Selective Optogenetic Dopamine Terminal Stimulation Reveals Role of GABAergic Signaling in Individual Differences in Dopamine Release
Authors: Leach Amy , Ferris Mark 
Published: May 2022

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 at lower doses 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 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 (α6β2*) 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, these studies utilized non‐specific electrical stimulation to record DA release. In the present study, we used ex vivo fast‐scan cyclic voltammetry with an optogenetic approach to selectively stimulate DA neuron terminals or cholinergic interneurons (CINs) within the NAc to examine the specific contributions of acetylcholine (ACh) to the overall DA response in HR and LR rats. We find that, contrary to previous results with electrical stimulation, selective DA phasic stimulation results in lower DA release in HRs compared to LRs, while blockade of α6β2* nAChRs using light stimulation results in higher DA release in HRs. This suggests that additional circuitry is likely involved in differential DA signaling within the NAc. Given the tonic activity of CINs and presence of nAChRs on GABA interneurons, we next used pharmacological manipulations to examine the possibility of GABA signaling contributing to individual differences in DA release. Here, we find that antagonism of GABA receptors blocks the previously seen differential effects of α6β2* nAChR antagonism on DA release, suggesting that GABA interneurons do play a critical role in differential DA signaling in HRs versus LRs. In sum, these data help form a clearer understanding of the mechanisms underlying individual differences in DA signaling, which may be a primary driver of differences in sensitivity to the reinforcing effects of drugs of abuse. Investigating these mechanisms allows us to better identify behavioral and neurochemical markers of SUD vulnerability in humans and to ultimately stimulate development of individualized and effective treatments.