Pharmacological and genetic manipulations reveal the opposing roles of the dopamine D2 receptor and tegmental pedunculopontine nucleus in opiate and ethanol motivation

With occasional use, an addictive drug may cause appetitive effects that encourage the user to increase their exposure to the drug. With repeated use, a drug may cause a physiological state of dependence, inducing withdrawal when the drug is removed. Historically, dopamine (DA) was thought to mediate the motivational effects of all drugs of abuse, under all states of exposure, but recently dopamine-independent mechanisms of ethanol and opiate motivation have been demonstrated. Presently, the mechanisms that mediate ethanol motivation and the specific DA receptor systems that mediate opiate motivation remain unclear. My thesis elucidates the neural substrates mediating the motivational effects of opiates and ethanol and the conditions in which these substrates are critical.; Using dopamine D2 receptor wild type [D2R (+/+)] and knockout [D2R (−/−)] mice I demonstrated that the DA D2R system mediates opiate motivation when animals were in an opiate-dependent and withdrawn state but not when animals were previously opiate-naive (experienced only occasional exposure to the drug). To the contrary, the tegmental pedunculopontine nucleus (TPP) system was crucial for opiate motivation when animals were previously opiate-naive but not when they were opiate-dependent and in withdrawal. My analysis of mutant mice depended upon critical background controls. I demonstrated that a significant genetic presence from the 129 mouse strain reduced the ability to express opiate motivation.; Additionally, I investigated the motivational effects of ethanol in D2R (−/−) mice. The D2R was critical in mediating ethanol motivation when an animal experienced occasional ethanol exposure but not once the animal became ethanol-dependent and withdrawn, whereas the TPP system mediated ethanol motivation in ethanol-dependent and withdrawn, but not previously ethanol-naive, states.; The results suggest that there are dissociable and opposing roles of the DA D2 receptor and TPP systems in mediating opiate and ethanol motivation, and that their roles depend upon whether the individual experiences the drug in naive or dependent and withdrawn states. The dichotomy of opiate and ethanol motivation may be attributed to these drugs having contrasting actions on GABA-A receptor function, acting upstream, perhaps at the point of divergence, of the DA D2R and TPP motivation pathways.