Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration

The present experiment examined whether ondansetron, co-administered with c ontinuous cocaine, would block the down regulation of accumbens 5-HT3 recep tors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg(-1) day(-1) cocaine or 0.9% saline via a su bcutaneously implanted osmotic minipump. In addition to the continuous coca ine or saline administration, all subjects received daily subcutaneous (s.c .) injections of either vehicle or 0.1 mg kg(-1) ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretre atment regimen for seven days, and slices from the nucleus accumbens obtain ed. The slices were perfused with 25 mM K+ in the absence and presence of 0 , 12.5, 25, or 50 mu M m-Chlorophenyl-biguanide HCl (mCPBG). The efflux sam ples were assayed for dopamine content by high pressure liquid chromatograp hy (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-induce dopa mine overflow compared to saline control rats. In addition, the rats that r eceived ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K+ stimulated dopamine release was not-signific antly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K+ stimulated dopamine releas e were Ca2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and that this down -regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT3 receptors represents a signif icant contribution to the tolerance induced by continuous cocaine administr ation. (C) 1999 Elsevier Science B.V. All rights reserved.