the senescence - accelerated mouse ( sam ) is a group of inbred mouse strains that are used as 
 animal models of senescence acceleration and age - associated disorders . during sister - brother 
 mating of akr / j mice obtained from jackson laboratories ( me , usa ) by the department of 
 pathology ,
chest disease research institute ( now the institute for frontier medical 
 sciences ) , kyoto university ( kyoto , japan ) , dr .
takeda and his colleagues became aware that 
 most of the mice in certain litters demonstrated senescent phenotypes , presenting as a lack 
 of activity , hair loss and lack of sheen , skin lesions , increased lordokyphosis , and 
 premature death .
selective breeding , based on senescence scores , life span , and 
 pathobiological phenotypes , was then carried out , leading to the development of nine senescence - accelerated - prone ( samp ) strains , 
 and three senescence - accelerated - resistant ( samr ) strains . each samp strain exhibits 
 accelerated senescence characteristics . among these strains , samp8 and samp10
have 
 age - related deficits in learning and memory [ 36 , 
 45 , 55 , 
 56 , 65 , 
 70 ] , emotional disorders [ 35 , 65 ] , and altered circadian 
 rhythm .
since these phenotypes are accelerated 
 with aging , samp8 and samp10 are frequently used as models for studying age - related changes 
 in higher brain function .
in contrast , samp6 is predominantly used as a model of senile 
 osteoporosis , since mice exhibit low bone mass , and slow bone loss .
after 4 months of age , samp6 has global low bone density , marrow osteogenic defects , and deficits in 
 endocortical mineralizing surface , as well as 
 reduced femoral weight , and calcium and phosphorus levels .
however , an aging - related increased expression of s100 , a factor underlying 
 the increased risk of alzheimer s disease , in the brain of samp6 was reported , compared with 
 samr1 , suggesting possible central nervous system alterations in samp6 .
we therefore decided to study whether samp6 was also 
 a model of senescence - related brain alterations and diseases .
since the bone mineral density of samp6 is highest at 4 months of age , this is thought to be the age at which these mice 
 have their optimal body function , while the median survival time of samp strains is 9.7 
 months .
we therefore performed a battery of 
 behavioral analyses using 1- ( juvenile ) , 46- ( adult ) , and 812-month - old ( old ) samp6 and 
 age - matched samr1 to study age - related changes in behavioral characteristics ( table 1table 1.summary of behavioral characteristics of samp6 compared with age - matched 
 samr1.behavioralcharacteristicsbehavioral testsjuvenileadultold1 mo 4 mo6 mo8 mo12 moactivityopen field testhigh * high * * high * * home cage activity testhigh * low y - maze testhigh high * high * * elevated plus maze testhigh * * high * * high * light - dark exploration testhigh * * high * * high * motor coordinationwire - hanging test ( score)low * low low * * wire - hanging test ( time)low * * low low * * rotating rod test ( static version)low * * low low rotating rod test ( accelerating version)low * * low * * low * * anxietyelevated plus maze test ( open arm entry)low * * low * low * elevated plus maze test ( time)low * * low * low * * light - dark exploration testlow * * low * * low * * marble - burying testlow * low * * low * * depressiontail suspension testlow * * low * low * learning and memoryy - maze testhigh high * high * novel object recognition testhigh * novel object location testhigh * * win - shift eight - arm radial maze testhigh * morris water maze ( reference memory)similar similarmorris water maze ( working memory)low * * low * * * : p<0.05 compared with age - matched samr1 . * * : 
 p<0.01 compared with age - matched samr1 .
c ) similar : the performance of samp6 is 
 similar to that of samr1 . ) . * : p<0.05 compared with age - matched samr1 . * * : 
 p<0.01 compared with age - matched samr1 .
c ) similar : the performance of samp6 is 
 similar to that of samr1 .
open field , home cage activity , y - maze , elevated plus maze , and light - dark exploration 
 tests all revealed that samp6 exhibits higher motor activity compared with samr1 . in the open field test , the distance traveled by 
 samp6 in 25 min was greater than that travelled by age - matched samr1 . in the y - maze test ,
the total number of arm entries of samp6 was 
 significantly higher than age - matched samr1 at 4 and 8 months , while a similar trend was 
 observed when mice were 1 month of age . 

similarly in the elevated plus maze test , the total number of arm entries of samp6 was 
 significantly higher than age - matched samr1 .
in 
 the light - dark exploration test , samp6 exhibited a significantly increased total number of 
 transitions compared with age - matched samr1 . 

