while anesthesia lasts (approximately 6 h after a single dose), and the ketamine-induced vacuolization of large cortical neurons. In the zebra finch, yohimbine (an alpha 2-adrenergic receptor agonist) counters the effects of ketamine/xylazine anesthesia, speeding recovery after the surgical procedure has been completed. In addition, administration of yohimbine reduces the formation of vacuoles in large cortical neurons and in neuropil. Yohimbine administration should be considered following all procedures involving ketamine/xylazine anesthesia.


The EEG of the sleep onset period in insomnia: a discriminant analysis.

A period of rapid change in the wave components of the electroencephalogram (EEG) marks the transition from wake to sleep. Twenty-six insomniac and 28 control nights were studied in a discriminant analysis to determine whether this transitional state is modified in any way in subjects diagnosed for psychophysiological insomnia. A discriminant function was derived based on 20 insomniac and 22 normal nights. All 42 nights were correctly classified by this function. The sleep onset period, extending on the average over about 3 minutes, was characterized essentially by the beta and delta components of the EEG signal and by an activity index given by the ratio beta/delta, measured at the temporal lobe sites. Other variables included the subject's age and the magnitude of the changes occurring in the difference between activities in the right and left hemispheres. The variables contributing most to the discrimination were the activity index and beta, especially at the transitions from wake to stage 1 and from stage 1 to stage 2. The contribution of delta to the discrimination was less, but extended further in time to include stage 2 sleep. A test on the remaining six insomniac and six control nights gave a 75% classification accuracy, thus validating the derived discriminant function.


Rewarding effectiveness of caudal MFB stimulation is unaltered following DMH lesions.

The dorsomedial hypothalamus (DMH) has been proposed to be a major part of the neural substrate for self-stimulation of the medial forebrain bundle (MFB). In this report, rate-frequency and rate-current curves were collected from 19 rats with lesions in or around the DMH and stimulation electrodes in or near the caudal MFB. Thirteen rats with lesions of the DMH showed little or no postlesion change in the rewarding effectiveness of caudomedial MFB stimulation. Six other lesions, affecting the anterior, dorsal, and/or ventromedial hypothalamus, were also ineffective in changing rewarding effectiveness. The one lesion that was followed by a substantial decrease in rewarding effectiveness, invaded the medial MFB at the level of the lateral hypothalamus but produced little DMH damage. These data do not support the notion that neurons arising in, terminating in, or projecting through the DMH play an important role in MFB self-stimulation.


Hedonic response of sucrose likers and dislikers to other gustatory stimuli.

The majority of individuals can be classified as sweet likers or dislikers based on their hedonic (pleasure) response to sucrose solutions of varying concentrations. Our results indicate that the sweet liker/disliker distinction generalizes to sugars other than sucrose, i.e., glucose and fructose. As well, these individual hedonic response patterns are maintained even when a flavor and color are added to sucrose solutions. However, whether one is a sweet liker or disliker does not predict hedonic response to nonsweet tastes such as salt. These results indicate that the sweet liker/disliker distinction is a robust phenomenon which appears to generalize over, but is restricted to, sweet-tasting substances. The possibility that individual differences in hedonic response may predict preferences for, and intake of, complex tastes characteristic of foods encountered in the real world, is discussed.


Activity rhythms in mice. III: Stability and plasticity of rhythm characteristics in experimental and environmental conditions.

The expression of a biological rhythm as measured by a given descriptor results from a set of components: the subject, the measuring device, and the experimental conditions. Rhythm of activity under four experimental conditions was observed in two strains of mice: BALB/c and C57BL/6. Condition 1, the optimal normal situation, was used as a reference; condition 2 was a retest of the animals used in condition 1 twelve days later; condition 3 tested animals for a period of 3 days in a food-deprivation situation; in condition 4, animals were isolated for 2 weeks prior to testing. Data analysis of rhythm of activity in the synchronic mode is based on a series of tests in the frequency and temporal domains. Analysis of condition-linked variation in the findings indicates that these parameters are only slightly affected by the four experimental conditions. The results, however, can be hierarchized according to condition and according to the kind of parameter. The temporal parameters are more sensitive than the frequency parameters, the least sensitive being the temporo-frequential measures. Isolation produces the greatest variation in parameter magnitude. The results show that rhythm of activity is fairly stable across a number of experimental conditions, a finding that could considerably simplify experimental protocols.


Hepatic vagotomy does not alter plasma insulin response to a low dose injection of glucose.

It has been reported that insulin concentration is altered by a hepatic vagotomy following intraperitoneal glucose injection (0.3 g/kg) resulting in supraphysiological blood glucose concentrations. On the other hand, neural activity of the hepatic vagus nerve has been shown to be substantially reduced by lower doses (0.05 g/kg intraportal; 0.1 g/kg intravenous). The present study was conducted in order to examine the role of the hepatic vagus nerve in insulin response after intraperitoneal injections of 0.1 and 0.3 g/kg of glucose. Measurements were made 5 days after section of this branch. In a first experiment, arterial glucose and insulin concentrations were not affected by the hepatic vagotomy following injections of either 0.1 or 0.3 g/kg of glucose. The same finding was also found in a second experiment in which portal glucose and insulin levels were measured after injection of 0.1 g/kg of glucose. These results suggest that large changes in neural activity are needed for the hepatic vagus nerve to influence the insulin response.


