The Effects of Glutamate and GABA Receptor Antagonists on Nicotine-induced Neurotransmitter Changes in Cognitive Areas*

In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested were NMDA, AMPA–kainate, and metabotropic glutamate receptor subtype antagonists (MK801, CNQX, and LY 341495, respectively) and GABA_A and GABA_B receptor subtype antagonists (bicuculline and hydroxysaclofen, respectively). We assayed nicotine-induced changes in dopamine (DA), norepinephrine (NE), serotonin (5-HT), and their metabolites. We found with the antagonists, both decreases and increases in nicotine-induced neurotransmitter responses. In the presence of nicotine all the antagonists (except LY 341495) caused a decrease in DA levels in the regions tested. NE levels were decreased in the cortex by all antagonists. In the hippocampus, GABA antagonists decreased NE levels, as did the metabotropic glutamate antagonist, LY 341495, while the other glutamate antagonists increased NE levels. The results of the 5-HT assay were more variable and dependent on the region and antagonist examined; increases were found slightly more often than decreases. The changes in metabolites were not often parallel with changes in their associated neurotransmitters, indicating that the antagonists also affect the metabolism of the neurotransmitters. The effect of the antagonists in the absence of nicotine was mostly to decrease the level of neurotransmitters, although increases were seen in a few cases. The results suggest that the excitatory glutamatergic- and inhibitory GABAergic-amino acid receptors are both involved in mediating nicotine-induced neurotransmitter responses, and their inhibitory or stimulatory effects are receptor subtype and brain region dependent. * To John P. Blass, an outstanding scientist, clinician and a great friend.