Neuropeptide Y system in accumbens shell mediates ethanol self-administration in posterior ventral tegmental area : AcbSh NPY in ethanol reward

In unanesthetized rats the intravenous administration of low doses of ethanol (0.125-0.5 g/kg) produced a dose-dependent increase (30-80%) in the firing rate of dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA). In agreement with previous observations, a dose range between 0.5 and 2 g/mg of ethanol was needed to produce comparable stimulant responses in DA neurons of the Substantia Nigra Pars Compacta. However, in anesthetized rats, doses of ethanol up to 1 g/kg failed to activate VTA-DA neurons. The high sensitivity of VTA-DA neurons to ethanol activation suggests that they might be involved in the reinforcing properties of the drug.

Intracranial self-administration (ICSA) and intracranial place conditioning (ICPC) methodologies have been mainly used to study drug reward mechanisms, but they have also been applied toward examining brain reward mechanisms. ICSA studies in rodents have established that the ventral tegmental area (VTA) is a site supporting morphine and ethanol reinforcement. ICPC studies confirmed that injection of morphine into the VTA produces conditioned place preference (CPP). Further confirmation that activation of opioid receptors within the VTA is reinforcing comes from the findings that the endogenous opioid peptide met-enkephalin injected into the VTA produces CPP, and that the mu- and delta-opioid agonists, DAMGO and DPDPE, are self-infused into the VTA. Activation of the VTA dopamine (DA) system may produce reinforcing effects in general because (a) neurotensin is self-administered into the VTA, and injection of neurotensin into the VTA produces CPP and enhances DA release in the nucleus accumbens (NAC), and (b) GABA(A) antagonists are self-administered into the anterior VTA and injections of GABA(A) antagonists into the anterior VTA enhance DA release in the NAC. The NAC also appears to have a major role in brain reward mechanisms, whereas most data from ICSA and ICPC studies do not support an involvement of the caudate-putamen in reinforcement processes. Rodents will self-infuse a variety of drugs of abuse (e.g. amphetamine, morphine, phencyclidine and cocaine) into the NAC, and this occurs primarily in the shell region. ICPC studies also indicate that injection of amphetamine into the shell portion of the NAC produces CPP. Activation of the DA system within the shell subregion of the NAC appears to play a key role in brain reward mechanisms. Rats will ICSA the DA uptake blocker, nomifensine, into the NAC shell; co-infusion with a D2 antagonist can block this behavior. In addition, rats will self-administer a mixture of a D1 plus a D2 agonist into the shell, but not the core, region of the NAC. The ICSA of this mixture can be blocked with the co-infusion of either a D1 or a D2 antagonist. However, the interactions of other transmitter systems within the NAC may also play key roles because NMDA antagonists and the muscarinic agonist carbachol are self-infused into the NAC. The medial prefrontal (MPF) cortex supports the ICSA of cocaine and phencyclidine. The DA system also seems to play a role in this behavior since cocaine self-infusion into the MPF cortex can be blocked by co-infusing a D2 antagonist, or with 6-OHDA lesions of the MPF cortex. Limited studies have been conducted on other CNS regions to elucidate their role in brain and drug reward mechanisms using ICSA or ICPC procedures. Among these regions, ICPC findings suggest that cocaine and amphetamine are rewarding in the rostral ventral pallidum (VP); ICSA and ICPC studies indicate that morphine is rewarding in the dorsal hippocampus, central gray and lateral hypothalamus. Finally, substance P mediated systems within the caudal VP (nucleus basalis magnocellularis) and serotonin systems of the dorsal and median raphe nuclei may also be important anatomical components involved in brain reward mechanisms. Overall, the ICSA and ICPC studies indicate that there are a number of receptors, neuronal pathways, and discrete CNS sites involved in brain reward mechanisms.

Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol-sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA-A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin-releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.