Effects of serotonin receptor antagonists on PAG stimulation induced aversion: different contributions of 5HT1, 5HT2 and 5HT3 receptors

Abstract

The effects of serotonin receptor antagonists with differential selectivity for the various classes of 5HT receptors (5HT₁, 5HT₂ and 5HT₃) were tested for their effects on the response to aversive brain stimulation. Electrical stimulation was administered to the dorsal part of the periaqueductal gray matter (PAG), one of the main cerebral structures subserving negative reinforcement. Stimulation frequency thresholds for escape responses were recorded before and following administration of the compounds. Ketanserin (0.32–32 mg/kg IP), trazodone (1.0–22 mg/kg), pirenperone (0.032–1.0 mg/kg) and spiperone (0.1–0.2 mg/kg) dose-dependently increased stimulation frequency thresholds necessary to induce escape responses. Opposite effects were observed with mianserin (0.01–32 mg/kg) and metergoline (0.032–10 mg/kg) which decreased threshold for escape. ICS 205-930 (0.01–10 mg/kg), MDL 72222 (0.1 22 mg/kg) and GR 38032 F (0.1–10 mg/kg) did not affect the stimulation frequency threshold for escape. Prazosin (0.1–2.2 mg/kg) did not specifically affect aversive brain stimulation. Haloperidol (0.02–1.0 mg/kg) increased the frequency threshold for escape responses but with some motoric side effects. These data show that the various types of 5HT receptors differentially contribute to the control of central aversive systems in rats. It is suggested that blockade of 5HT₂ receptors suppresses the central aversive system, whereas blockade of some 5HT₁ receptors enhances aversion and overcomes the 5HT₂-mediated suppression. Blockade of 5HT₃ receptors has no effects. Dopamine receptor blockade further contributes to the suppression of the central aversive system. The relevance of these findings to some pathophysiological mechanisms of anxiety and depressive disorders is discussed.