since behavioral changes are already apparent at 1 month of age , it is likely that this is 
 an innate behavioral characteristic of samp6 . in the home cage activity test ,
the total 
 activity of 6-month - old samp6 during a 24-h period was significantly higher than samr1 
 .
in contrast , the total activity of 
 12-month - old samp6 tended to be lower than age - matched samr1 , and was significantly lower 
 than 6-month - old samp6 .
the higher motor 
 activity of samp6 is observed until 8 months of age , after which motor activity begins to 
 decline , and is detectably lower at 12 months of age .
results of the wire hanging and rotating rod tests revealed that samp6 had an innate motor 
 coordination deficit . in the wire - hanging test , the mean score and latency to fall of 1- and 
 8-month - old samp6 were significantly lower than age - matched samr1 ( unpublished data ) . in 
 contrast , no significant difference either in the score or latency to fall off was detected 
 between samp6 and samr1 at 4 months of age . in 
 the rotating rod test , the latency of samp6 to fall off an accelerating rod was 
 significantly shorter than samr1 at 18 months of age [ 43 and unpublished data ] .
however , in 
 a 3-rpm constant speed , 1- and 8-month - old samp6 tended to fall off faster than age - matched 
 samr1 ( unpublished data ) , while 4-month - old samp6 had improved latency .
since there was no difference between the grip 
 strength of samp6 and samr1 at 18 months of age [ 43 and unpublished data ] , the motor 
 coordination deficit observed in samp6 is unlikely to be caused by reduced grip 
 strength .
reduced anxiety of samp6 , compared with samr1 , was revealed by results of the elevated plus 
 maze , light - dark exploration , and marble - burying tests . in the elevated plus maze test , 
 samp6 spent significantly greater periods of time on , and more frequently entered , the open 
 arms compared with age - matched samr1 at 18 months of age . in the light - dark exploration test , samp6 spent significantly longer in the 
 light box than age - matched samr1 .
finally in the 
 marble - burying test , the number of marbles buried by samp6 , and the length of time they 
 spent marble - burying , were significantly higher than age - matched samr1 . in samp6 , the time spent on the open arms and the 
 number of open arm entries in the elevated plus maze test
this suggests that there is an age - associated decrease in the difference between the 
 anxiety levels of samp6 and samr1 .
in contrast , there was no age - dependent change in the 
 time spent in the light box in the light - dark exploration test , the number of marbles buried 
 or the time of marble - burying behavior in the marble - burying test from 1 to 8 months of age 
 in samp6 .
the reason why samp6 exhibited age - associated decrease in anti - anxiety behavior in 
 elevated plus maze test , but not in light - dark exploration or marble - burying tests , might be 
 that elevated plus maze test gives animals stronger load compared with the other two 
 behavioral tests and samp6 has an age - dependent anxiety specifically related to 
 elevation .
the tail suspension test revealed that samp6 has innate anti - depressant activities compared 
 with samr1 . specifically , the immobility time of samp6 was significantly shorter than 
 age - matched samr1 at 18 months of age , but the difference in anti - depressant activities 
 gradually decreased as the mice aged . however , 
 since samp6 are hyperactive , it is unclear whether their shortened immobility time in the 
 tail suspension test is specifically due to depression - related mechanisms . the y - maze , novel object recognition , object location , and delayed spatial win - shift 
 eight - arm radial maze tests all revealed that samp6 has enhanced spatial learning and memory 
 compared with samr1 . in the y - maze test , the spontaneous alteration behaviors of 4- and 
 8-month old samp6 were significantly higher , while the behavior of 1-month - old samp6 tended 
 to be increased , compared with age - matched samr1 . in the novel object recognition test ,
4-month - old samp6 showed a significantly 
 higher exploratory preference for the novel , rather than old , object compared with samr1 
 . in the object location test
, 4-month - old 
 samp6 showed a significantly increased exploratory preference for the displaced object 
 compared with age - matched samr1 . in the delayed 
 spatial win - shit eight - arm radial maze test
, 4-month - old samp6 had a greater improvement in 
 the percentage of correct choices during days 26 of nine consecutive days , compared with 
 samr1 .
overall , samp6 mice exhibited enhanced 
 spatial learning and memory , and this behavioral characteristic was not affected by aging . 

