Alteration of dopamine receptor sensitivity by opiates and the subsequent effect of this alteration on opiate tolerance and dependence

The present study was undertaken to determine whether there is an alteration of dopamine receptor sensitivity following opiate administration, and whether this alteration has any influence on the development of opiate tolerance and dependence. Behavioral hypersensitivity to direct-acting dopamine agonists was observed in mice following acute or chronic morphine administration. Acute levorphanol administration also resulted in potentiation of dopamine agonist-induced behaviors. An increase in density of dopamine receptors, as measured by [3H]butyrophenone binding accompanied the development of behavioral hypersensitivity. This increase was localized to the striatum, an area important in the mediation of dopamine-agonist induced behaviors. Naloxone or LiCl coadministered with the opiates prevented the development of hypersensitivity and the increase in density of dopamine receptors. Coadministration of lithium enhanced the development of acute and chronic tolerance. Lithium enhanced the development of dependence as determined by naloxone-induced hypothermia in chronically morphine-treated mice. Apomorphine enhanced naloxone-induced withdrawal in acutely dependent mice. This enhancement was blocked by coadministration of lithium with the opiates. These results suggest that dopamine receptor supersensitivity influences the degree of tolerance and dependence