Nicotine’s Split Personality: A Biphasic Effect on Brain Energy

Whilst the popular narrative regarding nicotine often fixates on the dopamine rush, new research suggests the drug plays a far more complex game of cat and mouse with our neural circuitry. A recent study utilising male mice has revealed that nicotine possesses a distinct ‘biphasic’ personality: it acts as a metabolic stimulant at lower levels but a suppressant when the dose increases.

Researchers administered varying concentrations of nicotine to awake mice and tracked metabolic changes via advanced NMR spectroscopy. The results were striking. At lower doses, the drug acted like a metabolic supercharger for glutamatergic neurons—the brain’s primary excitatory cells. This surge in glucose oxidation was particularly pronounced in the hippocampus and the prefrontal cortex, areas critical for memory and executive function.

However, the narrative shifts dramatically at higher intakes. When the dose was raised, nicotine effectively slammed the brakes on, suppressing both excitatory and inhibitory (GABAergic) activity across the cerebral cortex, prefrontal cortex, and hippocampus. At the highest tested levels, even the metabolic activity of astrocytes—the brain’s vital support cells—plummeted. This data suggests that acute nicotine rewires the delicate balance of excitation and inhibition in the prefrontal cortex, a mechanism that may fundamentally underpin the mesocortical circuitry involved in addiction.