Grant: Operating Grant

Opiates are abused drugs that activate midbrain dopamine neurons indirectly via opioid receptors. Opioid receptors are associated with non-dopamine neurons, however, so how opiates cause abuse has not been clear. Ethanol abuse is treated by the opiate receptor blocker naltrexone in humans, suggesting shared mechanisms for opiate and ethanol drug choices. Morphine's activation of dopamine output in the nucleus accumbens was blocked by lesions of midbrain cholinergic neurons, by muscarinic receptor blockers, or by knockout of the M5 muscarinic receptor gene expressed by dopamine neurons. Furthermore, mice lacking the M5 muscarinic receptor showed less morphine-induced locomotion, drank less ethanol in two-bottle choice tests than wild type mice, and were less sensitive to the opioid receptor antagonist naltrexone in both tasks. M5 knockout males also showed fewer courtship calls during mating, but these were not affected by naltrexone. We propose to reverse these opiate sensitivity deficits in M5 knockout mice in three different ways: 1) By adding the M5 muscarinic receptor gene into dopamine neurons using the herpes simplex virus. 2) By infusing the growth factor BDNF into the same midbrain area to induce an opiate-dependent-like state. 3) By long-term opiate or ethanol exposure followed by withdrawal. The effects of these procedures on morphine-induced locomotion, ethanol preference, courtship calls in sex, and dopamine output will be measured in knockout and wild-type mice, to better understand dopamine-related changes in opiate and ethanol dependence. These studies will help us understand how the midbrain changes in opiate addiction, and how naltrexone works to treat alcoholism.