Neuroleptics receptor antagonism

Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. 

Using PET, Farde et al. found that D2 receptor occupancy in schizophrenic patients was reduced by 20-67% of the pretreatment levels in those successfully treated with clozapine. It was reduced to 80-90% of original values that occurred with other typical neuroleptics. He concluded that D2 receptor antagonism alone does not explain the efficacy of clozapine therapy. At low doses (125-172 mg/day), clozapine occupied more than 80% of 5-HT 2A receptors. 

Its activity at Di receptors has been put forward as a possibility and although it has a relatively higher affinity for Di than Dj receptors, compared with typical neuroleptics, it is still a weak antagonist at both and in the absence of evidence for Di (or D5) receptor involvement in schizophrenia the significance of any Di antagonism is unclear. 

Refractory cases respond to clozapine. If D2 antagonism is considered necessary, or at least desirable, for counteracting positive symptoms it is surprising that a relatively weak D2 antagonist like clozapine should not only be so effective but also prove successful in patients who have not responded to other neuroleptics more potent at D2 receptors. 

Unfortunately although much is known about the pathways and receptors involved in extrapyramidal activity and the mechanism of the EPSs that follow neuroleptic therapy and even the possible origin of negative symptoms in the prefrontal cortex, the precise site of origin and NT involvement in the overriding positive symptoms is less clear. Until that is corrected, permutations of NT antagonisms are likely to multiply with the neuroleptics. 

On this evidence one can confidently equate EPS with neuroleptic DA receptor (D2) antagonism in the striatum and possibly a reduction in the positive symptoms of schizophrenia through similar action in the limbic system (nucleus accumbens). 

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... 

Richelson E, Nelson A Antagonism by neuroleptics of neurotransmitter receptors of normal brain in vitro. Eur J Pharmacol 103 197-204, 1984 Rickels K, Schweizer E The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry 54 [suppl) 20-23, 1993 Rickels K, Weisman K, Norstad N, et al Buspirone and diazepam in anxiety a controlled study. J Chn Psychiatry 43(12 pt 2) 81-86, 1982 Rickels K, Feighner JP, Smith WT Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42 134-141, 1985 Rickels K, Schweizer E, Weiss S, et al Maintenance drug treatment for panic disorder, 11 short- and long-term outcome after drug taper. Arch Gen Psychiatry 50 61-68, 1993... 

The role of these agents, either as primary or adjunctive treatments for mood disorders, has yet to be fully explored ( 106, 108, 279, 280 and 281). Theories have included the differential effects of clozapine on dopamine receptor subtypes (e.g., increased activity at the receptors, which exist in high density in the limbic system) and the greater 5-HT2 to D2 antagonism of most novel agents in comparison with neuroleptics (282). More recently, controlled trials indicate that novel antispychotics (NAPs) may play an important and perhaps unique role for more severe, psychotic, and/or refractory mood disorders ( 112, 283, 384). 

Cessation of impulse flow in dopaminergic neurons can be achieved by administration of gammabutyrolactone (GBL). In the presence of a dopa decarboxylase inhibitor this induces an accumulation of DOPA. Administration of dopamine receptor agonists decreases this accumulation of DOPA, an affect which can be antagonized by pretreatment with neuroleptics (recently reviewed by Roth, 109). 

Systemical or intranigral application of dopamine receptor agonists depresses the firing of nigrostriatal dopamine cells by stimulating soma-dendritic autoreceptors in the zona compacta, an effect again antagonized by neuroleptics (110, 111, 112). ... 

---