Dopamine antipsychotics effects

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

Antipsychotic medications antagonize dopamine, which is believed to contribute to the antipsychotic effect of these medications. The atypical antipsychotics have other physiological properties as well, some of which appear to relate to antagonism of the serotonin type 2 (5-HT2) receptor, which may modify dopamine activity in a regionally specific manner. Dual 5-HT2 receptor-dopamine type 2 (D2) receptor antagonism is believed to account, at least in part, for the superior efficacy and more favorable side-effect profile of atypical antipsychotics. 

Other drug effects that decrease DA activity also support this position. Thus, when DA synthesis is blocked by a-methyl- p-tyrosine (AMPT), the dose necessary for an antipsychotic effect is reduced (i.e., the dose-response curve is shifted to the left by the interaction between dopamine and AMPT). A drug such as reserpine that can deplete DA stores also has relatively mild antipsychotic properties. Also, aripiprazole, which has D 2 presynaptic agonist properties, decreases the production of DA, as well as blocking D2 postsynaptic receptors. 

Kapur S, Zipursky R, Jones C, et al. A positron emission tomography study of quetiapine in schizophrenia a preliminary finding of an antipsychotic effect with only transiently high dopamine D 2 receptor occupancy. Arch Gen Psychiatry 2000 57 553-559. 

There is no doubt that dopamine-sensitive adenylate cyclase (D site) is not involved in the antipsychotic effect of neuroleptic drugs. 

Ungerstedt, V., Ljungberg, T. (1977). Behavioral patterns related to dopamine neurotransmission Effect of acute and chronic antipsychotic drugs. Advances in Biochemical Psychopharmacology, 16, 193-199. 

At this time, there was no knowledge of the molecular basis of chlor-promazine s effect or the molecular target. Knowledge of the molecular basis came 20 years later in 1972 when Paul Greengard s laboratory established the cormection with the dopamine receptor Dj. This led the whole industry to look for a new antipsychotic better than chlorpromazine and to new agents tested directly in multiple clinical trials. Further research 20 years later showed that much of the antipsychotic effect was through another variant of the dopamine receptor, the D2 receptor, not the originally... 

Antipsychotics have been used to promote sleep in resistant insomnia occurring as part of another psychiatric disorder, probably due to a combination of 5HT2-receptor, -adrenoceptor and histanaine Hj-receptor antagonism, in addition to their primary dopamine antagonist effects. Their long action leads to daytime sedation and extrap5n a-midal movement disorders may result from dopamine receptor blockade (see p. 380, Antipsychotics). Nevertheless, modern antipsychotics, e.g. quetia-pine, have been occasionally used for intractable insonmia. 

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