Stimulation of α2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats
Introduction
Tobacco addiction is a chronic disorder that is characterized by a loss of control over smoking, affective withdrawal symptoms upon smoking cessation, and relapse after periods of abstinence (American Psychiatric Association, 2000, McLellan et al., 2000, O’Brien, 2003). Nicotine is one of the main components of tobacco smoke that leads to and maintains smoking (Bardo et al., 1999, Crooks and Dwoskin, 1997, Stolerman and Jarvis, 1995). This is supported by studies that show that rodents, dogs, and nonhuman primates readily learn to self-administer nicotine (Corrigall and Coen, 1989, Goldberg et al., 1981, Risner and Goldberg, 1983). Furthermore, nicotine induces conditioned place preference and facilitates intracranial self-stimulation (ICSS) in rats (Harrison et al., 2002, Le Foll and Goldberg, 2005, Pradhan and Bowling, 1971). Conditioned place preference and facilitation of ICSS are indicative of a potentiation of brain reward function (Bardo and Bevins, 2000, Schaefer and Michael, 1992). Nicotine mediates its positive reinforcing effects (e.g., mild euphoria) at least partly via the activation of central nicotinic acetylcholine receptors (nAChRs). Pharmacological blockade of nAChRs or genetic deletion of the β2-subunit of the nAChR decreases nicotine self-administration in rodents (Corrigall et al., 1994, Corrigall and Coen, 1989, Donny et al., 1999, Picciotto et al., 1998, Watkins et al., 1999). Cessation of smoking in humans leads to an acute withdrawal syndrome that is characterized by affective symptoms such as depressed mood, anxiety, and difficulty concentrating (American Psychiatric Association, 2000, Bruijnzeel and Gold, 2005). It has been hypothesized that the acute negative affective aspects of nicotine withdrawal provide a powerful motivational force for the continuation of smoking (Koob et al., 1997, Markou et al., 1998).
Epidemiological studies indicate that exposure to stressors increases the risk for relapse to smoking in humans (Cohen and Lichtenstein, 1990, Doherty et al., 1995, Kassel et al., 2003, McKee et al., 2003, Niaura et al., 2002, Shiffman and Waters, 2004, Swan et al., 1988). Stressors also increase the risk for relapse to other drugs of abuse such as alcohol and opioids (Brown et al., 1995, Kosten et al., 1986). Animal models have been developed to delineate the neuronal mechanisms that underlie stress-induced relapse. In one of these models, rats are allowed to self-administer a drug for a specific amount of time and then drug seeking is extinguished by substituting saline for the drug solution. Exposure to footshocks leads to a resumption of extinguished drug seeking (Shaham et al., 2003). Footshocks have been shown to reinstate extinguished heroin, cocaine, alcohol, and nicotine seeking in rats (Buczek et al., 1999, Erb et al., 2001, Liu and Weiss, 2002, Shaham and Stewart, 1995). In a previous study we reported that exposure to the contextual stimuli associated with prior footshock-stress does not reinstate extinguished nicotine seeking (Zislis et al., 2007). Several studies have reported that footshocks do not reinstate operant responding that was previously maintained by food pellets, sucrose pellets, or sucrose solutions (Ahmed and Koob, 1997, Buczek et al., 1999, Le et al., 1998, Mantsch and Goeders, 1999). This suggests that stressors reinstate nonreinforced responding for addictive substances, but not for natural reinforcers, such as food pellets or sucrose.
Although exposure to stressors plays an important role in relapse to smoking in humans, only a few preclinical studies have investigated the neuronal mechanisms that mediate stress-induced relapse to smoking. Previous studies in our laboratory investigated the role of CRF and noradrenergic transmission in stress-induced reinstatement of nicotine seeking in rats. These studies demonstrated that central administration of the non-specific CRF1/CRF2 receptor antagonist d-Phe CRF(12–41) and the specific CRF1 receptor antagonist R278995/CRA0450, but not the CRF2 receptor antagonist astressin-2B, attenuates stress-induced reinstatement of nicotine seeking (Bruijnzeel et al., 2009, Zislis et al., 2007). Furthermore, it was shown that systemic administration of the α2-adrenergic receptor agonist clonidine attenuates footshock-induced reinstatement of nicotine seeking (Zislis et al., 2007). These studies suggest that CRF and noradrenergic transmission plays an important role in stress-induced reinstatement of nicotine seeking. This pattern of results is in line with the findings of studies that investigated the neurobiological substrates underlying footshock-induced reinstatement of cocaine and alcohol seeking (Erb et al., 2000, Le et al., 2000). The α2-adrenergic receptor agonists clonidine, lofexidine, and guanabenz attenuate stress, but not cue, induced reinstatement of cocaine seeking in rats (Erb et al., 2000). Furthermore, the intracerebroventricular (icv) administration of the non-specific CRF1/CRF2 receptor antagonist d-Phe CRF(12–41) or systemic administration of the specific CRF1 receptor antagonist CP-154,526 attenuates stress-induced reinstatement of alcohol seeking (Le et al., 2000). Recent studies indicate that the activation of α1-adrenergic receptor plays a role in cue and drug-induced reinstatement of drug seeking. The α1-adrenergic receptor antagonist prazosin attenuates nicotine and cue-induced reinstatement of extinguished nicotine seeking in rats (Forget et al., 2010). Furthermore, the norepinephrine transport inhibitor nisoxetine induces the reinstatement of cocaine seeking in squirrel monkeys and this effect is blocked by prazosin (Fuller et al., 1975, Platt et al., 2007). In contrast, prazosin does not prevent forced swim stress-induced reinstatement of cocaine-induced conditioned place preference in mice (Mantsch et al., 2010). These studies suggest that α1-adrenergic receptor antagonists attenuate drug and cue-induced reinstatement of drug seeking but not stress-induced reinstatement of drug seeking.
