Cellular Mechanisms of Intoxication
The action of alcohol at the cellular level is based on the premise that alcohol has a specific action on synaptic transmission, and the synapse is hypothesized to be one of the most sensitive sites for alcohol’s action. This hypothesis originated in part from early electrophysiological studies that showed a greater effect of alcohol in multisynaptic pathways than in monosynaptic pathways. Cellular studies of brain slices of the ventral striatum and extended amygdala supported this hypothesis. The neurotransmitter systems that have been the most studied at the cellular level are GABA and glutamate. For example, in the extended amygdala, alcohol has been shown to directly facilitate GABA function by enhancing GABA release in rats and mice. In contrast, alcohol has powerful glutamate antagonist effects.
Alcohol at intoxicating doses also activates neurons in the ventral tegmental area. At least part of this activation was shown to occur via a direct action on dopaminergic neurons in the ventral tegmental area. Acetaldehyde, a product of alcohol metabolism, also activates dopamine neuronal activity in the ventral tegmental area and may contribute to the reinforcing effects of alcohol. Other studies have identified non-dopaminergic, alcohol-sensitive neurons in the ventral tegmental area, including GABA neurons. Acute alcohol administration at doses within the intoxicating range decreased the spontaneous activity of ventral tegmental area GABAergic neurons, suggesting the possibility of both disinhibitory mechanisms and direct effects on dopaminergic neurons.
Figure 6.12 (A) Effects of oral alcohol self-administration on dopamine release in the nucleus accumbens in genetically heterogeneous Wistar rats (n = 11) and alcohol-preferring (P) rats (n = 9). Data from both strains are contrasted against the same control group (n = 9), consisting of alcohol-naive Wistar and P rats trained to respond for water only. Alcohol significantly increased dopamine release in both groups of rats (Wistar rats: ∗p < 0.01; P rats: ∗p < 0.05, ∗∗p < 0.01). The insets show the mean ± SEM alcohol intake per 5 min interval. (B) Dopamine release in the nucleus accumbens in Wistar rats (n = 4) and P rats (n = 4) that responded to saccharin reinforcement. The data for both strains are contrasted against the same control group that consisted of saccharin-naive Wistar and P rats trained to respond for water. Saccharin produced only negligible increases in dopamine efflux compared with alcohol. These data show that alcohol self-adminstration in rats can increase the release of dopamine in the nucleus accumbens, an effect produced by its pharmacological effects. Notice, however, that the increase in the release of dopamine was greater in the alcohol-preferring rats than in the outbred Wistar strain of rats. Saccharin produced similar amounts of self-administration and had no significant effect on dopamine release in the nucleus accumbens. [Taken with permission from Weiss F, Lorang MT, Bloom FE, Koob GF. Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants. Journal of Pharmacology and Experimental Therapeutics, 1993, (267), 250–258.].