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BEHAVIORAL PHARMACOLOGY

Induction by Antipsychotics of "Win-Shift" in the Drug Discrimination Paradigm

Centre de Recherche Pierre Fabre, Castres Cedex, France (F.C., J.B.); Department of Psychiatry, Alcohol and Drug Addiction Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas (W.K.); and Yaupon Therapeutics Inc., Radnor, Pennsylvania (M.K.)

In a two-lever, food-rewarded drug discrimination paradigm, behavior seems to be governed by a win-stay/lose-shift rule; rats continue to press the lever that yields food, and, when not rewarded, they shift responding to the alternative lever. Here, we report on the effects that antipsychotics and further neuropharmacological agents exert in those conditions. At higher doses, antipsychotics disrupt most or all behavioral parameters in this paradigm. However, at lower doses, rats may select the appropriate lever with normal latency and accuracy, obtain a first food pellet (i.e., "win"), and then, remarkably, shift responding to the alternative lever ("win-shift"). This suggests that antipsychotics can block the effects of reward selectively, i.e., at doses where the initial, secondarily reinforced behavior including the initiation of lever pressing, remains intact. Indeed, saline-treated rats that are given no reward (i.e., "lose") after having selected a lever, also press the alternative lever ("lose-shift"). The induction of selective win-shift is specific to antipsychotics, but it varies greatly among them. Perhaps relating to its alleged "incisive" action on delirium and hallucinations, and, surprisingly, in view of its extrapyramidal actions, acutely administered haloperidol (0.04–0.08 mg/kg) demonstrates win-shift to an exceptional extent, shared only with the newly proposed agent (3-cyclopent-1-enyl-benzyl)-[2-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)-ethyl]-amine fumarate (F 15063; 0.31–0.63 mg/kg); the more sedative antipsychotic chlorpromazine demonstrated little selectivity. The paradigm offers a novel tool to characterize antipsychotics with regard to presumably pathogenic motivational processes; mixed D₂-antagonist/5-hydroxytryptamine_1A-agonist agents such as F 15063 may conceivably share the powerful antipsychotic action of haloperidol while avoiding the sensitization that develops to extrapyramidal effects of haloperidol and consequent negative symptoms.

Address correspondence to: Dr. Francis C. Colpaert, Centre de Recherche Pierre Fabre, 17, avenue Moulin, F-81106 Castres Cedex, France. E-mail: francis.colpaert{at}pierre-fabre.com