Drug‐induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons

Abstract

Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre-clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self-administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3).

The amygdala-ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine

“…Although there are discrepancies in changes of DA level or DA activity during acute withdrawal, a decrease in DA activity has been consistently described in the literature following long-term withdrawal (Salin et al, 2021;Shen et al, 2007). This decrease could participate in the dysphoria described after protracted cocaine abstinence (Haake et al, 2019).…”

“…Rewarding properties of psychostimulants such as cocaine are associated with hyperdopaminergic state (Wise and Hoffman, 1992) whereas acute withdrawal from acute and chronic psychostimulants leads to a hypodopaminergic state, specifically in the mesolimbic system (Shen et al, 2007;Belujon et al, 2016;Salin et al, 2021), leading to hedonic deficits (Wise, 2008;Belujon and Grace, 2017). Reduction of DA activity is also observed after long abstinence (Diana et al, 1996;Salin et al, 2021); this reduction could be involved in dysphoria described after protracted abstinence (Haake et al, 2019).…”

The amygdala–ventral pallidum pathway contributes to a hypodopaminergic state in the ventral tegmental area during protracted abstinence from chronic cocaine

“…Although there are discrepancies in changes of DA level or DA activity during acute withdrawal, a decrease in DA activity has been consistently described in the literature following long‐term withdrawal (Salin et al, 2021; Shen et al, 2007). This decrease could participate in the dysphoria described after protracted cocaine abstinence (Haake et al, 2019).…”

“…A hypodopaminergic state has been proposed to be a major mechanism involved in drug addiction (Melis et al, 2005). Reduction of DA activity is also observed after long abstinence (Diana et al, 1996;Salin et al, 2021); this reduction could be involved in dysphoria (Haake et al, 2019) and anhedonia (Hatzigiakoumis et al, 2011) described after protracted abstinence. In patients, a positive correlation has been shown between craving and anhedonia in detoxified users, suggesting a strong association between hedonic capability and craving (Janiri et al, 2005).…”