Behavioral studies with anxiolytic drugs. V. Behavioral and in vivo neurochemical analyses in pigeons of drugs that increase punished responding

RS Mansbach, C Harrod, SM Hoffmann, MA Nader, Z Lei, JM Witkin and JE Barrett

Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

Behavioral and neurochemical effects of several drugs that increase punished responding were studied in pigeons. Key pecking was established under a schedule of reinforcement in which periods of food- maintained responding alternated with periods in which behavior also was suppressed by the presentation of electric shock. Buspirone (0.1- 10.0 mg/kg), gepirone (0.1-1.0 mg/kg), 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT; 0.1-3.0 mg/kg), chlordiazepoxide (3.0- 30.0 mg/kg) and to a lesser extent clozapine (0.1-1.0 mg/kg) all produced increases in punished responding at doses having little effect on or decreasing the rate of unpunished responding. Neurochemical analyses on samples of cerebrospinal fluid after administration of several doses of each compound were performed for the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), the noradrenergic metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). Gepirone, 8-OH-DPAT and the novel anxiolytic buspirone produced decreases in 5-HIAA at doses that increased punished responding in the behavioral studies. Buspirone increased levels of HVA and DOPAC, whereas its structural analog gepirone and the 5- hydroxytryptamine1A agonist 8-OH-DPAT had little effect on or decreased levels of these metabolites. Chlordiazepoxide, a prototypic benzodiazepine anxiolytic, produced only modest decreases in each of the metabolites studied. Clozapine, an atypical antipsychotic drug, produced increases in each of the metabolites studied, although only the 5-HIAA effect occurred at doses that were not behaviorally disruptive. Haloperidol (0.03-1.0 mg/kg) produced only decreases in punished and unpunished responding, whereas eliciting increases in the appearance of MHPG, DOPAC and HVA; levels of 5-HIAA were relatively unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 246, Issue 1, pp. 114-120, 07/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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