Nicotine produces a sex- and subregion-specific hypoglutamatergic state in rodent amygdala which can be reversed by motor-skill training

Nicotine abstinence is associated with negative affect and a high risk of relapse, but the neurophysiological underpinnings have not been fully outlined. Considering the role of the amygdala in emotional processing and stress regulation, changes in neurotransmission were assessed in the amygdala during nicotine withdrawal in female and male rats and putative molecular underpinnings were examined using proteomic analysis. Behavioral transformations elicited by repeated nicotine exposure were assessed in an open field arena and on the elevated plus maze (EPM). In addition, rats were trained on the Rotarod to explore if motor skill training could restore neurotransmission during nicotine abstinence. Repeated administration of nicotine produced behavioral sensitization in both male and female Wistar rats, with a more pronounced effect on female rats. While anxiety-like behavior on the EPM was not significantly affected, electrophysiological recordings demonstrated a hypoglutamatergic state, with reduced frequency and amplitude of spontaneous activity and impaired maintenance of action potential firing. Changes in neurotransmission were specific to the basolateral amygdala (BLA) of female rats and not observed in the central amygdala. Proteomic analyses identified parallel transformations in proteins involved in vesicle release and potassium and sodium homeostasis, which might contribute to synaptic impairments. Neurotransmission was restored following five days of motor skill training on the rotarod. In conclusion, nicotine produces sustained suppression of glutamatergic neurotransmission in the female BLA, which putatively could contribute to emotional dysregulation and enhanced relapse risk. Importantly, motor skill training was sufficient to restore neurotransmission, highlighting the therapeutic potential of exercise in nicotine dependence.