Water intake during chronic preoptic infusions of osmotically active or inert solutions.

To further elucidate the role of the lateral preoptic area (LPO) as an osmoreceptive region, rats received chronic infusions (2 weeks) of low volumes (0.5 microliters/h) solutions of hypertonic sodium chloride (NaCl; 0.16 M), hypertonic potassium chloride (KCl; 0.16 M), hypertonic (0.32 M) or hypotonic (0.16 M) mannitol, isotonic saline, or water delivered bilaterally via subcutaneous osmotic minipumps attached to intracranial cannulae. All cannulae terminated within the anterior hypothalamus-preoptic region. Hypertonic NaCl and KCl increased water intake over preinfusion levels in the majority of animals tested. However, the effects were variable, including some sizable increases as well as decreases. Hypertonic mannitol decreased daily water intake in 15 of 25 rats and produced essentially no change in the average intake of the group. Isotonic NaCl produced smaller increases and decreases, while water produced larger changes in individual rats, but neither solution had a significant effect on the average intake of the group. None of the infusates significantly altered food intake.


Burrowing and huddling in newborn porcupine: the effect on thermoregulation.

The newborn cape porcupine Hystrix africaeaustralis is a precocial rodent. However, the newborn spends its first 9 weeks in the burrow. Heat production (oxygen consumption--VO2) and body temperature (Tb) were measured at various ambient temperatures (Ta) in newborn (4-8-week-old) porcupines, with a body mass between 1340-1993 g during summer, from the colony kept at the Mammal Research Institute, University of Pretoria. To assess the effect of huddling, these parameters were also measured in adult pairs of porcupines (Ta = 15 and 25 degrees C) kept together in the metabolic chamber and the values were compared with those obtained from single porcupines. Overall minimal thermal conductance was calculated for newborn and paired adult porcupines. The newborn porcupines can regulate their body temperature at Tas between 10-28 degrees C. VO2 measured at lower critical point is 0.602 +/- 0.08 ml/O2/g.h. At Ta = 10 degrees C, VO2 oscillated with a characteristic amplitude and frequency, while body temperature was well regulated. Huddling decreases the lower critical point. The overall minimal thermal conductance (0.044 +/- 0.002 ml O2/g.h.1 degree C) is higher than expected from body mass, so that the young are liable to lose heat rapidly. It is well known that the newborn porcupine spends a long period in the burrow and the results of this study suggest that this may be in order to conserve energy and presumably allocate it to growth. Apart from decreasing vulnerability, delaying foraging also avoids heat loss in the newborn porcupine.


Postprandial sleep and thermogenesis in normal men.

Twelve normal male subjects were given low- (16.77 kj/kg) and high- (54.49 kj/kg) calorie liquid carbohydrate lunch meals on 4 days, during which measures of sleep EEG, thermogenesis (heat production), core body temperature, and skin surface temperature were obtained. On 2 days subjects were required to remain awake, and on 2 days sleep was allowed. Both meals were administered in each condition. On the days that subjects were instructed to remain awake, thermogenesis was significantly greater following high-calorie meals than low-calorie meals, and both meal conditions produced levels of thermogenesis that were greater than those observed when sleep was allowed. When given the opportunity, 11 of 12 subjects slept following both low- and high-calorie meals. There was no difference between meal conditions in the total minutes or percent of stages 1, 2, 3/4, or rapid eye movement (REM) sleep following meals. However, the onset of postprandial sleep episodes was associated with the peak of the postprandial rise in thermogenesis, and the occurrence of sleep was followed by precipitous and statistically significant declines in thermogenesis and core body temperature, as well as increases in skin surface temperature. These data suggest that postprandial sleep is associated with rises in thermogenesis, and that its occurrence decreases postprandial heat production and body temperature.


The influence of the stomach on crop function and feeding behavior in domestic turkeys.

We tested the hypotheses that motility of the crop and muscular stomach are coordinated and that the stomach exerts primary control over crop filling and emptying in domestic turkeys. Simultaneous recordings of motility of the crop, esophagus, and stomach with implanted strain gauge transducers and visual observations of food passage using image intensification radiography revealed an inverse relationship between the frequency of stomach and crop contractions. Artificially filling the stomach of a fasted turkey with a food slurry prior to feeding did not increase crop filling during the first morning meal, but it did inhibit crop emptying in fasted turkeys by markedly reducing the number of crop contractions. Artificially filling the crop of fasted turkeys prior to the first morning meal did not decrease the amount of feeding activity or the total amount of food consumed during that meal. It is suggested that meal termination is associated with the degree of inhibition of esophageal peristalsis.


Effects of thyroxine on the photoperiodic control of energy balance and reproductive status in Siberian hamsters.

