A single in vivo exposure to cocaine abolishes endocannabinoid-mediated long-term depression in the nucleus accumbens.
In the nucleus accumbens (NAc), a key structure to the effects of all addictive drugs, presynaptic cannabinoid CB1 receptors (CB1Rs) and postsynaptic metabotropic glutamate 5 receptors (mGluR5s) are the principal effectors of endocannabinoid (eCB)-mediated retrograde long-term depression (LTD) (eCB-LTD) at the prefrontal cortex-NAc synapses. Both CB1R and mGluR5 are involved in cocaine-related behaviors; however, the impact of in vivo cocaine exposure on eCB-mediated retrograde synaptic plasticity remains unknown. Electrophysiological and biochemical approaches were used, and we report that a single in vivo cocaine administration abolishes eCB-LTD. This effect of cocaine was not present in D1 dopamine receptor (D1R) -/- mice and was prevented when cocaine was coadministered with the selective D1R antagonist 8-chloro-2,3,4,5-tetrahydro-3-5-1h-3-benzazepin-7-ol (0.5 mg/kg) or with the NMDA receptor (NMDAR) blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (1 mg/kg), suggesting the involvement of D1R and NMDAR. We found that the cocaine-induced blockade of retrograde signaling was correlated with enhanced expression levels of Homer scaffolding proteins containing the coiled-coil domain and accompanied by a strong reduction of mGluR5 surface expression. The results suggest that cocaine-induced loss of eCB retrograde signaling is caused by a reduction in the ability of mGluR5 to translate anterograde glutamate transmission into retrograde eCB signaling.
Equipe Institut National de la Santé et de la Recherche Médicale Avenir (Plasticité Synaptique: Maturation et Addiction), Centre National de la Recherche Scientifique 5091, Institut Magendie des Neurosciences, 33077 Bordeaux Cedex, France.
Lawrence
L
Fourgeaud
Susana
S
Mato
Delphine
D
Bouchet
Agnès
A
Hémar
Paul F
PF
Worley
Olivier J
OJ
Manzoni
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004594:Electrophysiology; D063388:Endocannabinoids; D000072233:Homer Scaffolding Proteins; D015151:Immunoblotting; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D063385:Cannabinoid Receptor Modulators; D002352:Carrier Proteins; D063388:Endocannabinoids; C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine