Original Article

Neuropsychopharmacology (2007) 32, 2260–2266; doi:10.1038/sj.npp.1301365; published online 28 March 2007

Subchronic Cannabinoid Agonist (WIN 55,212-2) Treatment during Cocaine Abstinence Alters Subsequent Cocaine Seeking Behavior

Gustavo González-Cuevas1, Harinder Aujla2, Rémi Martin-Fardon2, José Antonio López-Moreno1, Miguel Navarro1,3 and Friedbert Weiss2,3

  1. 1Laboratorio de Psicobiología, Universidad Complutense de Madrid, Madrid, Spain
  2. 2Molecular and Integrative Neurosciences Department (MIND), The Scripps Research Institute, La Jolla, CA, USA

Correspondence: G González-Cuevas, Laboratorio de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, Campus de Somosaguas S/N, E-28223, Pozuelo de Alarcón, Madrid, Spain. Tel: +34 913943093; Fax: +34 913943189; E-mail: gugocu@psi.ucm.es

3These authors contributed equally to this work.

Received 26 June 2006; Revised 5 December 2006; Accepted 12 January 2007; Published online 28 March 2007.



The co-abuse of marijuana with cocaine is widespread, but it has not been until recently that the relationship between the behavioral effects of cannabinoids and cocaine has begun to be unveiled in animal models. Male Wistar rats were trained to intravenously self-administer cocaine until a stable baseline was reached. Rats then were subjected to a 5-day cocaine deprivation period during which they were treated daily with the cannabinoid receptor agonist WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) (0, 0.3, 1, and 3 mg/kg; i.p.). Following this subchronic treatment, rats were tested, in counterbalanced order, in a test of anxiety (elevated plus-maze), as well as extinction and cue-induced reinstatement tests, the latter conducted according to a between-within procedure. Subchronic administration of WIN 55,212-2 was found to produce dose-dependent alterations of performance in the extinction, reinstatement, and anxiety tests with the lowest dose of WIN 55,212-2 producing the highest resistance to extinction and reinstatement, and the highest dose of WIN 55,212-2 producing the highest anxiolytic activity. Subchronic treatment with WIN 55,212-2 in rats without a history of cocaine self-administration did not affect anxiety levels. The results suggest an important role of the cannabinoid system in neuronal processes underlying cocaine seeking behavior. However, further studies will be necessary to understand possible implications of these findings for a role of the cannabinoid system as a treatment target for human cocaine abuse.


cocaine, cannabinoids, WIN 55,212-2, extinction, reinstatement, anxiety

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