Individual differences in modulation of dopamine release in a rodent model of substance abuse vulnerability

Abstract

Despite significant advances in understanding the neurobiology underlying substance use disorders (SUDs), about 20.3 million Americans still suffered from SUD in 2018. This is due, in part, to limited effectiveness of current treatment strategies. Development of more effective treatments may be advanced by the ability to identify markers of increased risk of developing SUD following initial drug use and to target treatments to this vulnerable subpopulation. This need to better understand individual differences in SUD vulnerability is demonstrated in that only 10–20% of individuals that experiment with drugs of abuse ultimately develop SUD. Some behavioral traits such as sensation seeking are predictive of increased vulnerability, but the neurobiology underlying these individual differences remains unclear. To investigate this neurobiology, sensation seeking can be modeled in rodents by examining locomotor response to a novel environment. 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). Phasic firing of mesolimbic dopamine (DA) neurons plays an integral role in encoding reward‐associations and occurs in response to unexpected rewards and reward‐predictive stimuli. HR rats show increased phasic DA signaling to reward‐predictive cues compared to LR rats. Nicotinic acetylcholine receptors (nAChRs) on DA terminals in the nucleus accumbens (NAc) modulate DA release in an action potential‐independent manner through acetylcholine signaling. Our lab has previously shown that locomotor response to a novel environment can predict 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 signal in brain slices of HR but not LR animals. In the present study, we used ex vivo fast‐scan cyclic voltammetry (FSCV) to further investigate the role of NAc nAChRs in modulating DA release in HRs versus LRs. We find that modulation of DA release by α7 nAChRs can be predicted by locomotor response to novelty at phasic‐like stimulations. Given the role that nAChRs play in 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 stimulation frequencies modeling phasic firing 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.Support or Funding InformationK99/R00 DA 311791, P50 DA006634, P50 AA026117, T32 DA041349‐03, Peter F. McManus Charitable Trust