in contrast , liu et al . previously reported a working memory deficit of 4- 
 and 8-month - old samp6 in the morris water maze test compared with age - matched samr1 .
however , since the water maze and y - maze tests 
 measure different behavioral paradigms , these results can not be compared directly .
the 
 y - maze test is based on the natural tendency of mice to alternate their choice of arms , 
 whereas the water maze test is a stress paradigm based on aversive motivation [ 11 , 14 ] .
it is 
 possible that the reduced anxiety of samp6 
 affects their performance in each test in a different way . in the y - maze test , it could 
 positively influence performance by increasing the motivation to explore , whereas in the 
 morris water maze test , it may negatively influence working memory , since this test uses an 
 aversive stimulation as the reinforcer for memory .
the neurotransmitters dopamine and serotonin control motor activity , emotional behavior , 
 and the process of working memory [ 6 , 10 , 18 , 26 , 32 , 52 , 53 , 72 , 73 ] . in 
 addition ,
glutamate n - methyl - d - aspartate ( nmda ) receptors are well known to play a role in 
 many forms of learning and memory [ 7 , 30 , 39 , 48 , 51 ] . among the 
 nmda receptor ( nr ) family ,
the nr2b subunit is crucial for long - term potentiation ( ltp ) 
 [ 4 , 17 , 67 , 69 ] , while the 
 alpha calcium / calmodulin dependent protein kinase ii ( camkii)/ nr2b - containing nmda receptor 
 signaling pathway is important in maintaining synaptic plasticity and spatial cognition 
 [ 20 , 24 , 
 25 , 59 ] .
we 
 therefore studied these ltp - related molecules , as well as dopamine and serotonin , in 
 samp6 .
western blotting revealed increased expression of the dopamine - biosynthesizing enzyme 
 tyrosine hydroxylase ( th ) , as well as serine-40-phosphorylated th , in the striatum and 
 nucleus accumbens ( nac ) of 1-month - old samp6 compared with age - matched samr1 .
measurement of dopamine and its metabolites using high performance liquid chromatography 
 ( hplc ) revealed that the concentrations of dopamine and homovanilic acid ( hva ) in the 
 cortex , hva in the striatum , dopamine and hva in the cerebellum , and dopamine , 
 3-methoxytyramine ( 3-mt ) , and hva in the nac were all significantly higher in 6-month - old 
 samp6 than in samr1 [ 43 and unpublished data ] 
 ( table 2table 2.concentrations of dopamine , serotonin , and their metabolitesregiondopamine ( ng / g tissue)dopac ( ng / g tissue)hva ( ng / g tissue)samr1samp6samr1samp6samr1samp6cortex78.94  13.04189.70  38.22 * 34.51  2.9736.16  7.4049.03  3.4978.16  10.77*hippocampus9.71  3.058.99  1.199.78  2.3211.02  0.689.74  2.1610.81  1.30striatum2,970.74  206.822,672.13  264.84677.58  54.96551.19  38.93252.55  10.90353.50  26.24**nucleus accumbens339.23  90.00772.49  58.90**3.69  1.574.06  0.9958.31  9.42136.9  2.35**brain stem54.75  5.0062.02  10.3727.86  2.7129.39  3.1752.09  3.7733.53  2.14**cerebellum1.38  0.122.64  0.20**0.74  0.090.91  0.183.28  0.358.12  0.89**region3-mt
( ng / g tissue)5-ht ( ng / g tissue)5-hiaa ( ng / g tissue)samr1samp6samr1samp6samr1samp6cortex77.39  11.5768.69  14.78249.11  17.64337.98  23.00 * 428.121  32.016634.85
 42.97**hippocampus4.43  1.183.26  0.70193.30  18.85220.03  18.68777.90  46.551,090.00  64.74**striatum507.46  42.51582.66  77.35325.12  19.14329.93  38.28738.92  55.831,099.21  100.69*nucleus accumbens47.33  17.77167.14  33.19 * 285.94  35.44440.91  32.19 *
1,194.36  68.351,284.98  161.26brain stem27.90  2.6433.98  3.59481.84  40.00451.00  16.121,423.29  95.18922.33  39.30**cerebellum1.22  0.191.35  0.3133.11  1.0346.39  3.04**83.23  5.66196.83  12.27**data are expressed as mean  sem .
in contrast , the concentration of hva in the samp6 brainstem was 
 significantly lower than age - matched samr1 . 
 finally , increased expression of the dopamine receptor 1 ( d1 ) and dopamine transporter 
 ( dat ) in the striatum , dopamine receptor 3 ( d3 ) in the nac , and d1 and d3 in the 
 cerebellum were seen in samp6 mice , as assessed by western blotting .
