Biphasic effect of nicotine on glutamatergic activity in male mouse brain

Although the impact of nicotine on the dopaminergic system is well established, its effects on neural activity in the brain regions implicated in addiction remain unclear. The major objective of the study was to assess the impact of acute nicotine on neuronal and astrocytic metabolic activity in the prefrontal cortex, cerebral cortex and hippocampus of awake mice.

Nicotine (0.0125-2.00 mg kg^-1) was administered subcutaneously to 2- to 2.5-month-old C57BL/6NCrl male mice. The neuronal and astrocytic metabolic activity was measured by infusing [1,6-¹³C₂]glucose and [2-¹³C]acetate, respectively, 15 min after injection, and monitoring amino acids labelling in the ¹H-[¹³C]-NMR spectrum of brain tissue extracts.

Nicotine perturbed glucose metabolism in a dose- and brain- region-dependent manner. At lower doses, it enhanced the rate of glucose oxidation in glutamatergic neurons in the hippocampus (0.0125 mg kg^-1) and prefrontal cortex (0.025 mg kg^-1), with no change in the cerebral cortex. In contrast, a higher nicotine dose (1.0 mg kg^-1) suppressed glutamatergic and GABAergic neurometabolic activity in all three brain regions. Nicotine did not affect the astrocytic metabolic activity at the lower dose (0.025 mg kg^-1) but suppressed it at the high dose (2.0 mg kg^-1).

Nicotine has biphasic impacts on glutamatergic activity, enhancing excitatory activity at low doses but reducing both excitatory and inhibitory activity at higher doses. Most interestingly, acute nicotine increases neuronal excitability by shifting the excitation-to-inhibition balance in the prefrontal cortex, a critical component of the mesocortical circuitry.