The effects of continuous 5-HT(3) receptor antagonist administration on the subsequent behavioral response to cocaine.

A functional down-regulation of central serotonin3 (5-HT(3)) receptors represents a partial mechanism of the tolerance to cocaine induced by the continuous administration of cocaine. Blocking this down-regulation by co-administering continuous cocaine and daily injections of 5-HT(3) receptor antagonists blocks the development of tolerance. The present experiment evaluated the ability of continuously administered 5-HT(3) receptor antagonists, to induce sensitization (reverse tolerance) to the behavioral effects of cocaine, based on the hypothesis that chronic blockade of 5-HT(3) receptors should induce an up-regulation of these receptors. In all experiments, rats received a 14 day pretreatment involving the continuous administration of tropisetron (0.0, 1.0, 4.0, or 8.0 mg/kg/day) or LY 278584 (0.001, 0.01, or 0.1 mg/kg/day). The rats were withdrawn for 7 days from this pretreatment regimen. On day 7 of withdrawal from the pretreatment regiment, the rats received a 0.0, 7.5, or 15.0 mg/kg i.p. cocaine challenge. Ambulatory behavior was automatically recorded for 60 min. Both continuous tropisetron and LY 278584, opposite to the initial hypothesis, induced tolerance, and not sensitization, to the behavioral effects of cocaine. The results clearly indicate that central 5-HT(3) receptors are critical for the effects of chronic cocaine administration.