The projects in this proposal are designed to elucidate the role of serotonin-1B (5-HT1B) receptors in the mediation of ethanol reinforcement. Ethanol is known to interact with the serotonin (5-HT), dopamine, GABA and glutamate neurotransmitter systems, and each of these are believed to be involved in the production of the reinforcing effects of this widely abused drug. It is hypothesized that 5-HT1B receptors play a pivotal role in regulating the interactions among these four neurotransmitters in brain reward circuitries which are believed to mediate ethanol reward. The proposed experiments will employ behavioral and neurochemical strategies in rats to study the role of 5HT1B receptors in the regulation of ethanol self-administration, and to identify the specific neural mechanisms through which 5HT1B receptors exert their effect on ethanol consumption.
In Specific Aim I, the effects of 5HT1B receptor manipulations on oral ethanol self-administration under both fixed ratio and progressive ratio schedules of reinforcement will be examined. In these experiments, 5HT1B receptor-selective drugs will be administered both peripherally to assess the effects of global 5HT1B receptor manipulations on ethanol reinforcement, and locally into discrete brain regions to identify relevant substrates and circuitries through which 5-HT1B receptors regulate ethanol reward. Brain regions to be investigated include the ventral tegmental area nucleus accumbens, basolateral amygdala and prefrontal cortex.
Specific Aim II will employ in vivo microdialysis to investigate the neurotransmitter mechanisms involved in the modulation of ethanol reinforcement by 5-HT1B receptors. As in the first Specific Aim, 5-1HT1B receptor-selective drugs will be administered both peripherally to assess the effects of global 5-HT1B receptor manipulations on the neurochemical response to ethanol, and locally into the brain regions listed above to investigate the specific circuitries through which 5-HT1B receptors regulate ethanol reinforcement. The results of these experiments will provide new insight into this novel receptor system as a mechanism for modulating the motivational effects of alcohol. Because rat 5-HT1B receptors are homologous to human 5-HT1Dbeta receptors, the information gained in these experiments will have direct relevance for the neurobiological mechanisms of ethanol reinforcement in humans, and may have implications for the development of pharmacotherapeutic treatments of alcoholism.
