ROLE OF D2 RECEPTORS | ANTIPSYCHOTICS



Most effective antipsychotics, typical as well as atypical, have affinities for the DA D2 receptor high enough to suggest that they produce effective blockade of these receptors in vivo. The model for atypical antipsychotic drug action proposed by Meltzer et al. postulated that atypical antipsychotic drugs had to have some D2 receptor blockade in vivo, although weaker than 5-HT2A receptor blockade, to achieve a low EPS profile and, possibly, some of the other advantages of clozapine. 


An exception to this may be amperozide, with is a potent 5-HT2A antagonist and DA reuptake inhibitor with very low affinity for the D2 receptor. Recently, NRA0045, which has potent 5-HT2A, D4, and  but no D2 or D3 receptor blockade has been found to have atypical antipsychotic properties. Partial DA agonists, which may act as agonists at presynaptic DA receptors, and antagonists at postsynaptic DA receptors are a new class of antipsychotic drugs that has promise. Cartmell et al., (2000).

However, clinical testing of these agents is just beginning, and current data support only the view that they are atypical in the classic sense, i.e., they are antipsychotic in preclinical or clinical testing at doses that produce weak or absent EPSs. Other evidence of the importance of antagonism for atypical antipsychotic drug activity will be discussed subsequently.

The in vitro affinity of a drug at the DA D2 receptor is a useful predictor of the dose that produces EPSs and control of positive symptoms for typical neuroleptic drugs, although it does not do so for some atypical antipsychotic drugs, e.g., ziprasidone. Furthermore, there is no agreement on how to determine the doses used in such correlations because of the differences in dosage requirements as a function of stage of illness, body mass index, and age. There is little agreement even on the best dose for haloperidol, the most widely used antipsychotic drug. A wide range of 2 to 15 mg/day has been suggested, far removed from the 20 to 40 mg/day thought to be most effective in 1966. To date, no clinically proven antipsychotic with the possible exception of amperozide lacks significant D2 receptor antagonist properties. 

As will be discussed, the combination of D2 and 5-HT2A receptor blockade, in the right ratio, produces some of the effects of clozapine and other atypical antipsychotic drugs in rodents, e.g., increases DA efflux in the cortex and striatum of rats and blockade of the conditioned avoidance response, an indication of antipsychotic activity. There have been only limited tests of this hypothesis in humans, mainly using ritanserin, which is a mixed 5-HT2A/2B/2C antagonist.
Nevertheless, various comprehensive reviews of the action of the atypical antipsychotic drugs have concluded that the combination of 5-HT2A, D2, and receptor blockade is the probable basis of their antipsychotic action. The evidence for this hypothesis will be discussed subsequently. Cartmell et al., (2000).

Counter to the hypothesis of the importance of 5-HT2A receptor antagonism to the action of clozapine and other atypical antipsychotic drugs is the proposal of Seeman and Tallerico and Kapur and Seeman that the basis of atypical antipsychotics may lie in their rapid dissociation from the DA D2 receptor and their relatively easily displacement by surges of endogenous DA. It has also been proposed that rapid and extensive displacement of clozapine and quetiapine from binding sites accounts for the reported low occupancy of striatal D2 receptors by these drugs. The authors also suggested that this might account for more rapid relapse following clozapine and quetiapine withdrawal. 

Although the evidence cited for clozapine-induced relatively rapid relapse is robust, the evidence with regard to quetiapine and rapid relapse has never been published and does not accord with general clinical experience. Seeman and Tallerico found that the affinity for and rate of dissociation of antipsychotics from the D2 receptor are highly correlated. Drugs with low affinity for the D2 receptor, e.g., clozapine and quetiapine, were found to have a higher dissociation rate constant than drugs with higher affinity, e.g., haloperidol. Rapid dissociation from the D2 receptor was reported to also permit easier displacement of clozapine and quetiapine by endogenous DA, thereby avoiding side effects related to DA receptor blockade such as EPSs and hyperprolactinemia. It was also reported that olanzapine, risperidone, and sertindole, all of which are well established as atypical antipsychotic drugs, are comparable comparable to haloperidol in their rate of dissociation from the D2 receptor and are not displaced by raclopride or iodobenzamide, as are clozapine and quetiapine. 

Thus, this hypothesis could not explain the basis for their low EPSs. Moreover, for these agents to achieve their antipsychotic action, they would have to be less easily displaced from limbic and possibly cortical D2 receptors. There are no data to support this selectivity with regard to displacement as yet. Although there is evidence for higher occupancy of extrastriatal D2 receptors by clozapine and quetiapine in patients with schizophrenia and for atypical antipsychotic drugs that show more potent 5-HT2A receptor blockade in rodents, the same appears to be true for olanzapine, which does not show the higher off-rates of clozapine and quetiapine (R. Kessler and H. Meltzer, in preparation). Because clozapine produces a greater increase in DA release in the cortex than in the accumbens or striatum, at least in rodents and monkeys, clozapine might be expected to produce greater occupancy of D2 receptors in these regions than the cortex, but, as noted above, this is not the case. 

It is also not clear how this model could explain any of the advantages of clozapine with regard to efficacy in neuroleptic-resistant patients or for cognition. (Cartmell et al., 2000). Studies on the regulation of prefrontal cortical or limbic DA release also provide no evidence that blockade of D2 receptors alone, regardless of degree of occupancy, can mimic the effects of the multireceptor antagonists such as clozapine. Pharmacologic analysis of this important model for the action of atypical antipsychotic drugs on cognition and negative symptoms strongly supports the importance of combined blockade of 5-HT2A, D2, and possibly receptors.
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