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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 18, 2006; DOI: 10.1124/jpet.106.105270

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Received for publication March 27, 2006.
Revised October 16, 2006.
Accepted for publication October 17, 2006.

Extended access to nicotine self-administration leads to dependence: circadian measures, withdrawal measures and extinction behavior in rats

Laura E. O'Dell 1, Scott A. Chen 2, Ronald T. Smith 3, Sheila E. Specio 3, Robert L. Balster 4, Neil E. Paterson 3, Athina Markou 5, Eric P. Zorrilla 3, George F. Koob 3*

1 University of Texas, El Paso 2 National Institute on Alcohol Abuse and Alcoholism 3 The Scripps Research Institute 4 Virginia Commonwealth University 5 University of California at San Diego

* Address correspondence to: E-mail: gkoob{at}scripps.edu

Abstract

The present study characterized nicotine intake, circadian patterns of food and water intake, precipitated somatic signs of withdrawal, and extinction of nicotine- seeking behavior in rats with 23 h access to intravenous self-administration (IVSA). Separate groups of animals were allowed access to nicotine IVSA (0.015, n = 9; 0.03, n = 14; 0.06, n = 16; mg/kg/0.1 ml infusion/sec; fixed- ratio 1) and trained to nosepoke for food and water 23 h/day for 40 consecutive days. Somatic signs of nicotine withdrawal were examined following saline or mecamylamine administration (1.5 mg/kg, i.p.), and extinction of nicotine-seeking behavior was assessed. A dose-dependent decrease in lever responding and an increase in nicotine intake were observed, with the highest nicotine dose producing the lowest amount of lever responding and the highest amount of nicotine intake. Nicotine acutely reduced diurnal and nocturnal food intake, producing smaller and fewer meals and an increased rate of eating. Differences in rate of nicotine intake between the light and dark phase decreased significantly, especially in rats receiving higher unit nicotine doses (0.03 and 0.06 mg/kg), along with long-term decreases in the circadian profile and amplitude of feeding. Mecamylamine precipitated robust withdrawal signs, the magnitude of which was positively correlated with the total amount of self-administered nicotine. Extinction of nicotine- seeking behavior was observed and was facilitated by removal of nicotine-associated cues. The results demonstrate that rats will self-administer nicotine to the point of producing dependence, as measured by somatic signs, resistance to extinction, and measures of food intake.


Key words: circadian rhythm, escalation, meal pattern analysis, mecamylamine, nicotine, self-administration




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