and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects serotonin receptors (5-ht2, 5-ht6 and 5-ht7), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties. histamine receptors (h1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain) α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with intraoperative floppy iris syndrome due to its effect on the iris dilator muscle. m1 and m2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects). the presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. this assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess. chlorpromazine and other typical antipsychotics are primarily blockers of d2 receptors. in fact an almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the d2 receptor. therefore, a larger dose is required if the drug's affinity for the d2 receptor is relatively weak. a correlation exists between average clinical potency and affinity of the antipsychotics for dopamine receptors. chlorpromazine tends to have greater effect at serotonin receptors than at d2 receptors, which is notably the opposite effect of the other typical antipsychotics. therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is more similar to the atypical antipsychotics than to the typical antipsychotics. chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. furthermore, they are also among the most potent antipsychotics at histamine h1 receptors. this finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. furthermore, the brain has a higher density of histamine h1 receptors than any body organ examined which may account for why chlorpromazine and other phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines. in addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. this mechanism involves direct effects on antipsychotic drugs on glutamate receptors. by using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on nmda receptors that appeared to be mediated by action at the zn site. it was found that there is an increase of nmda activity at low concentrations and suppression at high concentrations of the drug. no significant difference in glutamate and glycine activity from the effects of chlorpromazine were reported. further work will be necessary to determine if the influence in nmda receptors by antipsychotic drugs contributes to their effectiveness. chlorpromazine does also act as a fiasma (functional inhibitor of acid sphingomyelinase). peripheral effects chlorpromazine is an antagonist to h1 receptors (provoking antiallergic effects), h2 receptors (reduction of forming of gastric juice), m1 and m2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-ht receptors (different anti-allergic/gastrointestinal actions). because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug". history advertisement for thorazine (chlorpromazine) from the early 1960s in 1933, the french pharmaceutical company laboratoires rhône-poulenc began to search for new anti-histamines. in 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.: 77 a year later, the french surgeon pierre huguenard used promethazine together with pethidine as part of a cocktail to induce relaxation and indifference in surgical patients. another surgeon, henri laborit, believed the compound stabilized the central nervous system by causing "artificial hibernation", and described this state as "sedation without narcosis". he suggested to rhône-poulenc that they develop a compound with better stabilizing properties. in december 1950, the chemist paul charpentier produced a series of compounds that included rp4560 or chlorpromazine. chlorpromazine was distributed for testing to physicians between april and august 1951. laborit trialled the medicine on at the val-de-grâce military hospital in paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. he also noted its hypothermic effect and suggested it may induce artificial hibernation. laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time. known colloquially as "laborit's drug", chlorpromazine was released onto the market in 1953 by rhône-poulenc and given the trade name largactil, derived from large "broad" and acti* "activity". following on, laborit considered whether chlorpromazine may have a role in managing patients with severe burns, raynaud's phenomenon, or psychiatric disorders. at the villejuif mental hospital in november 1951, he and montassut administered an intravenous dose to psychiatrist cornelia quarti who was acting as a volunteer. quarti noted the indifference, but fainted upon getting up to go to the toilet, and so further testing was discontinued (orthostatic hypotension is a known side effect of chlorpromazine). despite this, laborit continued to push for testing in psychiatric patients during early 1952. psychiatrists were reluctant initially, but on 19 january 1952, it was administered (alongside pethidine, pentothal and ect) to jacques lh. a 24-year-old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total. pierre deniker had heard about laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the sainte-anne hospital center in paris where he was men's service chief. together with the director of the hospital, jean delay, they published their first clinical trial in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents. the response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour. they also found that doses higher than those used by laborit were required, giving patients 75–100 mg daily. deniker then visited america, where the publication of their work alerted the american psychiatric community that the new treatment might represent a real breakthrough. heinz lehmann of the verdun protestant hospital in montreal trialled it in 70 patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis. by 1954, chlorpromazine was being used in the united states to treat schizophrenia, mania, psychomotor excitement, and other psychotic disorders. rhône-poulenc licensed chlorpromazine to smith kline & french (today's glaxosmithkline) in 1953. in 1955 it was approved in the united states for the treatment of emesis (vomiting). the effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. but the popularity of the drug fell from the late 1960s as newer drugs came on the scene. from chlorpromazine a number of other similar antipsychotics were developed. it also led to the discovery of antidepressants. chlorpromazine largely replaced electroconvulsive therapy, hydrotherapy, psychosurgery, and insulin shock therapy. by 1964, about 50 million people worldwide had taken it. chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not a perfect one. society and culture names brand names include thorazine, largactil, hibernal, and megaphen (sold by bayer in west-germany since july 1953).) research chlorpromazine has tentative benefit in animals infected with naegleria fowleri, and shows antifungal and antibacterial activity in vitro. veterinary use the veterinary use of chlorpromazine has generally been superseded by use of acepromazine. chlorpromazine may be used as an antiemetic in dogs and cats, or, less often, as sedative before anesthesia. in horses, it often causes ataxia and lethargy, and is therefore seldom used. it is commonly used to decrease nausea in animals that are too young for other common anti-emetics. it is also sometimes used as a preanesthetic and muscle relaxant in cattle, swine, sheep, and goats. the use of chlorpromazine in food-producing animals is not permitted in the eu, as a maximum residue limit could not be determined following assessment by the european medicines agency.