Nicotine elicits methamphetamine-seeking in rats previously administered nicotine

Abstract

Research has indicated a high correlation between psychostimulant use and tobacco cigarette smoking in human substance abusers. The objective of the current study was to examine the effects of acute and repeated nicotine administration on responding for intravenous methamphetamine (0.03 mg/kg/infusion) in a rodent model of self-administration, as well as the potential of nicotine to induce reinstatement of previously extinguished drug-taking behavior in male Sprague–Dawley rats. In addition, it was assessed whether nicotine-induced reinstatement of methamphetamine-seeking behavior and nicotine-induced locomotor sensitization require that nicotine be temporally paired with the methamphetamine self-administration session or the locomotor activity chamber. Nicotine acutely decreased methamphetamine self-administration, but did not persistently alter responding during the maintenance of methamphetamine self-administration. However, following extinction of methamphetamine self-administration, nicotine administration reinstated methamphetamine-seeking behavior only in rats that had previously been administered nicotine. Nicotine-induced reinstatement and expression of locomotor sensitization were not dependent on a temporal pairing of nicotine with either the methamphetamine self-administration session or the locomotor activity chamber, respectively. These results indicate that nicotine may be acting, at least in part, through a non-associative mechanism to reinstate methamphetamine-seeking behavior.

Introduction

Many individuals using illicit drugs also smoke tobacco cigarettes. Results derived from the National Household Survey on Drug Abuse (NHSDA) indicate that individuals who report previous participation in a drug treatment program have a threefold greater chance of being cigarette smokers compared to the general population (Richter et al., 2002). Moreover, a high percentage of individuals seeking treatment for methamphetamine abuse in Los Angeles County report previous tobacco use (Brecht et al., 2004). It is likely that both the behavioral and pharmacological interactions of methamphetamine and nicotine, derived from smoking tobacco cigarettes, contribute to the concomitant use of these substances. Further understanding of these interactions would aid in the development of more effective treatment strategies for methamphetamine dependence.

Several animal models have indicated a pharmacological interaction exists between amphetamine-like drugs and nicotine. In rats trained to discriminate amphetamine (1 mg/kg) from saline, nicotine administration results in partial substitution (Bardo et al., 1997). This suggests that amphetamine and nicotine share some common discriminative stimulus properties. In addition, studies have shown that the locomotor stimulant effect of nicotine cross-sensitizes with that of amphetamine. Animals pretreated with nicotine for 5 days display a sensitized locomotor response to a subsequent amphetamine challenge 3 weeks later (Schoffelmeer et al., 2002). Furthermore, when mecamylamine, a non-specific nicotinic antagonist, is co-administered with amphetamine across a 5-day pretreatment regimen, the sensitized response to amphetamine administration 3 weeks later is attenuated (Schoffelmeer et al., 2002). In addition, mecamylamine blocks amphetamine-induced neurochemical sensitization as assessed by electrically evoked ³[H]DA release in superfused nucleus accumbens slices. These studies suggest pharmacological manipulation of the nicotinic acetylcholinergic system alters amphetamine-induced locomotor sensitization, possibly through dopaminergic mechanisms.

While the effect of nicotine on the ongoing self-administration of amphetamine-like drugs has yet to be determined, the effect of nicotine on cocaine self-administration has been examined. Repeated nicotine pretreatment prior to cocaine self-administration sessions in rats results in a significant increase in progressive ratio break point compared to saline pretreatment controls (Bechtholt and Mark, 2002). Following extinction, nicotine reinstates cocaine-seeking only in nicotine pretreated rats, but not in saline pretreated rats. However, acute nicotine has been shown to reinstatement methamphetamine-seeking behavior, albeit to a lesser degree than methamphetamine itself (Hiranita et al., 2006). There is also evidence that mecamylamine decreases cocaine self-administration on a fixed ratio 1 schedule of reinforcement in rats (Levin et al., 2000). Further, administration of mecamylamine attenuates the escalation of cocaine self-administration observed in animals on an extended access self-administration schedule (Hansen and Mark, 2007). These studies provide evidence that pharmacological manipulation of the nicotinic acetylcholinergic system can alter the reinforcing effects of cocaine and may play a role in psychostimulant-induced drug-seeking behaviors.

Given the high comorbidity of nicotine and methamphetamine dependence, it is of clinical value to determine the behavioral effects of concurrent nicotine administration and methamphetamine self-administration. An initial experiment was conducted to establish the dose-dependent effect of nicotine administration on methamphetamine self-administration following acquisition of methamphetamine self-administration using a within-subjects design. A second experiment was conducted to assess the effects of repeated nicotine (0.2 mg/kg) administration on the acquisition of methamphetamine self-administration and drug-induced reinstatement. This lower dose of nicotine was used in order to assess the effects of nicotine-induced reinstatement of extinguished methamphetamine-seeking at a dose that has been shown to affect locomotor activity in our laboratory, as well as others, but did not acutely alter methamphetamine self-administration (Ksir et al., 1987, Wooters et al., 2008). Lastly, the dose of nicotine (0.4 mg//kg) that resulted in decreased methamphetamine intake was subsequently used to assess the effect of repeated nicotine on acquisition of methamphetamine self-administration and methamphetamine-induced reinstatement in rats. Given that nicotine can act as a conditional stimulus (CS) to signal the availability of response-contingent reward (Bevins and Palmatier, 2004, Chaudhri et al., 2006), this experiment also determined if nicotine-induced reinstatement of methamphetamine-seeking behavior and nicotine-induced locomotor sensitization require that nicotine be temporally paired with the methamphetamine self-administration session or the locomotor activity chamber, respectively.