Siberian hamsters (Phodopus sungorus sungorus) exhibit a variety of seasonal responses when exposed to short days (SD), including decreases in body weight and fat, gonadal regression, and changes in several nonsteroid serum hormone concentrations. One such SD-induced hormonal change is a modest decrease in serum thyroxine (T4) concentrations. In an attempt to determine any underlying hormonal influences for the SD-induced decreases in body weight and fat, we investigated the possible role of T4 and triiodothyronine (T3). This potential paradoxical effect of these hormones on body weight and fat, as compared with most other rodent species, is not without precedent in Siberian hamsters. Specifically, changes in the gonadal steroids have opposite effects on body weight and fat in Siberian hamsters compared with laboratory rats and mice, and Syrian hamsters. SD serum thyroid hormone concentrations were elevated to long-day (LD) levels via subcutaneous T4 injections. Vehicle- and noninjected controls were included, as well as three similar LD-housed groups. Although we found a trend towards decreased T4 serum concentrations in noninjected control hamsters following 9 weeks of SD exposure, this effect did not reach statistical significance. SD-housed, T4-injected hamsters had similar decreases in body, fat pad, and paired testes weights compared to the SD-housed, vehicle- and noninjected controls despite having LD-like serum T4 and T3 concentrations. Thus, no paradoxical effect of the thyroid hormones on body weight (fat) was found, nor do these hormones appear to play a role in the effects of SDs on reproductive status in this hamster species.


Use of running wheels regulates the effects of the ovaries on circadian rhythms.

Free-running circadian rhythms in core temperature, wheel-running and general locomotor activity were studied in ovariectomized or intact female rats housed with or without access to a running wheel. No differences in the monitored parameters were found between the intact and ovariectomized rats without a wheel. In the presence of a wheel, however, the intact rats differed from those that had been ovariectomized by displaying a shorter circadian period, an increased amplitude of the temperature rhythm, and strikingly higher rates of wheel-running and general locomotor activity. After estradiol treatment, the ovariectomized rats with a wheel developed a small increase in the temperature amplitude, and also in the correlation between wheel-running and general locomotor activity; these changes were not associated with a significant increase in wheel-running or a shortening of the circadian period. We conclude that some of the differences in circadian function between intact and ovariectomized rats are due to the differential use they make of running wheels, when available, and not directly attributable to the absence or presence of gonadal steroids.


Sodium preference in sheep excreting sodium predominantly in urine or faeces.

On moderate sodium intakes (0.5 mmol/kg/day approx.) sheep are readily divided into those that are predominantly urinary or faecal excretors of sodium (U or F sheep). Water turnover and obligatory sodium loss are lower in F sheep. In view of these differences, sodium preference was examined in U and F sheep offered water and sodium bicarbonate solutions (40 or 300 mmol/l). The F sheep took significantly more of the bicarbonate solutions and, therefore, had sodium intakes that were 51% higher on the lower concentration, 94% higher on the higher concentration. Thus, F sheep not only conserve sodium more readily when it is scarce, they select it more readily when it is available.


Group size modifies the patterns and muscle carbohydrate effects of aggression in Betta splendens.

Aggressive encounters of previously isolated individuals were investigated in dyads and groups of five. Fights were longer and more intense when they were performed in dyads compared to fights involving five fishes. During aggressive encounters, an elevation in carbohydrate catabolism was noticed in both dyads and groups. Losing a fight resulted in a reduction in glycogen content and an increase in glycogen synthesis. Similar changes in winners did not appear; thus, the metabolic response in losers was different from that noticed in winners, both in dyads and groups. In dyadic contest winners, a marked increase in the free glucose content and glucose consumption was noticed (without changes in losers). In groups, free glucose content of the winners was not modified, while glucose consumption was enhanced both in winners and losers. Thus, the differences existing between winners and losers were greater in dyads compared to those noticed in groups. The energy cost of aggression seems to be different in dyads compared to groups of five. The rate of glucose oxidation was strongly reduced in dyads (there were no differences between winners and losers in this respect), while in groups, this parameter was not modified.


Effects of thymectomy on reproductive function and behavior.

The effects of thymectomy in perinatal Long-Evans rat pups on their reproductive function in early adulthood were examined. Thymectomized females had decreased lordotic responsivity to estrogen, while thymectomized males exhibited differences in mount latency or postejaculatory interval; these results suggest a possible influence of the thymus on the normal development of the neural substrates of sexual behavior. Gonadal histology appeared unperturbed in rats of either sex. No statistical abnormalities in luteinizing hormone or testosterone levels were seen in male animals. Likewise, no disturbances were observed in the ability of females to exhibit normal positive feedback after estrogen and progesterone administration; negative feedback after unilateral ovariectomy (as judged by ovarian compensatory hypertrophy) was also normal. The timing of puberty was not statistically delayed in females, even though slowed growth rates were observed. A heightened surgical stress response, as judged by progesterone levels in experimental females, suggests that perinatal thymectomy may possibly alter the sensitivity of adults to stress.


Pimozide mitigates excessive running in the activity-stress paradigm.

