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place preferences for environments paired with morphine microinjections directly into the VTA in opiate-dependent and withdrawn, but not in previously drug-naive, rats.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for environments paired with VTA morphine microinjections in previously drug-naive, but not in opiate-dependent and withdrawn, rats.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.

Fig. 1.

A photomicrograph of a Nissl-stained coronal section showing representative cannulae placements into the VTA.

Fig. 2.

The effects of saline or α-flupentixol pretreatment on the absolute times spent in environments paired with intra-VTA injections of either 500 ng per 0.5 μl per side morphine or 0.5 μl per side saline in separate groups of animals that were trained (A) previously drug-naive or (B) in a state of opiate dependence and withdrawal. Data are represented as mean ± SEM.

Fig. 3.

The effects of saline or α-flupentixol pretreatment on the absolute times spent in environments paired with intra-VTA injections of either 500 ng per 0.5 μl per side morphine or 0.5 μl per side saline in animals that were initially trained previously drug-naive (A) and then subsequently retrained while in a state of opiate dependence and withdrawal (B). Data are represented as mean ± SEM.

Fig. 4.

A, Photomicrograph of a Nissl-stained coronal section showing the extent (arrows) of a representative bilateral ibotenic acid induced lesion of the TPP. B, Higher-magnification photomicrograph of the left side of the ibotenic acid-induced lesion shown in A. The extent of the lesion is indicated byarrows, whereas a healthy neuron is indicated by anarrowhead. C, High-magnification photomicrograph of the left side of a sham lesion.

Fig. 5.

A schematic representation of the size and extent of the ibotenic acid lesions of the ventromedial TPP. Thefilled-in areas represent the volume of the smallest lesion. The open outlined areas represent the volume of the largest lesion. The numbers to theright indicate the distance caudal from Bregma in millimeters.

Fig. 6.

The effects of bilateral sham or ibotenic acid lesions of the TPP on the absolute times spent in environments paired with intra-VTA injections of either 500 ng per 0.5 μl per side morphine or 0.5 μl per side saline in separate groups of animals that were trained (A) previously drug-naive or (B) in a state of opiate dependence and withdrawal. Data are represented as mean ± SEM.