* p<0.05 ; * * 
 p<0.01 . a d1 agonist , skf82958 ( 6-chloro-7 , 8-dihydroxy-3-allyl-1-phenyl-2 , 3 , 4 , 
 5-tetrahydro-1-phenyl-1h-3-benzazepine hydrobromide ) , was administered to 6- and 
 12-month - old samp6 , samr1 , and akr / j ( the original strain of sam ) , to compare the 
 sensitivity of this receptor among these strains .
treatment with skf82958 significantly 
 increased the motor activity of 6-month - old samp6 compared with age - matched akr / j and 
 samr1 .
moreover , the d1 sensitivity of 
 12-month - old akr / j and samr1 was similar to their corresponding 6-month - old mice , whereas 
 the d1 sensitivity of 12-month - old samp6 was significantly lower than at 6 months of age 
 .
these results revealed that samp6 has a 
 higher d1 sensitivity as adult , but then undergo an age - related decline .
western blotting revealed elevated expression levels of the serotonin - biosynthesizing 
 enzyme tryptophan hydroxylase ( tph ) , as well as serine-58-phosphorylated tph , in the brain 
 stem of 1-month - old samp6 compared with age - matched samr1 .
the measurement of serotonin and its metabolite using hplc revealed that the 
 concentration of serotonin in cortex , nac , and cerebellum , and the concentration of 
 5-hydroxyindole acetic acid ( 5-hiaa ) in cortex , hippocampus , striatum , and cerebellum , 
 were all significantly higher in 6-month - old samp6 compared with age - matched samr1 ( table 2 ) . in contrast , the concentration of 5-hiaa 
 in the brain stem of samp6 was significantly lower than samr1 ( table 2 ) .
the hallucinogenic chemical 1-[2 , 5-dimethoxy-4-iodophenyl]-2-aminopropane ( doi ) , a 
 serotonin receptor 2a ( 5-ht2ar ) agonist , activates extracellular signal - regulated kinase 
 1/2 ( erk1/2 ) signaling accompanied by head - twitching behavior .
although doi increased the 
 head - twitch response in a dose - dependent manner in both 8-week - old samp6 and age - matched 
 samr1 , the responses of samp6 treated with 0.3 and 1.0 mg / kg doi were significantly 
 greater than the responses of samr1 administered identical doses .
in addition , the phospho - erk1/2 and phospho - camp - responsive 
 element - binding protein ( creb ) levels in samp6 treated with 0.3 and 1.0 mg / kg doi were 
 significantly higher than samr1 given identical doses of doi .
these results suggest that the 5-ht2a - erk1/2-creb signaling 
 pathway is enhanced in samp6 .
four - month - old samp6 has increased expression of the nr2b subunit in the forebrain , and 
 camkii in the hippocampus compared with age - matched samr1 . on the other hand
, there was no 
 difference in nr1 and nr2a subunits , or the glur1 subunit of the 
 -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor ( ampa receptor ) [ 41 , 64 ] , as 
 revealed by western blotting .
these results suggest that the 
 nr2b - containing nmda receptor and camkii signaling pathways are enhanced in samp6 .
animals treated with ( )-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ( cpp ) , an 
 nmda receptor antagonist , were subjected to the y - maze and novel object recognition tests 
 to determine whether nmda receptors are associated with the enhanced short - term memory of 
 samp6 . in the y - maze test ,
the spontaneous 
 alternation behavior of 4-month - old samp6 was significantly higher than that of 
 age - matched samr1 at each dose tested ( 0 , 5 , and 10 mg / kg ) , and was similar to the results 
 of the y - maze test in untreated mice .
in samr1 , treatment with 10 mg / kg cpp significantly 
 impaired the alternation performance compared with untreated mice , while the spontaneous 
 alternation behavior of samp6 was reduced only slightly after treatment with10 mg / kg cpp . 
 in the retention phase of the novel object recognition test , samr1 injected with 10 mg / kg 
 cpp exhibited a significantly reduced exploratory preference compared with untreated mice . 