The present study investigated the role of dopamine in the maintenance of behaviors observed in the activity-stress paradigm. In Experiment 1, several doses (0, 0.125, 0.25, 0.50, and 1.0 mg/kg) of the dopamine D2-receptor blocker, pimozide, were administered to rats maintained on an ad lib feeding schedule. Results indicated that 0.25 mg/kg pimozide did not disrupt running activity when compared to control animals. In Experiment 2, injections of either 0, 0.25, or 0.50 mg/kg pimozide were given every 12 hours to rats subjected to the activity-stress paradigm. Although 0.25 mg/kg pimozide had no effect on dark-phase activity, it significantly suppressed light-phase activity and subsequently increased the number of survivors in the paradigm. It was concluded that dopamine plays a role in maintaining high running levels in the activity-stress paradigm.


Dietary restraint and responsiveness to sensory-based food cues as measured by cephalic phase salivation and sensory specific satiety.

Responsiveness to sensory-based food cues was examined in restrained and unrestrained, normal-weight subjects identified with the Three-Factor Eating Questionnaire. Salivary flow rate was measured with no food present and while subjects viewed hot pizza. In the presence of food, restrained eaters had a mean salivary flow rate (0.388 g/min) greater than twice that of the unrestrained eaters (0.186 g/min). During sensory specific satiety testing, subjects tasted and rated the pleasantness of 9 foods, then received a meal of either cheese and crackers or cookies. Changes in pleasantness for the tasted foods were evaluated at 2, 20, and 40 min following the meal. Both restrained and unrestrained subjects displayed similar patterns of sensory specific satiety, i.e., the pleasantness foods which were eaten decreased relative to foods tasted but not eaten. These patterns were unaffected by the type of food consumed in the test meal. These data demonstrate that restrained eaters show moderately enhanced salivary responses but no changes in sensory-specific satiety to food stimuli, suggesting that heightened responsiveness to the sensory properties of foods may not be a generalized phenomenon in restrained eaters.


Effect of glucoprivation on self-stimulation rate-frequency functions.

In a series of two experiments using rats, the effect of glucoprivation, induced by 2-deoxy-D-glucose (2-DG) or insulin injections, on self-stimulation rate-frequency functions, was evaluated at two levels of current intensity. At the higher current intensity, neither insulin nor 2-DG produced a significant change in rate-frequency function parameters. At the lower current intensity, insulin suppressed asymptotic responding while 2-DG produced a lateral curve shift. Results of this study would argue that glucoprivation produces changes in self-stimulation at lateral hypothalamic electrodes that are: a) unrelated to the involvement of the neurons in stimulation-induced eating, b) are most notable when a smaller number of reward relevant neurons is stimulated, and c) can be differentially attributed to changes in motoric performance capacity during insulin tests and to changes in the reward value of stimulating current during 2-DG tests.


Problem-solving behaviour in apomorphine-susceptible and unsusceptible rats.

Pharmacogenetically selected apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats were trained in a discrimination learning paradigm. After the initial discrimination task was solved, reinforcement contingencies were reversed. No differences between APO-SUS and APO-UNSUS animals were found in the rate of learning. However, negative transfer from the initial discrimination to its reversal was less for the APO-SUS rats than for the APO-UNSUS rats. Moreover, the APO-SUS rats responded more to the relevant dimension (light) than the APO-UNSUS rats in the last 100 trials before solving the initial problem as well as the reversal. During overtraining on the first problem, APO-SUS animals responded less to an irrelevant dimension (position of the lever) than APO-UNSUS animals. In the first 100 trials of the reversal APO-SUS rats responded more to another irrelevant dimension (noise) than APO-UNSUS rats. The data show that APO-SUS and APO-UNSUS rats used the various dimensions (visual, auditory, and spatial) differently in the chosen discrimination learning paradigm. It is concluded that the interline differences found are the consequences of the interline differences in the dopaminergic activity of the ventral and dorsal striatum.


Changes in male copulatory behavior after sexual exciting stimuli: effects of medial amygdala lesions.

A paradigm was developed to investigate how precoital sexual arousal affects parameters of sexual behavior in male rats. Estrous females in a wire mesh cage were used to induce sexual arousal before the sexual interaction test. In control procedures, males were presented in a wire mesh cage or else there was no stimuli at all. The results indicate that ejaculation latency is consistently reduced after preexposure to a female, but not after preexposure to a male, showing that the effect is specific for precoital sexual arousal. Other parameters were affected by precoital sexual arousal in some, but not in all experiments. Reductions in intromission latency moreover, were observed after both preexposure to a male and preexposure to a female, indicating that general social excitement affects this parameter. Preexposure to females for 10 minutes or 3 hours produced similar results. It was subsequently found that medial amygdala-lesioned (AME) animals differed from sham-lesioned (SHAM) controls with respect to their reaction to precoital sexual arousal. The results show that AME-lesioned animals, in contrast to SHAM-animals, do not show reduced ejaculation latencies after preexposure to an estrous female. The results are in line with the idea that AME-lesioned animals are deficient in the assimilation of information on sexual exciting stimuli.


Role of the cerebellum in habituation exploration behavior in the rat.

