Nicotine-induced neuroplasticity in amygdalo-striatal circuits

Abstract

Nicotine addiction emerges from widespread neurobiological adaptations across reward-, habit-, and emotion-related circuits, yet the mechanisms driving these changes, especially sex-dependent ones, remain insufficiently understood. This thesis investigates acute and chronic nicotine-induced neuroplasticity in subregions of the striatum and amygdala, with emphasis on astrocytic involvement and sex-specific adaptations. Studies involved a battery of techniques including ex vivo electrophysiology, in vivo microdialysis, slice cyclic voltammetry, slice photometry, proteomics, immunohistochemistry and behavioral assays. Overall, this thesis demonstrates that nicotine elicits a sex-independent and α4β2-dependent long-term depression (nic-LTD) at excitatory synapses in the dorsolateral striatum (DLS), an effect associated with impaired astrocyte function. Nicotine further facilitates LTD elicited by high frequency stimulation (HFS-LTD) in the DLS of female rats, which might promote the establishment of a nicotine taking habit. Following repeated exposure, however, a tolerance to nicotine develops and the influence of dopamine over LTD induction is transformed. During the abstinence phase, excitatory neurotransmission remains depressed, and the effect by 5-HT on neurotransmission is altered in a differential manner in distinct striatal subregions, putatively influencing emotional processing. A hypoglutamatergic state is further observed selectively in the female basolateral amygdala. This neuroplasticity may further contribute to negative effect during nicotine abstinence and reduce the chances of nicotine cessation. Thus, nicotine produces selective neuroplasticity, and the female brain appears to be especially vulnerable. Sex-specific strategies for reducing nicotine dependence may thus be warranted.