while the exploratory performance of samp6 treated with 10 mg / kg cpp showed a tendency to 
 be reduced , their performance was still greater than samr1 .
western blotting revealed increased expression of the dopamine - biosynthesizing enzyme 
 tyrosine hydroxylase ( th ) , as well as serine-40-phosphorylated th , in the striatum and 
 nucleus accumbens ( nac ) of 1-month - old samp6 compared with age - matched samr1 .
measurement of dopamine and its metabolites using high performance liquid chromatography 
 ( hplc ) revealed that the concentrations of dopamine and homovanilic acid ( hva ) in the 
 cortex , hva in the striatum , dopamine and hva in the cerebellum , and dopamine , 
 3-methoxytyramine ( 3-mt ) , and hva in the nac were all significantly higher in 6-month - old 
 samp6 than in samr1 [ 43 and unpublished data ] 
 ( table 2table 2.concentrations of dopamine , serotonin , and their metabolitesregiondopamine ( ng / g tissue)dopac ( ng / g tissue)hva ( ng / g tissue)samr1samp6samr1samp6samr1samp6cortex78.94  13.04189.70  38.22 * 34.51  2.9736.16  7.4049.03  3.4978.16  10.77*hippocampus9.71  3.058.99  1.199.78  2.3211.02  0.689.74  2.1610.81  1.30striatum2,970.74  206.822,672.13  264.84677.58  54.96551.19  38.93252.55  10.90353.50  26.24**nucleus accumbens339.23  90.00772.49  58.90**3.69  1.574.06  0.9958.31  9.42136.9  2.35**brain stem54.75  5.0062.02  10.3727.86  2.7129.39  3.1752.09  3.7733.53  2.14**cerebellum1.38  0.122.64  0.20**0.74  0.090.91  0.183.28  0.358.12  0.89**region3-mt
( ng / g tissue)5-ht ( ng / g tissue)5-hiaa ( ng / g tissue)samr1samp6samr1samp6samr1samp6cortex77.39  11.5768.69  14.78249.11  17.64337.98  23.00 * 428.121  32.016634.85  42.97**hippocampus4.43  1.183.26  0.70193.30  18.85220.03  18.68777.90  46.551,090.00  64.74**striatum507.46  42.51582.66  77.35325.12  19.14329.93  38.28738.92  55.831,099.21  100.69*nucleus accumbens47.33  17.77167.14  33.19 * 285.94  35.44440.91  32.19
* 1,194.36  68.351,284.98  161.26brain stem27.90  2.6433.98  3.59481.84  40.00451.00  16.121,423.29  95.18922.33  39.30**cerebellum1.22  0.191.35  0.3133.11  1.0346.39  3.04**83.23  5.66196.83  12.27**data are expressed as mean  sem .
in contrast , the concentration of hva in the samp6 brainstem was 
 significantly lower than age - matched samr1 . 
 finally , increased expression of the dopamine receptor 1 ( d1 ) and dopamine transporter 
 ( dat ) in the striatum , dopamine receptor 3 ( d3 ) in the nac , and d1 and d3 in the 
 cerebellum were seen in samp6 mice , as assessed by western blotting .
* p<0.05 ; * * 
 p<0.01 . a d1 agonist , skf82958 ( 6-chloro-7 , 8-dihydroxy-3-allyl-1-phenyl-2 , 3 , 4 , 
 5-tetrahydro-1-phenyl-1h-3-benzazepine hydrobromide ) , was administered to 6- and 
 12-month - old samp6 , samr1 , and akr / j ( the original strain of sam ) , to compare the 
 sensitivity of this receptor among these strains .
treatment with skf82958 significantly 
 increased the motor activity of 6-month - old samp6 compared with age - matched akr / j and 
 samr1 .
moreover , the d1 sensitivity of 
 12-month - old akr / j and samr1 was similar to their corresponding 6-month - old mice , whereas 
 the d1 sensitivity of 12-month - old samp6 was significantly lower than at 6 months of age 
 .
these results revealed that samp6 has a 
 higher d1 sensitivity as adult , but then undergo an age - related decline .
western blotting revealed elevated expression levels of the serotonin - biosynthesizing 
 enzyme tryptophan hydroxylase ( tph ) , as well as serine-58-phosphorylated tph , in the brain 
 stem of 1-month - old samp6 compared with age - matched samr1 .
