Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low- rate 72-second behavior

GJ Marek, AA Li and LS Seiden

University of Chicago, Department of Pharmacological and Physiological Sciences, Illinois.

Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5- HT2 antagonist methysergide and the 5-HT neurotoxin 5,7- dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n- propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m- trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.

Volume 250, Issue 1, pp. 60-71, 07/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				M. S. Cousins, G. Vosmer, D. H. Overstreet, and L. S. Seiden Rats Selectively Bred for Responsiveness to 5-Hydroxytryptamine1A Receptor Stimulation: Differences in Differential Reinforcement of Low Rate 72-Second Performance and Response to Serotonergic Drugs J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 104 - 113. [Abstract] [Full Text]

				M. Balcells-Olivero, M. S. Cousins, and L. S. Seiden Holtzman and Harlan Sprague-Dawley Rats: Differences in DRL 72-Sec Performance and 8-Hydroxy-Di-Propylamino Tetralin-Induced Hypothermia J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 742 - 752. [Abstract] [Full Text]