Small Animal Model for Evaluating Neuroleptic Potency

Abstract

The prolactin response in the rat is proposed as a convenient and inexpensive test system for the assessment of the clinical potency of neuroleptic agents. Times of maximum elevation (p < 0.01) of serum prolactin levels were determined by a one-way analysis of variance and the Newman-Keuls test for a period of 180min following intraperitoneal administration of chlorpromazine hydrochloride, fluphenazine hydrochloride, perphenazine, prochlorperazine edisylate, and trifluoperazine hydrochloride (phenothiazines); haloperidol (a butyrophenone); chlorprothixene (a thioxanthene); loxapine succinate (a dibenzoxazepine); and molindone hydrochloride (a dihydroindolene). Maximum serum prolactin elevations occurred as follows: chlorpromazine hydrochloride, 30-90 min; chlorprothixene and trifluoperazine hydrochloride, 30-150 min; fluphenazine hydrochloride, 90-150 min; haloperidol, 90 min; loxapine succinate, 30 min; molindone hydrochloride, 30 and 60 min; and perphenazine and prochlorperazine edisylate, 30-180min. For drugs that exhibited statistically indistinguishable maximum serum prolactin elevations at more than one sampling time, one of these times was selected arbitrarily for construction of a log dose-prolactin response curve. Log dose-serum prolactin curves were constructed at a time of maximum serum prolactin elevation for each drug. Thirty minutes was utilized for loxapine succinate and molindone hydrochloride, and 90min was used otherwise. These curves were nearly parallel, and each had an excellent linear fit Based on these curves, the ratio of the weights of the neuroleptic and chlorpromazine hydrochloride required to produce the same prolactin-stimulating potency was determined for each drug. This ratio was compared to the clinically accepted ratio of the weights of the neuroleptic and chlorpromazine hydrochloride required to produce the same antipsychotic potency. This technique demonstrated a close correlation between the prolactin-stimulating potencies of neuroleptics in rats and accepted antipsychotic potency relationships in humans.