Involvement of beta-endorphin and mu-opioid receptors in mediating the aversive effect of lithium in the rat.

The role of beta-endorphin and mu-opioid receptors in mediating the motivational effect of lithium was examined by use of an unbiased place-preference conditioning procedure. Administration of lithium to drug-naive rats resulted in a dose-related aversion for the drug-associated place. Radiofrequency lesions of the medio-basal arcuate hypothalamus, which markedly reduced the levels of immunoreactive beta-endorphin in the hypothalamus, abolished the lithium-induced aversion. However, suppression of circulating beta-endorphin levels by chronic dexamethasone treatment was without effect. Infusion of the opioid antagonist, naloxone, throughout the conditioning procedure at a dose (0.5 mg/kg per h) that blocks mu- but not kappa-opioid receptors, resulted in the complete abolition of the lithium-induced place aversion. These data demonstrate an involvement of endogenous opioidergic systems in the motivational effect of lithium and indicate that the aversive properties of this drug result from its interactions with beta-endorphin and mu-opioid receptors in the CNS.