Abstinence-induced nicotine seeking relays on a persistent hypoglutamatergic state within the amygdalo-striatal neurocircuitry.

Nicotine robustly sustains smoking behavior by acting as a primer reinforcer and by enhancing the incentive salience of the nicotine associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood. In here we used a contingent nicotine and saline control self-administration model to disentangle the contribution of cue-elicited seeking responding for nicotine after drug abstinence in male Wistar rats. Using ex vivo electrophysiological recordings and a network analysis approach, we defined temporal and brain-region specific amygdalo-striatal glutamatergic alterations that occur during nicotine abstinence. The results from this study provide critical evidence indicating a persistent hypoglutamatergic state within the amygdalo-striatal neurocircuitry over protracted nicotine abstinence. During abstinence-induced nicotine seeking, electrophysiological recordings showed progressive neuroadaptations in dorsal and ventral striatum already at 14-days abstinence while neuroadaptations in subregions of the amygdala emerged only after 28-days abstinence. The observed neuroadaptations pointed to a brain network involving the amygdala and the dorsolateral striatum (DLS) to be implied in cue-induced reinstatement of nicotine seeking. Together these data suggest long-lasting neuroadaptations that might reflect neuroplastic changes responsible to abstinence-induced nicotine craving. Neurophysiological transformations were detected within a time window that allows therapeutic intervention advancing clinical development of preventive strategies in nicotine addiction. SIGNIFICANT STATEMENT Most people attempting to quit smoking, experience multiple periods of remission and relapse within the first month of abstinence. Our results provide evidence of a persistent hypoglutamatergic state over four weeks of nicotine abstinence when assessing parallel changes in evoked glutamate transmission in multiple amygdalo-striatal subregions at once. The observed neuroadaptations pointed to a brain network involving the amygdala and the dorsolateral striatum that correlated with cue-induced reinstatement of nicotine seeking. The importance of these findings resides in an improved picture when capturing a single frame of the amygdalo-striatal circuitry in abstinence-induced nicotine craving. The neurophysiological transformations were detected within a time window that allows therapeutic intervention advancing clinical development of preventive strategies in nicotine addiction.