Sarah B. Appel

Ethanol effects on dopaminergic "reward" neurons in the ventral tegmental area and the mesolimbic pathway

Dopaminergic (DA) neurons in the ventral tegmental area (VTA) provide the DA innervation of the nucleus accumbens. This mesolimbic DA pathway is important for the reinforcing effects of alcohol and plays a central role in alcohol-related behaviors. This Research Society on Alcoholism symposium included a discussion of the acute and chronic effects of ethanol and ethanol withdrawal on DA VTA neurons. The experiments that were discussed ranged from studies in the freely moving behaving rat and electrophysiological studies in vivo, to electrophysiological studies in brain slices and acutely dissociated DA VTA neurons, to neurochemical studies that explored the cellular basis of ethanols actions. Because ethanols effects on this reinforcement pathway are critically important for voluntary intake of alcohol and alcohol addiction, this symposium report may be of interest to both basic science and clinical researchers in the alcohol field. This symposium focused on effects of ethanol on the mesolimbic dopamine pathway, specifically the VTA and the nucleus accumbens. The organizer/co-chairs were Sarah B. Appel and Mark S. Brodie. The presentations were (1) Introduction, by Mark S. Brodie; (2) Reinforcing Actions of Alcohol in the Ventral Tegmental Area: Intracranial Self-Administration Studies, by William J. McBride; (3) A Possible Mechanism Mediating the Direct Excitation of Dopaminergic Ventral Tegmental Area Neurons by Ethanol, by Sarah B. Appel; (4) Effect of Chronic Ethanol and Withdrawal on Dopaminergic Ventral Tegmental Area Neurons: In Vivo Electrophysiological Studies, by Marco Diana; (5) Ethanol Induces Protein Kinase A Translocation Into the Nucleus, Cyclic AMP Response Element Binding Protein Phosphorylation, and Increases in Cyclic Adenosine Monophosphate–Dependent Gene Expression, by Ivan Diamond; and (6) Co-activation of Dopamine D1 and D2 Receptors Is Necessary for Dopamine-Mediated Increases in Firing Activity in Nucleus Accumbens Neurons, by Antonello Bonci.

The effects of long chain-length n-alcohols on the firing frequency of dopaminergic neurons of the ventral tegmental area

The dopaminergic neurons of the ventral tegmental area (DA VTA neurons) have been implicated in the reinforcing properties of drugs of abuse, including ethanol (ethyl alcohol). Ethanol increases the spontaneous firing frequency of DA VTA neurons in vitro, in both brain slices and acutely dissociated neurons, and also in vivo. In many systems, longer n-alkyl alcohols have a more potent effect than ethanol, and the potency is a function of the number of carbons in the alkyl chain. We studied n-alcohols of chain length 1 (methanol) to 5 (pentanol) on the firing rate of DA VTA neurons in brain slice preparations. All of the alcohols studied produced increases in the spontaneous firing frequency in DA VTA neurons; as the chain length increased, lower concentrations of the alcohols were needed to produce the same percentage increase in firing. With very high concentrations of all the alcohols except methanol, we observed apparent depolarization block of firing. In addition, trichloroethanol (TCE), the active metabolite of chloral hydrate, increased the firing frequency of DA VTA neurons, and the EC40 (concentration to produce a 40% increase in firing rate) of TCE was below that of ethanol. These studies indicate that excitation of VTA dopamine neurons by n-alcohols is related to the chain length of the carbons. This is likely to be a characteristic of the ethanol-sensitive element of DA VTA neurons and may be useful in identifying the element of the membrane that is responsible for ethanol-induced excitation.