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.

Figure 1

(A) Dose Effect of Nicotine on Methamphetamine Self-Administration Low doses of nicotine pretreatment had no effect on active lever responses for methamphetamine, while the highest dose of nicotine tested (0.4 mg/kg) induced a significant attenuation in active lever responses and number of methamphetamine infusions earned (both *p<0.05). (B) Nicotine Pretreatment on Methamphetamine Self- Administration: Timecourse. Nicotine pretreatment (0.4 mg/kg) decreased active lever responding for methamphetamine compared to saline pretreatment during the first 5 min of the operant session (*p<0.05).

Figure 2

(A) Repeated Nicotine (0.2 mg/kg) Pretreatment on Methamphetamine Self-Administration and Reinstatement of Methamphetamine-Seeking Behavior. Left panel: NIC pretreatment did not alter operant responding for methamphetamine compared to SAL pretreatment. Right panel: Extinction of operant responding was evident across sessions with no significant difference between groups. (# p< 0.05 compared to first extinction session). (B) Effect of Nicotine on Reinstatement of Methamphetamine-Seeking Behavior. Responses on the previously active lever were increased by NIC challenge in rats pretreated previously with NIC and were increased by METH challenge in rats pretreated previously with either SAL or NIC (*p<0.05 compared to corresponding SAL challenge group).

Figure 3

(A) Effect of Repeated Nicotine (0.4 mg/kg) Pretreatment Administered in a Paired or Unpaired Manner on Methamphetamine Self-Administration (FR1). Left panel: Treatment during acquisition had no effect on lever responding. Right panel: Extinction of operant responding was evident in all groups and no group differences were observed during the extinction phase (#p<0.05 compared to first extinction session). (B) Effect of Nicotine (0.4 mg/kg) on Reinstatement of Methamphetamine-Seeking Behavior. Responses on the previously active lever were decreased by nicotine challenge in SAL-SAL group (#p<0.05 compared to corresponding saline challenge group) and were increased by nicotine challenge in NIC-SAL and SAL-SAL groups (*p<0.05 compared to corresponding saline challenge groups).

Figure 4

Effect of Repeated Nicotine (0.4 mg/kg) Pretreatment on Locomotor Activity. Left panel: NIC pretreatment prior to the locomotor session (SAL-NIC group) initially decreased activity and subsequently increased activity compared to the SAL-SAL group (*p<0.05). Right panel: During the extinction phase of the experiment, no group differences in locomotor activity were evident on any session; however, a significant decrease in activity between the first and last extinction session was observed (#, p<0.01 compared to the first extinction session). (B) Effect of Nicotine-Sensitization Following the Extinction Phase. Activity was decreased by nicotine challenge in SAL-SAL group (#p<0.05 compared to corresponding saline challenge group) and was increased by nicotine challenge in NIC-SAL and SAL-NIC groups (*p<0.05 compared to corresponding saline challenge groups).