E Martín-García, V.Deroche et al. dans Neuropsychopharmacology

Le 11 décembre 2015

Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors.
Martín-García E, Bourgoin L, Cathala A, Kasanetz F, Mondesir M, Gutiérrez-Rodriguez A, Reguero L, Fiancette JF, Grandes P, Spampinato U, Maldonado R, Piazza PV, Marsicano G, Deroche-Gamonet V.  Neuropsychopharmacology. 2015 Nov 27. doi: 10.1038/npp.2015.351. 

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Cocaine taking behavior: CB1 receptors in Glu and GABA neurons don’t play the same role. 

The endocannabinoid system acts on brain regions involved in reinforcement and addiction to drugs of abuse such as cocaine. The CB1 receptor is the main component of the endocannabinoid system and plays a key role in these processes. So far, however, CB1 receptors have been globally targeted, independent of their localization on specific neuronal populations, including glutamatergic or GABAergic neurons, generating controversial and potentially biased results. Here we demonstrate that the control exercised by CB1 receptors over cocaine taking behavior is differential depending on their localization in glutamatergic or GABAergic neurons. Thus, CB1 receptors in glutamatergic neurons control associative learning through which environmental stimuli gain control over drug seeking while CB1 receptors located on GABAergic neurons control the sensitivity to the primary rewarding effects of the drug.

Véronique Deroche: « For the first time, we studied cocaine intravenous self-administration in transgenic mice lacking CB1 either in cortical glutamatergic (Glu-CB1) or in forebrain GABAergic neurons (GABA-CB1).

In addition, we uniquely and extensively questioned several key components of cocaine use, allowing us to eventually disentangle components controlled by “glutamatergic” CB1 receptors from those controlled by “GABAergic” ones. Indeed, cocaine seeking relies on various dimensions, including sensitivity to the primary rewarding effects of the drug, ability to associative learning through which environmental stimuli gain control over drug seeking, altered cognitive inhibitory control…, which predominantly involve either the glutamatergic or the GABAergic transmission. We showed that GABA-CB1 dampens sensitivity to cocaine reinforcing effects while Glu-CB1 modulates cocaine taking by controlling associative learning processes.

Finally, we also investigated neurobiological mechanisms by which these subpopulations of receptors exert their respective control. GABA-CB1 exerts its effects by modulating cocaine-induced release of dopamine in the nucleus accumbens, the primary neurobiological target of cocaine reinforcing effects, while Glu-CB1 alters long term markers of synaptic plasticity in the same structure.

Contributions of our study:

1. We demonstrate that both Glu- and GABA-CB1 receptors control cocaine use. This is a break with the common thinking, issued from full CB1 blockade, that CB1 only controls glutamate-related dimensions of cocaine use.

2. We do not simply test cocaine intake, but uniquely and extensively question psychopharmacological dimensions controlling cocaine seeking and taking, thereby precisely identifying specific mechanisms underlying cocaine use.

3. We reveal that CB1 receptor controls very distinct aspects of cocaine use depending on its glutamatergic or GABAergic localization, i.e. associative learning-dependent processes and sensitivity to cocaine, respectively. By showing that this dichotomy is not limited to cocaine reward but extend to behaviors driven by natural reinforcers, we shed new and unsuspected light on previous observations.

4. Our study suggests that altered balance in Glu-CB1 and GABA-CB1 activities could define a threshold between “safe” cocaine use and vulnerability to cocaine addiction. »

Contact: Dr Veronique DEROCHE-GAMONET PhD, HDR, Research Director INSERM /

Dernière mise à jour le 14.12.2015

First author

Elena Martín García PhD, Post-Doc. Currently Assistant professor in the Dept of Experimental Sciences and health (DCEXS) at the University Pompeu Fabra (UPF) in Barcelona (Spain).