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Psychopharmacology (Berl). 2012 Apr;220(3):541-50. doi: 10.1007/s00213-011-2505-z. Epub 2011 Sep 27.

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

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Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS, 39216, USA.



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


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.


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.


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.


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.

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