Gamma-amino butyric acid (GABA) is the major inhibitory neurotransmitter in the brain. It has been theorized for many years that the depressant effects of ethanol could be mediated by enhancement of the effects of GABA. The action of GABA at the GABA alpha receptor is modulated by benzodiazepines as well as barbiturates, suggesting that this receptor system may be involved in the anxiolytic and sedative/hypnotic responses to ethanol. Several early studies indicated that the motor-coordinating and hypnotic effects of ethanol could be increased by the administration of GABA agonists and attenuated by GABA antagonists. Tobacco and alcohol are often co-abused producing interactive effects in the brain. Although nicotine enhances memory while ethanol impairs it, variable cognitive changes have been reported from concomitant use. This study was designed to determine how nicotine and alcohol interact at synaptic sites to modulate neuronal processes. Acute effects of nicotine, ethanol, and both drugs on synaptic excitatory glutamate and inhibitory GABA transmission were measured using whole-cell recording in hippocampal CA1 pyramidal neurons from brain slices of mice on control or nicotine-containing diets. Acute nicotine (50 nM) enhanced both GABA and glutamate synaptic transmission; potentiated GABA receptor currents via activation of nAChRs, and increased N-methyl- d-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor currents through α7* receptors. While ethanol (80 mM) also increased GABA currents, it inhibited NMDA currents. Although ethanol had no effect on AMPA currents, it blocked nicotine-induced increases in NMDA and AMPA currents. Following chronic nicotine treatment, acute nicotine or ethanol did not affect NMDA currents, while the effects of GABA responses were not altered. Acute ethanol ingestion selectively attenuated nicotine enhancement of excitatory glutamate NMDA and AMPA receptor function, suggesting an overall reduction in excitatory output from the hippocampus. It also indicated that ethanol could decrease the beneficial effects of nicotine on memory performance. In addition, chronic nicotine treatment produced tolerance to the effects of nicotine and cross-tolerance to the effects of ethanol on glutamate activity, leading to a potential increase in the use of these drugs.
Proctor, W., Dobelis, P., Moritz, A., & Wu, P. (2011). Chronic nicotine treatment differentially modifies acute nicotine and alcohol actions on GABA<sub>A</sub> and glutamate receptors in hippocampal brain slices. British Journal of Pharmacology, 162(6), 1351-1363. doi:10.1111/j.1476-5381.2010.01141.x
No comments:
Post a Comment