The central nervous system mechanisms that control the subjective effects of alcohol are not well characterized. Research has implicated ligand- gated ion channels, particularly GABA/A and NMDA receptor systems, in producing the discriminative stimulus properties of ethanol. Pilot data indicate that centrally administered ethanol partially generalizes to, and augments, the systemically administered ethanol discriminative stimulus. However, the brain regions and neurochemical systems involved in this process have not been studied. The limbic system has been implicated in reinforcement by many drugs, and in discrimination of cocaine, amphetamine, and benzodiazepines. This suggests that the reinforcing and subjective effects of these drugs may be mediated by the same neural systems. Our research has shown that a portion of this system is involved in ethanol reinforcement. The overall aim of this proposal is to examine the involvement of 1) the direct actions of ethanol, and 2) GABA/A and NMDA neurotransmission in specific regions of the limbic system in the discriminative stimulus effects of ethanol.
Two specific aims, using microinjection techniques and procedures common to the behavioral analysis of drug discrimination, are proposed to address this question.
Specific Aim 1 will determine the role of limbic brain regions in ethanol discrimination by testing whether ethanol administered into the 1) medial prefrontal cortex, 2) amygdala, 3) hippocampus, or 4) nucleus accumbens will substitute for and/or augment the discriminative stimulus produced by systemic ethanol administration. These studies will provide a test of whether the direct actions of ethanol in limbic brain regions contribute to its discriminative stimulus properties. Because GABA/A and NMDA neurotransmitter systems are known to be involved in ethanol discrimination.
Specific Aim 2 will determine the role of these transmitters in limbic brain regions in determining the discriminative stimulus effects of ethanol. These studies will test (1) whether GABA/A agonist or NMDA antagonist injections in limbic regions will substitute for systemically administered ethanol, (2) if GABA/A antagonist or an NMDA agonist injections will block the discriminative stimulus properties of systemically administered ethanol. Finally, because ethanol has simultaneous effects on both GABA and NMDA systems, studies will also be conducted to test the ability of combinations of GABA/A and NMDA drugs, administered into limbic regions, to substitute for or block the ethanol discriminative stimulus.
Showing the most recent 10 out of 21 publications
