Chronic nicotine treatment differentially modifies acute nicotine and alcohol actions on GABAA and glutamate receptors in hippocampal brain slices


William R Proctor, Department of Psychiatry, Mail Stop 8344, University of Colorado Denver, 12800 E. 19th Avenue, Room 8101, Aurora, CO 80045, USA. E-mail:


BACKGROUND AND PURPOSE 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.

EXPERIMENTAL APPROACH Acute effects of nicotine, ethanol, and both drugs on synaptic excitatory glutamatergic and inhibitory GABAergic transmission were measured using whole-cell recording in hippocampal CA1 pyramidal neurons from brain slices of mice on control or nicotine-containing diets.

KEY RESULTS Acute nicotine (50 nM) enhanced both GABAergic and glutamatergic synaptic transmission; potentiated GABAA receptor currents via activation of α7* and α4β2* 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 GABAA 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 GABAergic responses were not altered.

CONCLUSIONS AND IMPLICATIONS Acute ethanol ingestion selectively attenuated nicotine enhancement of excitatory glutamatergic 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 glutamatergic activity, leading to a potential increase in the use of these drugs.