Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

Abstract

Chronic exposure to drugs of abuse is linked to long-lasting alterations in the function of limbic system structures, including the nucleus accumbens (NAc). Although cocaine acts via dopaminergic mechanisms within the NAc, less is known about whether phasic dopamine (DA) signaling in the NAc is altered in animals with cocaine self-administration experience or if these animals learn and interact normally with stimuli in their environment. Here, separate groups of rats self-administered either intravenous cocaine or water to a receptacle (controls), followed by 30 d of enforced abstinence. Next, all rats learned an appetitive Pavlovian discrimination and voltammetric recordings of real-time DA release were taken in either the NAc core or shell of cocaine and control subjects. Cocaine experience differentially impaired DA signaling in the core and shell relative to controls. Although phasic DA signals in the shell were essentially abolished for all stimuli, in the core, DA did not distinguish between cues and was abnormally biased toward reward delivery. Further, cocaine rats were unable to learn higher-order associations and even altered simple conditioned approach behaviors, displaying enhanced preoccupation with cue-associated stimuli (sign-tracking; ST) but diminished time at the food cup awaiting reward delivery (goal-tracking). Critically, whereas control DA signaling correlated with ST behaviors, cocaine experience abolished this relationship. These findings show that cocaine has persistent, differential, and pathological effects on both DA signaling and DA-dependent behaviors and suggest that psychostimulant experience may remodel the very circuits that bias organisms toward repeated relapse.

Prior Cocaine Experience Impairs Normal Phasic Dopamine Signals of Reward Value in Accumbens Shell

“…Surprisingly, core Late-Phase DA signals in Cocaine subjects showed an enhanced ability to distinguish reward magnitudes, while shell Late-Phase DA was essentially abolished. In a previous report, we showed a similar pattern of encoding during a Pavlovian task in which core DA was enhanced during signaled rewards, while associative encoding was abolished in the shell (Saddoris et al, 2016). One explanation for this could be a cocaine-mediated shift in the mesolimbic DA system signals along a dorsolateral gradient, such that previous shellrelated signals are now being represented in the core following chronic self-administration.…”

“…Detailed descriptions of this task appear elsewhere (Saddoris and Carelli, 2014;Saddoris et al, 2016). Briefly, at least 1 month prior to testing, a subset of rats (n = 19) were implanted with intrajugular catheters.…”

“…For example, chronic cocaine use is associated with alterations in synaptic transport of DA (Addy et al, 2010;Calipari et al, 2012;Ferris et al, 2012), augmentations in phasic DA signals to salient rewarding stimuli (Saddoris et al, 2016;Willuhn et al, 2014), and impairments in valuebased behaviors, such as outcome devaluation (LeBlanc et al, 2013;Schoenbaum and Setlow, 2005) and reversal learning (Calu et al, 2007;Jentsch et al, 2002;Schoenbaum et al, 2004). Collectively, such drug-associated behavioral changes suggest that intact DA signaling may be important for aspects of reward encoding and that chronic experience with cocaine disrupts this process.…”

“…For example, either optogenetic stimulation or inhibition of DA neurons in the ventral tegmental area (VTA) during reward receipt is sufficient to alter outcome sensitivity in a Pavlovian blocking and unblocking tasks (Chang et al, 2016;Steinberg et al, 2013). Relatedly, DA signals during reward receipt is disrupted in cocaine-experienced animals, with subjects displaying abnormally large reward-related DA release in the NAc core where it is normally low and virtually none in the shell where it was normally present (Saddoris et al, 2016).…”

Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

“…Previous studies in outbred rats have shown that exposure to ethanol during adolescence (McClory and Spear 2014) increases sign-tracking behavior, as does exposure to psychostimulants either during adolescence (Doremus-Fitzwater and Spear 2011) or in adulthood (Saddoris et al 2016). While the specific neurobiological mechanisms underlying these drug-induced effects on sign-tracking behavior have not been elucidated, dopaminergic transmission in the NAc core is likely involved (Saddoris et al, 2016), as it has been shown to play a critical role in the sign-tracking, but not the goal-tracking response (Flagel et al 2011; Saunders and Robinson 2012; Yager et al 2014).…”