the measurement of serotonin and its metabolite using hplc revealed that the 
 concentration of serotonin in cortex , nac , and cerebellum , and the concentration of 
 5-hydroxyindole acetic acid ( 5-hiaa ) in cortex , hippocampus , striatum , and cerebellum , 
 were all significantly higher in 6-month - old samp6 compared with age - matched samr1 ( table 2 ) .
in contrast , the concentration of 5-hiaa 
 in the brain stem of samp6 was significantly lower than samr1 ( table 2 ) .
the hallucinogenic chemical 1-[2 , 5-dimethoxy-4-iodophenyl]-2-aminopropane ( doi ) , a 
 serotonin receptor 2a ( 5-ht2ar ) agonist , activates extracellular signal - regulated kinase 
 1/2 ( erk1/2 ) signaling accompanied by head - twitching behavior .
although doi increased the 
 head - twitch response in a dose - dependent manner in both 8-week - old samp6 and age - matched 
 samr1 , the responses of samp6 treated with 0.3 and 1.0 mg / kg doi were significantly 
 greater than the responses of samr1 administered identical doses .
in addition , the phospho - erk1/2 and phospho - camp - responsive 
 element - binding protein ( creb ) levels in samp6 treated with 0.3 and 1.0 mg / kg doi were 
 significantly higher than samr1 given identical doses of doi .
these results suggest that the 5-ht2a - erk1/2-creb signaling 
 pathway is enhanced in samp6 .
four - month - old samp6 has increased expression of the nr2b subunit in the forebrain , and 
 camkii in the hippocampus compared with age - matched samr1 . on the other hand
, there was no 
 difference in nr1 and nr2a subunits , or the glur1 subunit of the 
 -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor ( ampa receptor ) [ 41 , 64 ] , as 
 revealed by western blotting .
these results suggest that the 
 nr2b - containing nmda receptor and camkii signaling pathways are enhanced in samp6 .
animals treated with ( )-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid ( cpp ) , an 
 nmda receptor antagonist , were subjected to the y - maze and novel object recognition tests 
 to determine whether nmda receptors are associated with the enhanced short - term memory of 
 samp6 . in the y - maze test ,
the spontaneous 
 alternation behavior of 4-month - old samp6 was significantly higher than that of 
 age - matched samr1 at each dose tested ( 0 , 5 , and 10 mg / kg ) , and was similar to the results 
 of the y - maze test in untreated mice .
in samr1 , treatment with 10 mg / kg cpp significantly 
 impaired the alternation performance compared with untreated mice , while the spontaneous 
 alternation behavior of samp6 was reduced only slightly after treatment with10 mg / kg cpp . 
 in the retention phase of the novel object recognition test , samr1 injected with 10 mg / kg 
 cpp exhibited a significantly reduced exploratory preference compared with untreated mice . 

while the exploratory performance of samp6 treated with 10 mg / kg cpp showed a tendency to 
 be reduced , their performance was still greater than samr1 .
results of the behavioral tests revealed that samp6 exhibits innate behavioral alterations ; 
 specifically higher motor activity , motor coordination deficit , lower anxiety , 
 anti - depressant activity , and enhanced learning and memory .
the higher motor activity of 
 samp6 was observed until the adult stage , at which point motor activity began to decline . by 
 later old ages ,
mice had lower motor activity , suggesting that this characteristic of samp6 
 undergoes an accelerated senescence - like pattern .
the marked motor coordination deficit of 
 samp6 was observed at juvenile and old ages , while a slight amelioration in the motor 
 coordination deficit was seen in adult mice , suggesting that the motor coordination of samp6 
 also exhibits an accelerated senescence - like pattern .
in contrast , the differences in 
 anxiety and anti - depressant activity between samp6 and samr1 decreased gradually with age , 
 suggesting that these actions of samp6 are a result of an alternative pattern of age - related 
 change .
the expression of th and phosphorylated th were increased in the striatum and nac of 
 juvenile samp6 , suggesting these regions had an increase in the concentration of dopamine . 

