Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

Abstract

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism?Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions.As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.

Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy

“…Thirty years after the description of a direct linear correlation between dopamine (DA) D 2 receptor-binding affinities and antipsychotic drug potencies for ameliorating psychosis (Seeman et al, 1976;Creese et al, 1976), this association remains an important cornerstone of current hypotheses of both the etiology and treatment of psychotic disorders (Emilien et al, 1999;Seeman, 2002;Seeman and Tallerico, 1998). However, over the past quarter century significant advances have been made in expanding our understanding of receptor-binding affinities and clinically effective drug dosages for a steadily expanding list of antipsychotic medications.…”

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

“…The rationale behind the development of compounds interacting with D 3 receptor remains intriguing according to preclinical and clinical data. Firstly, all antipsychotics are D 2 /D 3 antagonists with limited binding preferences at D 2 receptor (Leysen et al, 1993;Schwartz et al, 2000;Seeman and Tallerico, 1998). Secondly, D 3 receptors have been implicated in behavioral sensitization, which could be a potential contributor to the pathogenesis of schizophrenia (Glenthoj and Hemmingsen, 1997;Guillin et al, 2001;Lieberman et al, 1997;Pilla et al, 1999;Richtand et al, 2001).…”

Is Neuroleptic Dysphoria a Variant of Drug-Induced Extrapyramidal Side Effects?

“…A review of the concept of atypicality and the proposed mechanisms of action of secondgeneration antipsychotic drugs may provide some clues toward their low dysphoria liability and improved tolerability. The "dopaminergic" theories of atypicality are based on the following themes: the extent of dopamine D 2 receptor blockade (27,28); the degree of affinity of drug molecules to D 2 receptors (29,30); the contribution of other dopamine receptors, such as D 1 , D 3 , and D 4 , toward subjective attributes such as sensation-seeking behaviour (31); prefrontal dopamine release, either through serotonergic action or independently (32); and selective dopaminergic blockade in the shell of the nucleus accumbens that does not affect the core (33). The original speculation was that the ratio of D 2 and 5-HT 2 receptor blockade is crucial in determining EPSE liability or the lack of it (28,34).…”