Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

Abstract

Nicotine, the main psychoactive ingredient of tobacco smoke, induces negative motivational symptoms during withdrawal that contribute to relapse in dependent individuals. The neurobiological mechanisms underlying how the brain signals nicotine withdrawal remain poorly understood. Using electrophysiological, genetic, pharmacological, and behavioral methods, we demonstrate that tonic but not phasic activity is reduced during nicotine withdrawal in ventral tegmental area dopamine (DA) neurons, and that this pattern of signaling acts through DA D2 and adenosine A2A, but not DA D1, receptors. Selective blockade of phasic DA activity prevents the expression of conditioned place aversions to a single injection of nicotine in nondependent mice, but not to withdrawal from chronic nicotine in dependent mice, suggesting a shift from phasic to tonic dopaminergic mediation of the conditioned motivational response in nicotine dependent and withdrawn animals. Either increasing or decreasing activity at D2 or A2A receptors prevents the aversive motivational response to withdrawal from chronic nicotine, but not to acute nicotine. Modification of D1 receptor activity prevents the aversive response to acute nicotine, but not to nicotine withdrawal. This double dissociation demonstrates that the specific pattern of tonic DA activity at D2 receptors is a key mechanism in signaling the motivational effects experienced during nicotine withdrawal, and may represent a unique target for therapeutic treatments for nicotine addiction.negative reinforcement | place conditioning | burst firing | population activity | osmotic minipumps T obacco addiction is the leading avoidable cause of disease and premature death in North America (1). Of more than 3,000 chemicals present in tobacco smoke, nicotine is the main psychoactive ingredient responsible for tobacco addiction (2). Withdrawal from chronic nicotine is hypothesized to represent a powerful source of negative reinforcement that drives relapse and compulsive tobacco use (3); therefore, understanding the neurobiological substrates mediating the motivational properties of nicotine withdrawal is an important step in the development of new treatments for nicotine addiction. Current hypotheses suggest that nicotine withdrawal leads to a decrease in dopamine (DA) signaling in the brain (4) and that DA neurons exhibit two activity states, phasic and tonic, that mediate separate aspects of behavior (5-7).Nicotine acutely produces both aversive and positive motivational effects (8, 9) by activating the mesolimbic DA system (7, 10) as well as non-DAergic neural substrates (11,12). DA neurons exhibit burst-and population-firing activity that leads to phasic and tonic DA release, respectively (5-7). Burst-firing produces a fast and large phasic DA release that mainly activates postsynaptic DA D1 receptors (D1Rs), and population-firing produces a slower tonic DA release that mainly activates the higher affinity (13) DA D2 receptors (D2Rs) (5, 6). The phasic and tonic activities of DA neurons are though...

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

“…This phasic/tonic dopamine signaling ratio increase, as observed during withdrawal in previous studies (Grieder et al, 2012;Zhang et al, 2012), is implicated in habit learning (Aggarwal and Wickens, 2011), enhanced reward association and acquisition of incentive salience (Grieder et al, 2012). Thus, these studies might further explain the greater motivation to seek a reward, whether it is an electric stimulation or a substance of abuse, both observed here by the use of ICSS and CPP and the latter in a recent study by Cohen et al (2012), or the enhanced cue association, observed by Scott and Hiroi (2010), during withdrawal.…”

Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

“…This previously unreported finding is of particular interest as numerous animal studies have suggested that the dysphoric effects associated with withdrawal could be DAmediated (Grieder et al, 2012), and this study provides evidence for such a relationship in humans. We also found that while the total puff volume correlated with the craving and not [ 11 C]-( þ )-PHNO binding, the number of puffs subjects made during the smoking condition did correlate with both DA level elevation in LST and decrease in urge to smoke.…”

“…Therefore, the role of DA in nicotine addiction still remains unclear (refer to the study by Le Foll et al (2009a) for a review). While some authors agree that DA signaling at the D2/3 receptor appears to mediate the rewarding and motivational effects of nicotine, other have argued that DA may instead mediate aversion to acute nicotine or nicotine withdrawal (Grieder et al, 2012;Laviolette and Van Der Kooy, 2003a, b). Because of this complexity, it appears that the use of smoking topography to characterize smoking behavior may yield valuable insights, as rate of nicotine administration or latency to drug-use are critically related to drug reinforcements and warrants further study.…”

The Volitional Nature of Nicotine Exposure Alters Anandamide and Oleoylethanolamide Levels in the Ventral Tegmental Area

“…Screening of two independent clinical populations revealed that CB 1 gene variants are associated with nicotine dependence (Chen et al, 2008) and the CB 1 receptor antagonist Rimonabant (SR141716A) prolonged abstinence rates in smokers expressing motivation to quit . SR141716A and the related CB 1 antagonist AM251 reduce nicotine selfadministration (SA) by rats (Cohen et al, 2002(Cohen et al, , 2005Forget et al, 2009;Shoaib, 2008), attenuate nicotine-induced increases in nucleus accumbens (NAc) dopamine (DA) (Cheer et al, 2007;Cohen et al, 2002;Grieder et al, 2012), and reduce reinstatement of nicotine-seeking behavior in animal models of relapse (Forget et al, 2009). Collectively, these findings provide strong evidence for a CB 1 receptor involvement in the motivational effects produced by nicotine, and imply a role for endocannabinoid (eCB) signaling in this process.…”