in addition , the concentration of dopamine in the nac of adult samp6 was significantly 
 higher than in samr1 .
it was reported previously that increased dopamine release in the nac 
 is related to hyperactivity [ 13 , 74 ] , and this is thought to be an underlying mechanism 
 causing the higher motor activity in samp6 .
since d1 is known to modulate motor activity 
 [ 15 , 37 , 
 50 , 63 , 
 68 ] and striatal d1 plays a role in locomotor 
 activity , the increased expression of d1 in the 
 striatum , coupled with an over - active d1 signaling cascade , in adult samp6 may also explain 
 the higher activity of this strain .
in addition , the accelerated senescence - like decrease in 
 motor activity of old samp6 may be explained by the apparent decrease in the sensitivity of 
 d1 that was observed in aged , compared with adult , samp6 . since it was reported that the injection of a d2/d3 agonist into lobules 9 and 10 of the 
 cerebellar cortex , where d2 is not expressed , 
 induced balance and motor coordination disturbance in the rotarod test , increased d3 expression in the cerebellum of adult 
 samp6 was thought to be one of the mechanisms that contributed to the deficit in motor 
 coordination .
however , further examination of d3 expression in the cerebellum of juvenile 
 and old samp6 is needed to evaluate whether altered d3 expression is involved in the 
 accelerated senescence - like alteration of this behavior .
the expression of tph and phosphorylated tph were increased in the brainstem of juvenile 
 samp6 , suggesting elevated serotonin concentrations in the juvenile samp6 brain . in 
 addition
since serotonin levels in the cortex and nac are related to low anxiety and anti - depressant 
 activity [ 8 , 22 , 23 , 71 ] , this may be a mechanism by which samp6 mice exhibit these behavioral changes . 

in addition , increased expression of d3 in the nac may be involved in the anti - depressant 
 activity of adult samp6 , since the d3 receptor in nac was reported to play a role in 
 anti - depressant activity .
however , measuring the 
 serotonin concentration and d3 expression in juvenile and old samp6 brains is necessary to 
 determine whether the altered levels of serotonin and d3 are involved in the age - related 
 changes of anxiety and anti - depressant activity in samp6 .
the increased dopamine and serotonin concentrations in the cortex of adult samp6 were also 
 thought to contribute to the enhanced memory of samp6 , since these monoamines are known to 
 modulate working memory [ 6 , 10 , 32 , 53 ] .
in addition , adult samp6 mice demonstrated increased expression of 
 nr2b in the forebrain , and camkii in the hippocampus , while elevated phosphorylation of nr1 
 and camkii was also observed .
although these results suggest that these pathways may be 
 involved in the enhanced memory of adult samp6 , additional studies of the mechanisms and 
 pathways involved in this behavioral property using juvenile and old samp6 are needed . in 
 contrast , elevated level of s100 was reported to cause decreased working memory .
the working memory deficit of samp6 reported by liu 
 et al .   might be due to an 
 age - related increased expression of s100 in the brain .
several quantitative trait loci ( qtls ) for senile - osteoporosis - related parameters were 
 reported in samp6 [ 3 , 38 , 46 , 47 , 49 , 57 , 58 ] suggesting that the senile 
 osteoporosis observed in samp6 is caused by some genetic alterations .
spontaneous genetic 
 alteration ( s ) near these qtls might have been co - fixed in samp6 through selective breeding , 
 leading to the alterations in the dopamine , serotonin , and ltp - related - molecule systems as 
 described above .
since neurotransmission systems of dopamine , serotonin , and glutamate are 
 known to affect one another [ 1 , 5 , 16 , 28 , 33 , 61 , 62 ] , a genetic alteration 
 related to these neurotransmitter pathways might trigger the multiple molecular and 
 behavioral alterations in samp6 . identifying qtls for behavioral characteristics of samp6
 the senescence - accelerated mouse ( sam ) was developed by selective breeding of the akr / j 
 strain , based on a graded score for senescence , which led to the development of both 
 senescence - accelerated prone ( samp ) , and senescence - accelerated resistant ( samr ) strains . 
 among the samp strains , 
 samp6 is well characterized as a model of senile osteoporosis , but 
 its brain and neuronal functions have not been well studied . 
 we therefore decided to 
 characterize the central nervous system of samp6 , in combination with different behavioral 
 tests and analysis of its biochemical and pharmacological properties . 
 multiple behavioral 
 tests revealed higher motor activity , reduced anxiety , anti - depressant activity , motor 
 coordination deficits , and enhanced learning and memory in samp6 compared with samr1 . 
 
 biochemical and pharmacological analyses revealed several alterations in the dopamine and 
 serotonin systems , and in long - term potentiation ( ltp)-related molecules . in this review , 
 
 we discuss the possibility of using samp6 as a model of brain function . 
Introduction
Behavioral Characteristics
Potential Mechanisms of Action
Dopamine
Serotonin
LTP-related molecules
Conclusion and Perspectives