Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats

Abstract

Rationale Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon. Methods Rats were trained to achieve stable performance on a delay discounting task, which involved lever press-based choice between a single food pellet (small reward) available immediately and three food pellets (large reward) available after a 10-, 20-, 40-, or 60-s time delay. Rats then received Pavlovian context-cocaine (15 mg/kg, i.p.) and context-saline (1 ml/kg, i.p.) pairings in two other, distinct contexts. Subsequently, delay discounting task performance was assessed in the previously cocaine-paired or saline-paired context following pretreatment with saline or cocaine (15 mg/kg, Experiment 1) or with saline or the nAChR antagonist, mecamylamine (0.2, 2 mg/kg, Experiment 2), using counterbalanced within-subjects testing designs. Results Independent of cocaine pretreatment, rats exhibited greater decrease in preference for the large reward as a function of delay duration in the cocaine-paired context, relative to the saline-paired context. Furthermore, systemic mecamylamine pretreatment dose-dependently attenuated the decrease in preference for the large reward in the cocaine-paired context, but not in the saline-paired context, as compared to saline. Conclusion Cocaine-paired contextual stimuli evoke a state of impulsive decision making, which requires nAChR stimulation. Drug context-induced impulsivity likely increases the propensity for drug relapse in cocaine users, making the nAChR an interesting target for drug relapse prevention.

Phasic Mesolimbic Dopamine Signaling Encodes the Facilitation of Incentive Motivation Produced by Repeated Cocaine Exposure

“…That said, drugassociated situational cues are known to alter DA system activity (Duvauchelle et al, 2000;Weitemier and Murphy, 2009) and expression of voluntary reward-seeking actions (Ostlund et al, 2010;Xie et al, 2012), and this raises the possibility that cocaine-induced learning contributed to the effects described here. However, rats in the current study were administered cocaine in the chambers used for initial training, but were retrained and tested in a distinct chamber (used for FSCV recordings) that was never directly associated with cocaine.…”

Repeated Cocaine Exposure Facilitates the Expression of Incentive Motivation and Induces Habitual Control in Rats

“…For instance, context-mediated learning has been shown to play an important role in other forms of behavioral sensitization [76]–[78]. Furthermore, a recent study found that cocaine-paired contextual stimuli can provoke impulsive decision making in rats [79]. We have also recently shown that contextual cues paired with alcohol intoxication produce a transient disruption in instrumental control, causing rats to shift from goal-directed to habitual performance [31].…”

α4β2∗ and α7 nicotinic acetylcholine receptor binding predicts choice preference in two cost benefit decision-making tasks

“…Additionally, there is limited evidence from studies in rodents and humans that pharmacological modulation of nicotinic acetylcholine receptors (nAChRs) can shift choice preference in tasks that assess cost benefit decision making (Mitchell, 2004; Reynolds et al, 2004; Dallery and Locey, 2005; Kolokotroni et al, 2011; Mendez et al, 2012; Xie et al, 2012). Finally, cholinergic signaling has been implicated in the etiology and/or treatment of numerous neuropsychiatric conditions in which cost benefit decision making is altered, including schizophrenia, Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), Parkinson’s disease, and addiction (Clark and Robbins, 2002; Kalivas and Volkow, 2005; Karlawish et al, 2005; Thompson et al, 2007; Williams and Adinoff, 2008; Euteneuer et al, 2009; Weiler et al, 2009;Gleichgerrcht et al, 2010).…”