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The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice



Cocaine is a psychostimulant drug that facilitates monoaminergic neurotransmission. The endocannabinoid system, comprising the cannabinoid receptors (CB1R and CB2R), the endocannabinoids, and their metabolizing-enzymes, modulates the mesolimbic dopaminergic pathway and represents a potential target for the treatment of addiction.


Here, we tested the hypothesis that the cannabinoid receptors are implicated in cocaine-induced motor sensitization, conditioned place preference (CPP), and hippocampal activation.


Male Swiss mice received injections of AM251 (CB1R antagonist; 0.3–10 mg/kg) or JWH133 (CB2R agonist; 1–10 mg/kg) before acquisition or expression of cocaine (20 mg/kg)-induced sensitization and CPP. After the CPP test, cFos-staining was employed as a marker of neuronal activation in the hippocampus.


AM251 inhibited the acquisition (0.3, 1, and 3 mg/kg) and expression (1 and 3 mg/kg) of sensitization, as well as the acquisition (10 mg/kg) of CPP. JWH133 inhibited the acquisition (0.3 and 1 mg/kg) and expression (1 and 3 mg/kg) of both sensitization and CPP. JWH133 effects were reversed by AM630 (CB2R antagonist; 5 mg/kg). AM251 and JWH133 also prevented neuronal activation (c-Fos expression) in the hippocampus of CPP-exposed animals.


CB1R and CB2R have opposite roles in modulating cocaine-induced sensitization and CPP, possibly by preventing neuronal activation in the hippocampus.

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This research was funded by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG; APQ-02064-15), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 406122/2016-4) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; 2017/24304-0).

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Correspondence to Fabrício A. Moreira.

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Lopes, J.B., Bastos, J.R., Costa, R.B. et al. The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice. Psychopharmacology 237, 385–394 (2020). https://doi.org/10.1007/s00213-019-05370-5

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  • Psychostimulants
  • Reward
  • Drug abuse
  • Addiction
  • Memory
  • Endocannabinoids