Adult control and cerebellectomized DA/HAN-strained male rats were submitted to habituation of exploration behavior in a test environment consisting of a novel cage in which four objects were displayed. Seven days after the initial session of habituation, retention of the habituation was tested. Within-session habituation was observed in cerebellectomized and control rats. However, retention of habituation was impaired in rats that were cerebellectomized after the initial session but not in those cerebellectomized before the session. These results are consistent with the hypothesis that the cerebellum has a role in memory of habituation to environmental stimuli.


Repeated weight fluctuation increases plasma insulin in the obese Wistar fatty diabetic rat.

Weight fluctuation may contribute to the expression of hyperglycemia in genetically susceptible individuals. Alternating between diets with low and high fat content also may play a contributory role. To test these hypotheses, plasma glucose and insulin levels were measured in obese prediabetic Wistar-Fatty rats after two episodes of diet switching, with and without concomitant weight loss. Following two cycles of weight loss and regain, glucose levels did not differ between weight-cycled rats and static weight controls. However, insulin concentrations of weight-cycled rats were 74% higher than those of controls, suggesting an impairment of insulin resistance. Insulin and glucose levels of animals subjected to episodes of diet switching without accompanying weight loss and regain did not differ reliably from those of controls. A single cycle of weight loss followed by regain appeared to have no effect on either glucose tolerance or insulin resistance. Together, these results suggest that insulin resistance of Wistar-Fatty rats was worsened by repeated weight fluctuation. Further, the effect of repeated weight fluctuation on insulin concentrations is not due to diet switching. Repeated weight fluctuation did not lead to the expression of hyperglycemia under the present conditions. Additional studies are needed to determine what factors modify the effects of weight fluctuation on health, behavior, and metabolism.


The role of prostaglandins in interleukin-1 induced gastroparesis.

Interleukin-1 is a small molecular weight peptide that is thought to mediate much of the acute phase response to infection, including fever and anorexia and gastric stasis. In the present study, we examined the effects of recombinant human IL-1 alpha (rhIL-1a) on food intake and gastric emptying, and the role of prostaglandins (PG) in IL-1 induced gastroparesis. We report that pretreatment with ibuprofen significantly improved food intake and gastric emptying in IL-1 injected rats, but did not return them to control levels. We conclude that PGs mediate, at least in part, IL-1 induced gastroparesis. The role of gastroparesis in IL-1 induced anorexia remains to be determined.


No persistent effect of preweaning nutrition on postweaning food intake, feeding efficiency, or body energy stores in Long-Evans rats.

The purpose of this study was to determine the relative importance of pre- and postweaning nutrition on body mass, body fat, and feeding efficiency in Long-Evans rats up to a period of 18 weeks following weaning. Female rats were bred and pups were redistributed to form large (14-19 pups), normal (11-13 pups) and small (4 pups) litter groups. Weaned rats were housed as pairs (40 pairs) or singletons (n = 16) and fed either a mixed-fat diet (36.6% fat) or a standard chow diet (13.5% fat). Food intake, body mass, and feeding efficiency were measured at 4, 8, 12, and 18 weeks postweaning. Total body fat and depot fat pad mass were also measured at 18 weeks postweaning. At weaning, pups from small litters were fatter (p less than 0.001), and had a greater mass (p less than 0.03) than pups from large litters. There were no persistent effects of preweaning litter size after covarying for preweaning mass on body mass, and postweaning growth, food intake, feeding efficiency, or body fat accretion. Male rats ingesting the mixed-fat diet had a greater body mass (p less than 0.05), greater body fat accretion (p less than 0.008) and a higher feeding efficiency (p less than 0.001) than their chow-fed counterparts, despite an overall lower energy intake (p less than 0.05). Female rats ingesting the mixed-fat diet had a lower food energy intake (p less than 0.005) and a greater feeding efficiency (p less than 0.001) than chow-fed rats during the early postweaning period, only. Thus, postweaning nutrition may play a more important role in postweaning adult mass and depot fat in freely eating rats than early nutritional experiences.


The effects of cocaine on maternal behaviors in the rat.

Although recent research has focused on the behavioral teratology of cocaine, there has been little attention centered on the effects of cocaine use on parenting behaviors after birth. This experiment investigated the effects of cocaine on parental (generally termed maternal) behavior in the rat. Four types of adult rats were tested for these effects over a 10-day testing period: lactating primiparous female dams, primiparous females, nulliparous females, and males. Subjects were injected daily with cocaine (5 mg/kg) or saline. Ten minutes postinjection each subject was placed in a cage with three stimulus pups and nesting material, and observed for several measures of maternal behavior for 5 minutes, including sniffing, licking, and retrieving pups. Subjects were also rated on a maternal behavior scale at 60 minutes and 24 hours postinjection, and on nest quality. Cocaine reduced both the total number and duration of sniffing and licking maternal behaviors, and resulted in a lower maternal behavior rating at 60 minutes compared to saline-treated subjects. Among those subjects that retrieved pups within the first 5 minutes, cocaine-injected subjects retrieved for a longer duration. These results also suggest impaired maternal behavior, since rapid retrievals would have been more efficient in maintaining a nest huddle. Thus, cocaine impaired the parenting ability of both male and female rats, with and without previous parenting experience.