Experimental evidence suggests that noradrenergic transmission in the central nucleus of the amygdala (CeA) plays a role in stress-induced reinstatement of drug seeking. This is supported by the observation that footshocks induce the release of norepinephrine in the amygdala (Galvez et al., 1996, Iimori et al., 1982). In addition, the administration of a mixture of the β1-adrenergic receptor antagonist betaxolol and the β2-adrenergic receptor antagonist ICI-118,551 into the CeA attenuates footshock-induced reinstatement of cocaine seeking (Leri et al., 2002). The aim of the present experiments was to investigate the role of noradrenergic transmission in the CeA in stress-induced reinstatement of nicotine seeking. The first experiment investigated the effects of clonidine in the CeA and the second experiment investigated the effects of dexmedetomidine in the CeA on stress-induced reinstatement of nicotine seeking. Clonidine (Ki α2: 3.2 nM; Ki α1: 713 nM) and dexmedetomidine (Ki α2: 1.1 nM; Ki α1: 1750 nM) are potent α2-adrenergic receptor agonists and they also bind with a relatively low affinity to α1-adrenergic receptors and imidazoline 1 (I1) and I2 receptors (Smith et al., 2009, Virtanen et al., 1988). Dexmedetomidine is a somewhat more selective α2-adrenergic receptor agonist than clonidine. Dexmedetomidine has a 7 fold greater selectivity for α2 over α1-adrenergic receptors than clonidine (Dexmedetomidine, α2/α1 ratio: 1620; Clonidine, α2/α1 ratio: 220) (Savola and Virtanen, 1991, Virtanen et al., 1988). Both the I1 and I2 receptor have been detected in the central nervous system (Dardonville and Rozas, 2004, Smith et al., 2009). Dexmedetomidine has a lower affinity for the I1 receptor than clonidine (Dexmedetomidine Ki: 637 nM; Clonidine Ki: 55 nM)(Piletz and Sletten, 1993). Both dexmedetomidine and clonidine have a very low affinity for the I2 receptor (Dexmedetomidine Ki: 38,700 nM; Clonidine Ki: 300,000 nM)(Piletz and Sletten, 1993). The third experiment investigated the effects of the nonselective β1/β2-adrenergic receptor antagonist propranolol in the CeA on footshock-induced reinstatement of nicotine seeking. The fourth experiment investigated the effects of the specific α1-adrenergic receptor antagonist prazosin in the CeA on footshock-induced reinstatement of nicotine seeking. These studies may improve the understanding of the role of noradrenergic transmission in the CeA in stress-induced reinstatement of nicotine seeking.
Section snippets
Subjects
Male Wistar rats (Charles River, Raleigh, NC) weighing 250–300 g at the beginning of the experiments were used. Animals were single-housed in a temperature and humidity-controlled vivarium and maintained on a 12 h reversed light–dark cycle (lights off at 9 AM). All testing occurred during the first 3 h of the dark cycle. Food and water were available ad libitum in the home cages. All subjects were treated in accordance with the National Institutes of Health guidelines regarding the principles
Experiment 1: effects of intra-CeA administration of clonidine on stress-induced reinstatement of nicotine seeking
The mean (±S.E.M.) number of responses on the active lever and responses on the inactive lever during the last day of nicotine self-administration were 50.8 ± 5.3 and 9.4 ± 5.3, respectively. Substituting saline for nicotine lead to a decrease in the number of responses on the active lever (Fig. 2A; F7,98 = 10.70, P < 0.0001) and the inactive lever (F7,98 = 4.11, P < 0.0005). The extinction criterion (fewer than 2 infusions) was met on day 7. The administration of footshocks increased the
Discussion
These studies investigated the role of α2, α1, and β1/β2-adrenergic receptors in the CeA in stress-induced reinstatement of nicotine seeking in rats. It was shown that pretreatment with the α2-adrenergic receptor agonists clonidine and dexmedetomidine in the CeA attenuated stress-induced reinstatement of nicotine seeking. Doses of clonidine and dexmedetomidine that attenuated stress-induced reinstatement did not affect responding for food pellets. In contrast to the α2-adrenergic receptor
Acknowledgements
This work was funded by National Institute on Drug Abuse grant (DA023575) to Adrie Bruijnzeel.
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