Deprivation State Switches the Neurobiological Substrates Mediating Opiate Reward in the Ventral Tegmental Area

Abstract

The population of mesolimbic dopaminergic neurons is believed to be a primary site at which opiates produce their rewarding effects. Using an unbiased, counterbalanced place conditioning paradigm, we reexamined the contribution made by these cells to the rewarding properties of morphine. Rats were conditioned such that distinct environments were paired with an intra-ventral tegmental area (VTA) microinfusion of either 500 ng per 0.5 microl per side morphine or 0. 5 microl per side sterile saline. Furthermore, rats were conditioned either previously drug-naive or while in a motivational state of opiate dependence and withdrawal. We report that pretreatment with the broad-spectrum dopamine antagonist alpha-flupentixol blocked the acquisition of conditioned place preferences for environments paired with morphine microinjections directly into the VTA in opiate-dependent and withdrawn, but not in previously drug-naive, rats. Lesions of the tegmental pedunculopontine nucleus (TPP) produced exactly the opposite pattern of results. TPP lesions blocked the acquisition of conditioned place preferences for environments paired with VTA morphine microinjections in previously drug-naive, but not in opiate-dependent and withdrawn, rats. These data double-dissociate two independent reward substrates within the VTA itself and suggest that deprivation state selects which of these two substrates will be active. Furthermore, these findings are the first to demonstrate a nondopaminergic substrate for reward within the VTA itself.