Roles of 5-HT 3 and opioid receptors in the ethanol-induced place preference in rats exposed to conditioned fear stress

Abstract

The effect of the selective 5-HT 3 receptor antagonist ondansetron on the ethanol-induced place preference in rats exposed to conditioned fear stress, which stimulates the release of endogenous opioid peptides (β-endorphin and enkephalins), was investigated using the conditioned place preference paradigm. In addition, we also examined the effect of ondansetron on the ethanol-induced place preference enhanced by the administration of μ- and δ-opioid receptor agonists (exogenous opioids). The administration of ethanol (300 mg kg , I.p.) induced a significant place preference in rats exposed to conditioned fear stress. Pretreatment with ondansetron (0.01 and 0.1 mg kg , S.c.) effectively attenuated this ethanol-induced place preference. When the μ-opioid receptor agonist morphine (0.1 mg kg , s.c.) or the selective δ-opioid receptor agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino [2,3,3-g] isoquinoline (TAN-67; 20 mg kg , s.c.) was administered in combination with 75 mg kg ethanol (which tended to produce a place preference), the ethanol-induced place preference was significantly enhanced. The selective μ-opioid receptor antagonist β-funaltrexamine at a dose of 10 mg kg significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Ondansetron (0.1 mg kg , s.c.) also significantly attenuated the enhancement of the ethanol-induced place preference produced by morphine. Furthermore, the selective δ-opioid receptor antagonist naltrindole at a dose of 3 mg kg significantly attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. Ondansetron (0.1 mg kg , s.c.) slightly, but significantly, attenuated the enhancement of the ethanol-induced place preference produced by TAN-67. These results suggest that 5-HT 3 receptors may be involved in the rewarding mechanism of ethanol under psychological stress, and may play an important role in the rewarding effect of ethanol through the activation of μ- and δ-opioid receptors.