Effects of caffeine on persistence and reinstatement of nicotine-seeking behavior in rats: interaction with nicotine-associated cues

Abstract

Rationale: Caffeine and nicotine are the most commonly co-used psychostimulants. However, it is still unclear whether caffeine exposure enhances nicotine-seeking behavior.

Objective: The present study examined the effects of caffeine on nicotine-seeking in rats trained to self-administer nicotine with and without presession administration of caffeine.

Methods: Male Sprague-Dawley rats were trained to intravenously self-administer nicotine (0.03 mg/kg/infusion, freebase) on a fixed ratio 5 schedule of reinforcement and associate a stimulus cue with each nicotine administration. Five minutes before the sessions, the rats received an intraperitoneal administration of caffeine (5 mg/kg). Extinction tests were conducted under four conditions: presession caffeine administration, response-contingent presentation of nicotine cues, neither condition, or both conditions. Reinstatement tests were conducted after responding was extinguished by withholding presession caffeine, nicotine, and its cues. A separate group of rats trained without presession caffeine exposure was also subjected to the reinstatement tests.

Results: In the rats trained with presession caffeine exposure, continued caffeine administration sustained nicotine-seeking responses and interacted with nicotine cues to significantly delay the extinction of nicotine-seeking behavior. Readministration of caffeine after extinction effectively reinstated nicotine-seeking behavior. In caffeine-naive rats, caffeine administration did not reinstate extinguished nicotine-seeking behavior but significantly potentiated the cue-induced reinstatement of nicotine-seeking.

Conclusion: These data demonstrate that caffeine administration sustained and reinstated nicotine-seeking behavior, possibly via its acquired discriminative-stimulus properties predictive of nicotine availability. These findings suggest that smokers who attempt to quit may benefit from stopping caffeine consumption.

Fig. 1

Lever responses in the final three sessions of the nicotine self-administration phase in rats that received an intraperitoneal administration of 5 mg/kg caffeine (n=28) or saline (n=8) 5 min before the sessions. The data are expressed as mean±SEM responses

Fig. 2

Extinction of active lever responding (nicotine-seeking behavior) under different test conditions in rats (n=6–8) that received presession caffeine (5 mg/kg, i.p.) in the nicotine self-administration phase. SA indicates lever responses averaged across the final three self-administration sessions. Saline/− represents the presession saline + no cues condition. Caffeine/− represents the presession caffeine + no cues condition. Saline/cue represents the presession saline + cues condition. Caffeine/cue represents the presession caffeine + cues condition. The data are expressed as mean±SEM responses. *p<0.05, significant main effect of group

Fig. 3

Lever responses in the reinstatement tests in rats (n=7) that received presession caffeine (5 mg/kg) in the nicotine self-administration phase. Caffeine represents the presession caffeine + no cues condition. Cue represents the presession saline + cues condition. Caffeine/cue represents the presession caffeine + cues condition. The data are expressed as mean±SEM lever responses. *p<0.05, **p<0.01, significant difference from extinction baseline

Fig. 4

Lever responses in the reinstatement tests in rats (n=8) that received presession saline in the nicotine self-administration phase. Caffeine represents the presession caffeine + no cues condition. Cue represents the presession saline + cues condition. Caffeine/cue represents the presession caffeine + cues condition. The data are expressed as mean±SEM lever responses. *p<0.05, ***p<0.0001, significant difference from extinction and caffeine conditions; ⁺p<0.05, significant difference from cue condition