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Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles

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Abstract

Rationale

Selective 5-HT2C receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated.

Objectives

The primary aim was to evaluate the highly selective 5-HT2C agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-HT2C receptor agonists lorcaserin and Ro 60–0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials.

Results

CP-809101 (0.3–3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60–0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials.

Conclusions

These studies support the utility of 5-HT2C agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-HT2C agonists.

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Acknowledgments

We wish to acknowledge the statistical support of Sandy Thevarkunnel (InterVivo Solutions Inc). Bioanalytical method development and sample analysis were performed under the guidance of Dr. Henrianna Pang (NoAb BioDiscoveries Inc.).

Conflict of interest

The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. InterVivo Solutions Inc, 120 Carlton St., Toronto, ON, M5A 4K2, Canada

    G. A. Higgins, L. B. Silenieks & W. Lau

  2. Department of Pharmacology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    G. A. Higgins & A. D. Le

  3. NoAb Biodiscoveries, 2820 Argentia Road, Mississauga, ON, L5N 8G4, Canada

    I. A. M. de Lannoy, D. K. H. Lee & J. Izhakova

  4. Centre for Addiction and Mental Health, 250 College St., Toronto, ON, M5T 1R8, Canada

    K. Coen, A. D. Le & P. J. Fletcher

  5. Department of Psychology, University of Toronto, Toronto, ON, M5S 3G3, Canada

    P. J. Fletcher

  6. Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8, Canada

    P. J. Fletcher

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  1. G. A. Higgins
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  2. L. B. Silenieks
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  3. W. Lau
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  4. I. A. M. de Lannoy
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  5. D. K. H. Lee
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  7. K. Coen
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  8. A. D. Le
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  9. P. J. Fletcher
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Correspondence to G. A. Higgins.

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Higgins, G.A., Silenieks, L.B., Lau, W. et al. Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles. Psychopharmacology 226, 475–490 (2013). https://doi.org/10.1007/s00213-012-2919-2

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  • DOI: https://doi.org/10.1007/s00213-012-2919-2

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