Abnormal taste preference for saccharin in hypothyroid rats.

Taste preferences for saccharin in concentrations ranging from 0.16 mM to 50 mM were determined in rats made hypothyroid with radioactive iodine and in their littermate controls. Hypothyroid rats demonstrated taste preferences for saccharin which were similar to those of controls only at very low (0.016 mM) or very high (49.0 mM) saccharin concentrations. At these concentrations of tastant, the preferences for tastant and water were similar to one another. At a concentration of 5.1 mM, preferences were also very similar in both groups but were very high. At intermediate saccharin concentrations of 1.1 and 3.0 mM, hypothyroid animals showed significantly lower percent preferences for the sweet tastant than did controls, mean +/- SEM (62.48 +/- 5.97 vs. 82.92 +/- 4.60, p = 0.0002) for the 1.1 mM concentration and (74.98 +/- 5.12 vs. 89.40 +/- 2.54, p = 0.0029) for the 3.0 mM concentration. These changes in taste preference for saccharin in hypothyroid rats were similar in direction and magnitude to those previously published by this laboratory using sucrose as the tastant. Thus, hypothyroid rats demonstrate abnormalities in taste preference for both the nonnutritive sweetener, sodium saccharin, as well as for the nutritive sweetener, sucrose.


PNMT inhibition decreases exercise performance in the rat.

The purpose of this investigation was to examine the effect of phenylethanolamine N-methyltransferase (PNMT) inhibition on the regulation of peripheral metabolic and hormonal responses during treadmill exercise in the rat. Changes in plasma catecholamine (epinephrine, norepinephrine, and dopamine), glucagon and glucose, and the glycogen content of the liver and two skeletal muscles were studied in four groups of rats. Two groups of rats were studied at rest: one group had been treated with LY134046, an inhibitor of PNMT, and the second group was treated with physiological saline. A third group treated with LY134046 was studied after treadmill exercise (28 m.min-1 and 8% slope). In this group of rats, exhaustion came after 37.5 +/- 7.9 minutes of exercise. In order to make appropriate comparisons, a fourth group of rats treated with physiological saline was exercised for 37.5 min. Running endurance during the treadmill exercise was thus reduced in LY134046-treated rats. Plasma epinephrine and glucagon concentrations and other metabolic (plasma glucose and gastrocnemius lateralis and superficial vastus lateralis muscles and liver glycogen contents) responses were similar between LY134046- and saline-treated rats at rest and after exercise. These results suggest that PNMT inhibition in epinephrine brain neurons might be the principal factor involved in the LY134046-induced reduction of exercise endurance.


Relationships between epinephrine, waking time, and self-estimates for naps at night.

In a previous study, we established a basal regression line between epinephrine excretion and percent of waking time in bed-rested humans under conditions involving minimal stress. We suggested that this regression line might be clinically useful for observing insomnia. The present study was undertaken to examine whether epinephrine excretion during short-duration sleep, such as naps, is influenced by a transient insomniac state. Polysomnograms during a 2-hour nap from 0000 to 0200 were recorded three times for six healthy male subjects. Epinephrine excretion levels during sleep were found to increase along the basal regression line when percent of waking time went up. The subjects with over 30% waking time during this 2-hour period reported that their sleep was light and not satisfactory at all. These results support our position that the regression line can be useful for observing a transient insomniac state.


Auditory potentials elicited by the grass photic stimulator in the rat.

Flash visual evoked potentials were recorded from the rat to determine whether the Grass photic stimulator could generate an auditory component of the waveform. When the click associated with each lamp flash remained unmuffled, the primary response of the visual cortex (P30) was preceded by an earlier positivity with a latency between 6-8 ms. When the photic stimulator lamp was subsequently insulated in order to deaden the sound of the click, the P30 potential remained intact while the earlier response disappeared. It is concluded that the photic stimulator is capable of eliciting a distinct auditory potential of probable collicular origin.


[Mechanism of attention in sleep--the changes of waveforms of event-related potentials in sleep].

Since attention has such a close correlation with arousal level, the influence of sleep on the waveforms of event related potential (= ERP) must be studied in advance for evaluating attentiveness of human mental activity. ERP, which odd-ball paradigm was used to elicit, was examined in 9 adult and healthy subjects from arousal to sleep. And ERP during a whole night was also examined in 5 of them to study the relation of the waveforms of ERP and sleep stages including a stage of rapid eye movement. As a result, there were some clear differences between the waveforms of the rare and frequent stimuli, and with change of sleep stages the differences also changed. Remarkable increase of amplitude and prolongation of latency of P200 and N200 were found in the waves of target stimuli in stage I. Activities of both components were connected with each other like a complexed component and preceded by the change of P300 activities. The waveforms of target stimuli in stage II had same kind of components with those of arousal stage. There were increased P200, N200, P300 activities and subsequent large negative activity which we called N3. These components were not clear in the waveforms of non-target stimuli. But P300 and N3 components were disappeared gradually during stage III. The averaged waveforms in stage III accompanied with 14-16 Hz fast wave suggested that they were identical with K-complex of sleep EEG. Add to this result, the habituation usually observed on P200 and N200 of nontarget stimuli in arousal let us to think that they are also identical with orienting reflex by rare and novel stimuli of external events (Sokolov). According to the result of examination changing the probability of target stimuli (20%----50%----80%), the waves of target stimuli in stage II were dependent on the probability of rare stimuli as well as in arousal stage. The dependence on probability was thought to reflect an automatic processing of selecting stimuli by orienting reflex in sleep. Another 3 subjects were examined of auditory evoked response in sleep with the same stimuli and without a task of counting numbers of rare stimuli. In stage II, however, they showed the waveforms by rare stimuli just like those by rare and target stimuli of 9 subjects. Then, it was supposed that attentiveness for external stimuli might be existent in sleep and changeable with sleep stages.


