Repeated Administration of the GABAB Receptor Agonist CGP44532 Decreased Nicotine Self-Administration, and Acute Administration Decreased Cue-Induced Reinstatement of Nicotine-Seeking in Rats

Abstract

Acute administration of g-aminobutyric acid B (GABA B ) receptor agonists decreased nicotine, cocaine, ethanol, and heroin selfadministration. GABA B receptor agonists also decreased cue-induced cocaine craving or seeking in humans and animals, respectively. The present study investigated the effects of repeated subcutaneous administration of the GABA B receptor agonist CGP44532 on nicotineand food-maintained responding under a fixed ratio 5 schedule of reinforcement. The second part of the study determined whether contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior, and whether acute subcutaneous CGP44532 administration affected cue-induced reinstatement of extinguished nicotine-seeking behavior. The results indicated that repeated administration of 0.25 mg/kg CGP44532 selectively decreased nicotine self-administration compared to foodmaintained responding during the first 7 days of treatment. Repeated administration of 0.5 mg/kg/day CGP44532 nonselectively decreased both nicotine-and food-maintained responding. Contingent presentation of previously nicotine-associated cues reinstated extinguished nicotine-seeking behavior. Further, acute CGP44532 administration (0.125 and 0.25 mg/kg) decreased cue-induced reinstatement of nicotine-seeking behavior. In summary, the present results indicated that 0.25 mg/kg/day CGP44532 selectively decreased nicotine self-administration compared to food-maintained responding, and acute administration of CGP44532 (0.125 and 0.25 mg/kg) dose-dependently decreased cue-induced reinstatement of nicotine-seeking behavior.

Complex interactions between nicotine and nonpharmacological stimuli reveal multiple roles for nicotine in reinforcement

“…While basic circuits underlying nicotine reinforcement have been extensively investigated Corrigall et al 1994;Corrigall et al 1992;Corrigall and Coen 1991;Jose Lanca et al 2000;Lanca et al 2000), only limited research has been conducted on the neural underpinnings for the interactions between nicotine and nonpharmacological stimuli (Liu et al 2004;Cohen et al 2005;Paterson et al 2005). The present paradigm has potential utility in such investigations, because it provides a means to dissociate the primary reinforcing and reinforcement-enhancing effects of nicotine.…”

“…Removing the stimulus after animals have maintained responding for it during saline substitution causes a further decrease in lever pressing, providing additional support for this hypothesis (Cohen et al 2005;Caggiula et al 2001;Donny et al 2000). Finally, following extinction of responding induced by removing nicotine and concurrent non-drug stimuli, reinstatement of lever pressing can be stimulated by either priming infusions of nicotine (Chiamulera et al 1996;Shaham et al 1997;Andreoli et al 2003), or by presentations of a non-drug stimulus that was previously combined with nicotine (Caggiula et al 2001;Lesage et al 2004;Paterson et al 2005). These data are consistent with a large body of clinical evidence that environmental stimuli associated with nicotine intake via smoking not only trigger craving and induce relapse in abstinent smokers (Caggiula et al 2001;Brody et al 2002;Heishman et al 2004;Rose and Levin 1991), but also greatly influence reinforcement derived from smoking .…”

“…Within the context of self-administration a broad spectrum of receptor antagonists block cue-induced nicotine seeking in rats (Liu et al 2004;Paterson et al 2005;Cohen et al 2005). However, little attention has been paid to identifying distinct neural structures that mediate either the establishment of conditioned reinforcers by nicotine, or the recently identified reinforcement-enhancing properties of nicotine.…”

“…The importance of contingent stimuli in nicotine self-administration is further highlighted by evidence that removing the stimulus markedly reduces lever pressing for nicotine (Caggiula et al 2001), and contingent presentations of the stimulus after nicotine is replaced with saline continue to support reduced but stable responding (Caggiula et al 2001;Cohen et al 2005). Finally, while removing both nicotine and the stimulus causes behavior to decrease to negligible levels, reintroducing the stimulus alone elicits rapid reinstatement of operant responding (Caggiula et al 2001;Lesage et al 2004;Paterson et al 2005;Cohen et al 2005). This body of research supports two important hypotheses.…”

“…Contingent nonpharmacological stimulus presentations facilitate the acquisition Caggiula et al 2002a;Donny et al 2003) and retard the extinction of nicotine self-administration (Caggiula et al 2001;Cohen et al 2005). Additionally, environmental stimuli associated with nicotine can reinstate drug seeking behavior after extinction (Caggiula et al 2001;Lesage et al 2004;Paterson et al 2005) and activate prefrontal cortex and limbic areas in rats, as determined by patterns of immediate early gene expression (Schroeder et al 2001). …”