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BEHAVIORAL PHARMACOLOGY

Effects of a Cannabinoid₁ Receptor Antagonist and Serotonin_2C Receptor Agonist Alone and in Combination on Motivation for Palatable Food: A Dose-Addition Analysis Study in Mice

Departments of Pharmaceutical Sciences (S.J.W., T.W.L., C.J., E.A.W.) and Pharmacology (R.J.T.), Temple University, Philadelphia, Pennsylvania

The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid (CB)₁ receptor antagonist and a serotonin (5-HT)_2C 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 i.p.) with either the CB₁ receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) (SR; Rimonabant or Acomplia) or the 5-HT_2C 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-HT_2C 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/mCPP in the combination.

Address correspondence to: Dr. Sara Jane Ward, Department of Pharmaceutical Sciences, 3307 North Broad Street, Temple University School of Pharmacy, Philadelphia, PA 19140. E-mail: saraward{at}temple.edu