[Influence of family history over several generations on schizophrenic patients--study of a special type of stem family where a husband is found for the heiress].

Family histories over several generations were studied, since it was considered that these might have various influences on the descendants, We hypothesized that poor home management policy by the parental generation would have greater influence on the onset of schizophrenia in the offsprings, and later their social adjustment. To test this theory, twenty families of a special type, called "mukotori-kazoku" in Japanese, which literally means a family that takes in a husband for the sole heiress in the absence of a male heir, were chosen; ten of these families had a schizophrenic patient (schizophrenic group) and the other ten did not (control group). In this type of stem family, the husband (bridegroom) changes his family name to that of the wife and lives with the wife's family, to whom he is generally obliged to devote himself. Such a "mukotori-kazoku" tends to be run mainly in order to preserve or develop the family, and thus provides a good model for investigation of home management policy. Before presenting the results of this study, our former findings should be mentioned. We found that there tends to be a cycle in the family history over several generations consisting of three periods: a period of destruction, a period of reconstruction and a period of stability. All of the schizophrenic patients we studied previously became ill as the cycle was approaching the period of stability. The results of the present study were as follows. In the schizophrenic group on the maternal side, there was always a period of destruction during the great-grandparents' and/or grandparents' generation. Most of the patients' mothers (heiresses) were forced to devote themselves to family reconstruction and had married unwillingly. Similarly, in the former generation on the paternal side, a period of destruction was often observed. Most of the patients' fathers had been treated as a nuisance in their family or origin, and had been obliged to marry out of the family, and/or they had considered that marriage was the easiest path to economic independence. The patients' family members were so indifferent to the father that he became isolated within the family.(ABSTRACT TRUNCATED AT 400 WORDS)


[Studies of the correlations between morphological brain changes on MRI and computerized EEG changes in schizophrenics].

Several researchers have investigated the relationships between computed tomographic and electroencephalographic abnormalities in schizophrenics. In this present investigation, 28 medicated schizophrenic patients fulfilling the DSM-III-R criteria for schizophrenia and 21 normal volunteers were studied by means of MRI and EEG examinations. All subjects had given informed consent to the investigation. The schizophrenic patients (14 males, 14 females) were aged from 21 to 39 with a mean age of 30.2. The control group consisted of age- and sex-matched healthy volunteers (11 males, 11 females) with no history of neurological disease or head trauma. All the subjects were right-handed as determined by the Edinburgh Inventory. Schizophrenic and control subjects underwent MRI scan and EEG within two weeks. Three trained psychiatrists evaluated patients for BPRS and SANS and the score each item was the median of the three raters. MRI scans were performed by a Asahi Super 200 scanner operating at a 2.0 Tesla magnetic field. A midsagittal scan (8 mm thickness, Spin Echo 500/26) was taken. Subsequently, 15 axial and coronal slices of 5 mm interslice with 2 mm gap were obtained using an Inversion-Recovery sequence (TR: 3000, TI: 800, TE: 14). For measurement purposes, the three MRI scans (Fig-1) were recorded on transparent film, and the boundaries of the cerebral structures were taken traced from the film onto a digitizing tablet. The EEGs were recorded from 16 scalp electrodes of the standard 10/20 system referenced to linked ear electrodes at rest and digitized by a topographic system (Neuromap system MCE-5100, QCE-510B, Nihon Kohden). To calculate EEG power, the frequency spectrum was divided into six EEG frequency bands by 0.25 Hz bands. Each power value was taken from the average percentage of total power and then log-transformed. Schizophrenic patients showed a significantly larger VBR on the axial and coronal planes than control subjects. The areas of the bilateral anterior horns, left body, left posterior horn of the lateral ventricle and the third ventricle were significantly larger in schizophrenic patients than in control subjects. The area of middle half of the corpus callosum in schizophrenic patients was smaller than in control subjects. Schizophrenic patients showed more delta and theta activities in the centro-parieto-occipital regions than control subjects. Schizophrenic patients also showed more beta 1 and beta 2 activities in front-central regions than control subjects. On the other hand, schizophrenic patients showed a markedly decrease in alpha 2 activity in all regions.(ABSTRACT TRUNCATED AT 400 WORDS)


Rebound insomnia and newer hypnotics.

