Response to Novelty Predicts α7 Nicotinic Receptor and Voltage‐Gated Calcium Channel Modulation of Dopamine Release

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An estimated 70.5% of Americans aged 12 or older report having used an illicit substance at least once, while about 10-20% of those individuals ultimately develop a substance use disorder (SUD). These data highlight substantial individual variability in the risk of developing SUD following initial drug use. Identifying markers of increased risk provides a significant opportunity to identify at-risk populations and to aid in the prevention of the development of SUD. In preclinical rodent models, locomotor response to a novel environment predicts drug use vulnerability. Rodents that demonstrate higher locomotor response to an inescapable novel environment (high responders; HR) acquire self-administration (SA) of drugs more rapidly and stably compared to low responders (LR). Striatal dopamine (DA) signaling is critical for the acquisition of drug SA and tonic/phasic firing patterns of DA neurons encode information about salient environmental stimuli and rewards. HR rats show increased phasic DA signaling to reward-predictive cues compared to LR rats. Dopamine release dynamics are tightly controlled by local modulation within the nucleus accumbens (NAc), including through glutamatergic signaling and modulation by nicotinic acetylcholine receptors (nAChRs), but the mechanisms by which this local modulation may contribute to differential DA release is not fully understood. Our lab has previously shown that locomotor response to a novel environment predicts nAChR modulation of phasic DA signals in the NAc. Specifically, desensitization or blockade of α6β2-containing nAChRs within the NAc was found to augment phasic DA signals in brain slices of HR rats, and reduce phasic DA signals in LR rats. However, other nAChR subtypes may also contribute to individual differences in DA signaling, including α7 nAChRs localized to striatal glutamate terminals. In the present study, we used ex vivo fast-scan cyclic voltammetry to examine how antagonism of α7 nAChRs impacts DA release across a range of stimulation frequencies in the NAc of HR and LR animals and examine what mechanisms may be mediating this effect. We find that modulation of DA release by α7 nAChRs can be predicted by response to novelty at phasic-like stimulations. Given the role that nAChRs play in calcium (Ca2+) entry into the cell, we additionally tested the possibility that differential Ca2+ utilization is one mechanism underlying differential DA modulation by nAChRs and utilized pharmacological manipulations to test possible voltage-gated Ca2+ channel (VGCC) subtype-specific effects. Here, we demonstrate that lowered Ca2+ concentration unmasks a diverging DA release profile between HRs and LRs at phasic-like stimulation frequencies and find that P/Q-type VGCCs appear to drive these individual differences in Ca2+ utilization. In sum, these data help form a more coherent understanding of the mechanisms underlying individual differences in vulnerability. Investigating these mechanisms allows us to better identify behavioral and neurochemical markers of substance abuse risk in humans and to ultimately stimulate development of more individualized and effective treatments.