The overall objective of these studies is to understand how ethanol acts on brain areas involved in the mediation of reward, and to determine how specific neurotransmitter systems modify the action of ethanol on brain reward pathways. This knowledge might be exploited to develop drugs which reduce alcohol craving, leading to effective treatments for alcohol abuse. Recent studies have shown that serotonin (5-HT) reuptake inhibitors decrease alcohol abuse in problem drinkers. Although the reason for this is not clear, it is possible that 5-HT reuptake inhibitors act in brain areas involved in reward to reduce alcohol craving. One brain area shown to be important for mediating the rewarding effects of many drugs of abuse is the ventral tegmental area of Tsai (VTA). The VTA is the source of dopaminergic innervation to a number of brain areas (e.g., the nucleus accumbens and the prefrontal cortex) thought to be involved in the rewarding effects of drugs of abuse, and dopamine is an important neurotransmitter in reward. Intracellular and extracellular recording in rat brain slices will be used to assess the action of ethanol and 5-HT on dopaminergic neurons in the VTA. Slices (400 micromoles thick) will be mounted and totally submerged in the recording chamber. Ethanol will be applied in known concentrations in the bath. Ethanol, in concentrations within the behaviorally active range, causes excitation of dopaminergic VTA neurons. Our preliminary data indicates that 5-HT potentiates the excitatory effect of ethanol on some of these VTA neurons. The electrophysiological effects of 5-HT on dopamine-containing neurons of the VTA will be characterized in order to elucidate the mechanism by which 5-HT enhances ethanol-induced excitation in these neurons. Furthermore, the specific 5-HT receptor subtype(s) which mediate this potentiation will be identified. 5-HT reuptake blockers will be examined to determine if they also potentiate the effects of ethanol on VTA neurons, and whether potentiation by these agents is due to their action at serotonergic synapses. In addition, inbred strains of rats (Lewis and Fisher 344) which differ in voluntary EtOH intake will be used to determine whether the sensitivity of VTA neurons to 5-HT potentiation of EtOH excitation is correlated with a genetic predisposition to drink more or less EtOH. Ultimately, these studies may provide a rationale for the efficacy of 5-HT reuptake inhibitors in reducing alcohol abuse, and might also provide a basis for the development of more selective 5-HT-related drugs which would be useful in the treatment of uncontrolled ethanol intake.
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