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Mantsch, J. R.

Publications and source records attributed to Mantsch, J. R..

2 recordsLinked to original sources

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

neuroscience↗

Role of mesolimbic endocannabinoid signaling in stress-driven cocaine use in rats

Stress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration (SA) escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine SA requires CB1 cannabinoid receptor signaling. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min SA components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine SA that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine SA, regardless of stress history, increases CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during SA. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1R signaling is required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use enhances mesolimbic CB1R signaling through a currently unknown mechanism.

neuroscience↗