Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats

Abstract

Rationale: Drugs with addictive liability have a high probability of co-abuse in many addicts. For example, cocaine users are several times more likely to smoke cigarettes than non-cocaine users, and smoking increases during cocaine use. Previous work has provided evidence that nicotine and cocaine have interactive neurochemical effects, particularly with regard to dopamine (DA) transmission.

Objectives: The present study examined the impact of nicotine treatment on the reinforcement efficacy of self-administered cocaine and non-reinforced responding for cocaine in rats.

Methods: Rats were trained to self-administer cocaine (i.v.) on a progressive ratio (PR) schedule of reinforcement. Self-administration training continued until stable responding was obtained. Acute nicotine pretreatment consisted of a subcutaneous injection (0.15, 0.3 and 0.6 mg/kg) 3 min prior to cocaine access. In the repeated treatment condition, a separate group of animals was given nicotine (0.6 mg/kg, s.c.) 3 min prior to cocaine access for 14 consecutive days. During extinction trials, these animals were injected with nicotine (0.6 mg/kg, s.c.) after 45 min of non-reinforced responding.

Results: Acute nicotine treatment produced an inverted U-shaped dose-response function with lower doses increasing and the highest dose decreasing the number of cocaine infusions obtained during a session. Animals treated repeatedly with the highest dose of nicotine showed a significant increase in the number of cocaine infusions by day 8 of nicotine treatment. During extinction sessions when cocaine was not available, injections of nicotine in these animals caused a reinstatement of the previously rewarded lever-press behavior.

Conclusions: These findings indicate that nicotine can facilitate cocaine reinforcement, may contribute to the transition from moderate drug-taking to an escalation of drug intake which is characteristic of addiction, and may trigger relapse.

Fig. 1

A Dose-related effects of cocaine dose for a fixed ratio (FR) 1 schedule of reinforcement (3-h session) on the mean (±SEM) number of cocaine infusions obtained during a 3-h session (n=8). Asterisk denotes a significant difference from the other two cocaine concentrations (0.03 mg and 0.25 mg per infusion; P<0.001). B Dose-related effects of cocaine dose for a progressive ratio (PR) schedule of reinforcement (maximum session length = 5 h) on the mean (±SEM) number of cocaine infusions obtained before 1 h of non-reinforcement (n=8). Asterisk denotes a significant difference from the 0.03 mg and 0.3 mg per infusion cocaine concentrations and # indicates significant difference from 0.03 mg and 0.1 mg per infusion cocaine concentrations (P<0.01; Tukey’s HSD after one-way, repeated-measures ANOVA)

Fig. 2

Effects of nicotine (0.15, 0.3 and 0.6 mg/kg, s.c.) pretreatment on the mean (±SEM) number of cocaine infusions (% baseline) on a progressive ratio (PR) schedule of reinforcement obtained before 1 h of non-reinforcement (n=6). Asterisks denote a significant difference from saline treatment (P<0.05) and # denotes a significant difference from the highest dose of nicotine (0.6 mg/kg; P<0.05; Tukey’s HSD after one-way, repeated-measures ANOVA)

Fig. 3

Effects of nicotine (0.60 mg/kg) on cocaine self-administration on a progressive ratio (PR) schedule of reinforcement. A Example of an infusion record showing the effect of initial nicotine treatment and the effect of nicotine after repeated treatment. Numbers in parentheses indicate infusions obtained during the first 60 min of the session. B Effect of repeated nicotine on cocaine self-administration. Animals injected with nicotine (n=15) 3 min before daily cocaine access show a significant increase in number of cocaine infusions relative to animals injected with saline (n=7) beginning at day 8. Data are from the first 60 min of each session and are reported as the percentage (mean±SEM) of 3 days prior to the beginning of injections (i.e., baseline). C Animals treated with nicotine did not differ from those treated with saline in responding on the inactive lever. Data are number of responses (mean±SEM) during the first 60 min of each session. *P<0.05 [Tukey’s HSD after mixed two-way ANOVA; drug (between subjects) × day (within subjects)]

Fig. 4

A Example of a response record showing the effect of a nicotine injection during an extinction session. Numbers in parentheses indicate the responses made during the 45-min period after the injection. B The effect of nicotine administered during an extinction trial on non-reinforced responding for cocaine in animals previously treated with nicotine 3 min prior to cocaine self-administration sessions. Data are presented as responses per 5 min (mean±SEM). During the extinction session, animals reached near-zero levels of responding. However, when animals were injected with nicotine (arrow) after 45 min of non-reinforced responding, they showed a significant increase in responding during the 5-min period following the injection relative to when they were injected with saline (n=11). C Responding on the inactive lever was not significantly different when animals were treated with nicotine relative to when they were treated with saline. Data are presented as the number of responses per 5 min (mean±SEM). *P<0.001 [Tukey’s HSD after repeated-measures, two-way ANOVA analyses (drug × time) across 90 min]

Fig. 5

A The effect of nicotine administered during an extinction trial on non-reinforced responding for cocaine in animals previously treated with saline 3 min prior to cocaine self-administration sessions for 2 weeks. Data are presented as responses per 5 min (mean±SEM). No differences were observed when animals were injected with nicotine (closed circles; injections indicated by the arrow) after 45 min of non-reinforced responding relative to saline (open circles). B Responding on the inactive lever was not significantly different when animals were treated with nicotine relative to when they were treated with saline. Data are presented as the number of responses per 5 min (mean±SEM)