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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 6, 2008; DOI: 10.1124/jpet.107.131771

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Received for publication September 20, 2007.
Revised February 3, 2008.
Accepted for publication February 4, 2008.

Effects of a CB1 receptor antagonist and 5-HT2C receptor agonist alone and in combination on motivation for palatable food: A dose-addition analysis study in mice

Sara Jane Ward 1*, Timothy W. Lefever 1, Cavario Jackson 1, Ronald J. Tallarida 2, Ellen A. Walker 1

1 Temple University School of Pharmacy 2 Temple University School of Medicine

* Address correspondence to: E-mail: saraward{at}temple.edu

Abstract

The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid CB1 receptor antagonist and a serotonin 5-HT2C receptor agonist alone and in combination attenuate motivation for the liquid nutritional drink Ensure® as measured by a progressive ratio (PR) schedule of reinforcement in male C57BL/6 mice. Pretreatment (15 min, IP) with either the CB1 receptor antagonist SR141716 (SR) or the 5-HT2C receptor agonist m-chlorophenylpiperazine (mCPP) dose-dependently decreased the maximum ratio completed under the PR schedule (break point) in mice. ED25 values for SR and mCPP to decrease break point were determined and the relative potency of each drug alone was quantified. Fixed dose-ratio pairs of SR/mCPP based on their relative potency were then administered. Dose-addition analysis comparing the experimentally determined potency for SR/mCPP combinations with their predicted additive potency revealed that SR/mCPP combinations in 1:1 and 2:1 ratios based on relative potency produced significant synergistic attenuation of break point for Ensure®. The ED25 values for decreasing break point were consistently lower than ED25 values for decreasing response rate, and synergistic effects of SR/mCPP combinations on break point were seen independent of synergistic effects on response rate. These results indicate that cannabinoid CB1 and serotonin 5-HT2C receptors are involved in motivated feeding behavior in mice and that these compounds can synergistically modulate motivation for palatable food with the synergy dependent upon the ratio of SR to mCPP in the combination.


Key words: cannabinoid, dose-addition analysis, drug combination, motivation, progressive ratio, serotonin




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