Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry

Abstract

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 STATEMENTMost 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.

Subregion specific neuroadaptations in the female rat striatum during acute and protracted withdrawal from nicotine

“…The lack of effect on GABAergic neurotransmission is partially in disagreement with findings from male rats (Licheri et al 2020 ), suggesting that the previously observed increase in GABAergic neurotransmission during acute withdrawal may be sex specific. While GABAergic neurotransmission produces a tonic inhibition of striatal field potentials, measured responses primarily reflect glutamatergic neurotransmission, and evoked PS amplitudes are rapidly blocked by the AMPA receptor antagonist CNQX (Lagstrom et al 2019 ; Domi et al 2023a ). Considering that PPR was not significantly modulated by treatment it is thus likely that the increased excitability is associated with changes in AMPA receptor subunit composition or increased AMPA receptor density, thereby strengthening AMPA receptor signaling.…”

“…While the reinforcing properties of nicotine especially have been attributed to its effect on neurotransmission in the ventral tegmental area and the concomitant elevation of dopamine levels in the ventral striatum (nucleus accumbens, nAc) (Imperato et al 1986 ; Nisell et al 1994 ; Pidoplichko et al 1997 ; Akers et al 2020 ), other striatal regions may also be important for nicotine induced behaviors. In fact, dorsal striatum regions, which are essential for both goal-directed behavior and habit formation, also appear to undergo neuroplastic transformations in response to repeated nicotine exposure (Adermark et al 2016 ; Smith and Graybiel 2016 ; Clemens et al 2014 ; Domi et al 2023a ). Changes in dorsal striatal dopaminergic neurotransmission have further been connected to behavioral sensitization to drugs of abuse and compulsive drug-seeking behavior, as well as cue-induced craving and relapse, all critical components for the later stages of addiction (Bamford et al 2008 ; Volkow et al 2006 ; Durieux et al 2012 ).…”

“…Changes in dorsal striatal dopaminergic neurotransmission have further been connected to behavioral sensitization to drugs of abuse and compulsive drug-seeking behavior, as well as cue-induced craving and relapse, all critical components for the later stages of addiction (Bamford et al 2008 ; Volkow et al 2006 ; Durieux et al 2012 ). Considering that distinct subregions of the striatum appear to work together to drive nicotine-induced behaviors (Domi et al 2023a ), monitoring parallel neuroplasticity in striatal subregions may be a valuable approach for understanding the neurophysiological underpinnings of nicotine addiction.…”

Pre- and postsynaptic signatures in the prelimbic cortex associated with “alcohol use disorder” in the rat

“…Field potential recordings. In field potential recordings population spikes (PS) were evoked with a stimulation frequency of 0.05 Hz in PL, NacC and BLA [38]. Stimulation electrodes were positioned locally, 0.2-0.3 mm from the recording electrode (resistance 2.5 to 4.5 MΩ), and the amplitude of evoked PSs were measured.…”