Effects of selective 5-hydroxytryptamine-2 and nonselective 5-hydroxytryptamine antagonists on the...

The effects of antidepressant drugs, administered with and without a 5-hydroxytryptamine (5-HT) antagonist that is not selective for 5-HT receptor subtypes, were assessed in rats responding under a differential-reinforcement-of-low-rate 72-second (DRL 72-s) schedule of reinforcement. The increases in reinforcement rate seen after low dose tricyclic antidepressant drug administration were antagonized by the 5-HT antagonist methysergide. Methysergide did not antagonize either the increases in reinforcement rate or the decreases in response rate induced by the atypical antidepressant trazodone or the putative antidepressant clenbuterol. In addition, the effects of 5-HT receptor antagonists with varying selectivity for the 5-HT2 relative to the 5-HT1 receptor subtypes were assessed when administered alone. The rank order potency series for the maximal increase in the reinforcement rate after administration of the 5-HT antagonists was ketanserin greater than pipamperone greater than trazodone greater than cyproheptadine greater than cinanserin greater than metergoline greater than methysergide, in close agreement with the selectivity of these drugs for the 5-HT2 relative to the 5-HT1 receptor subtypes. In addition, the specificity of the DRL 72-s schedule was further assessed with the alpha adrenergic antagonists phentolamine and phenoxybenzamine which both decreased the response rate but did not increase the reinforcement rate as do antidepressant drugs. These results suggest that the therapeutic effect of atypical antidepressants such as trazodone and mianserin may be related to selective antagonism of 5-HT2 receptors. Furthermore, agonist action at a 5-HT1 receptor and antagonist action at 5-HT2 receptors both appear to contribute to antidepressant-like activity on the DRL 72-s schedule.