The prescription of hypnotics, mostly benzodiazepines, continues at a high level. One problem with their use is rebound insomnia: upon discontinuation sleep worsens compared with pretreatment levels. Factors influencing rebound include the type of subject, the duration of action of the hypnotic, the dosage and perhaps duration of treatment. The detection of rebound requires both sleep-laboratory and clinical studies with night-by-night analyses of individual patient data. This review concentrates on the newer compounds, (quazepam and zolpidem) which act selectively on subtypes of benzodiazepine receptors or bind atypically (zopiclone). It concludes that present evidence, while limited, is consistent with claims of less rebound potential than older benzodiazepine hypnotics of equivalent duration of action. Nevertheless, further rigorous studies are essential before these claims can be totally accepted.


Effects of ritanserin and chlordiazepoxide on sleep-wakefulness alterations in rats following chronic cocaine treatment.

The effects of ritanserin, a 5-hydroxytryptamine-2 (5-HT2) receptor antagonist, and chlordiazepoxide, a benzodiazepine agonist, on sleep-wakefulness disturbances in rats after acute administration of cocaine and after discontinuation of chronic cocaine treatment were examined. Intraperitoneal (IP) injection of chlordiazepoxide (10 mg/kg) but not ritanserin (0.63 mg/kg) prevented the increase of wakefulness (W) and the reduction of light slow wave sleep (SWS1) and deep slow wave sleep (SWS2) induced by an acute injection of cocaine (20 mg/kg IP). Daily injection of cocaine (20 mg/kg for 5 days, then 30 mg/kg for 5 days IP) at the onset of the light phase elicited an increase of W and a concomitant decrease of SWS1, SWS2 and paradoxical sleep (PS) in the light phase, followed by a rebound in SWS2 and PS in the subsequent dark phase. Following cocaine discontinuation, the circadian distribution of sleep-wakefulness states remained disturbed in saline-treated rats for at least 5 days. Both ritanserin (0.63 mg/kg IP/day) and chlordiazepoxide (10 mg/kg IP/day) reduced the alteration in the distribution of W and SWS2 throughout the light-dark cycle from the first day of administration on, but failed to prevent PS alterations. The mechanisms by which both compounds exert their effect are probably quite different. For chlordiazepoxide sedative and sleep-inducing properties probably play a major role. In contrast, for ritanserin SWS2-increasing properties and its ability to reverse preference for drugs of abuse without inducing aversion might be key factors.


Effects of repeated MK-801 on ambulation in mice and in sensitization following methamphetamine.

The noncompetitive NMDA receptor antagonist MK-801, (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cyclohepten-5,10-imine , increased ambulatory activity in the mouse at doses over 0.1 mg/kg (IP). The effect was enhanced when 0.3 mg/kg MK-801 was repeatedly administered at intervals of 3-4 days. In contrast, a reduction of the effect was induced with repeated doses of 0.1 and 1 mg/kg. The mice that had repeatedly experienced 1 mg/kg MK-801 exhibited a decrease in the sensitivity to methamphetamine (2 mg/kg SC). In addition, the repeated co-administration of 1 mg/kg MK-801 with methamphetamine induced a decrease in the sensitivity to methamphetamine. No modification of methamphetamine sensitivity was elicited by 0.1 and 0.3 mg/kg MK-801 in both the single and co-administration schedules. On the other hand, established sensitization to methamphetamine was hardly affected by repeated treatment with 0.1-1 mg/kg MK-801. These results indicate that the mechanism of the inhibitory action of MK-801 on the development of methamphetamine sensitization is different from that of dopamine D2 antagonists, which may act to decrease the effective unit dose of methamphetamine and reduce ambulation-increasing effect of methamphetamine.


Social status and voluntary alcohol consumption in mice: interaction with stress.

Dominant rats are found to consume less alcohol than their subordinate cage-mates. It is unclear whether the difference is due to dominant, aggressive animals consuming low levels of alcohol or whether social stress increases alcohol intake in subordinate animals. The present study investigated alcohol drinking patterns in aggressive alpha mice, their fight-stressed submissive cage-mates and non-fighting control mice before and after the establishment of social hierarchies. The results revealed that both moderately and severely fight-stressed submissive mice showed increased consumption of 5% alcohol, expressed as g/kg, but only severely wounded submissive mice showed increased alcohol preference over total fluid consumption, as compared with alpha mice. The difference in alcohol consumption was not seen prior to the establishment of submissive and alpha status, indicating that the submissive mice increased their alcohol consumption only after experiencing fight-stress. The amount of alcohol consumed did not differ between alpha and non-fighting control mice. To further investigate the possible connection between alcohol intake and aggressivity, the mice were studied in the resident-intruder test before group-housing. The results failed to show a consistent pattern of correlations between the time spent in aggression in this test and subsequent alcohol intake measures. The data indicate that severe fight-stress increases alcohol consumption in mice. Alcohol intake of aggressive, dominant alpha mice is not significantly altered, as compared with non-fighting animals. Furthermore, the level of aggressiveness prior to the establishment of social status does not directly affect alcohol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)