Potentiation by α‐Methyltyrosine of the Suppression of Food‐Reinforced Lever‐Pressing Behaviour Induced by Antipsychotic Drugs

Abstract

The mode of action whereby .alpha.-methyltyrosine (.alpha.-MT) potentiates the behavioral effects induced by catecholamine receptor blocking antipsychotic drugs was investigated in rats trained to lever-press for food on a fixed-ratio 40 schedule of reinforcement. .alpha.-MT (20 mg/kg i.p., 4 h) potentiates the effects induced by pimozide (0.04 mg/kg i.p., 6 h) which preferentially blocks central dopamine (DA) receptors, but not the effects induced by phenoxybenzamine (0.5 mg/kg i.p., 30 min.) which blocks central noradrenaline (NA) receptors. The behavioral suppression induced by chlorpromazine (0.5 mg/kg i.p., 15 min.), thioridazine (1.5 mg/kg i.p., 15 min.), or haloperidol (0.02 mg/kg i.p., 15 min.) were not potentiated by the administration of the inhibitor of DA-.beta.-hydroxylase, bis-(4-methyl-1-homopiperazinylthiocarbonyl) disulfide (FLA-63) (4 mg/kg s.c., 1 h). The potentiation by .alpha.-MT of the clinical effects of antipsychotic drugs and of their behavioral effects in animals experiments is in all probability due to a blockade by .alpha.-MT of a feedback mediated compensatory increase in the catecholamine synthesis as a result of a blockade of central NA and/or DA receptors by the antipsychotic drugs. Since, in the present experiments, the behavioral effects induced by drugs which block central DA but not NA receptors were potentiated by the simultaneous administration of .alpha.-MT, it seemed probable that the disruption of conditioned behaviors by antipsychotic drugs is due to a blockade of central DA receptors. In view of the fact that the ability to selectively disrupt conditioned behaviors is shared by a wide range of antipsychotic drugs differing in chemical structure and also in their mode of action, it is possible that a blockade of DA neurotransmission is also of primary importance for the clinical effects induced by antipsychotic drugs.