Article

Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons.

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Journal of Neuroscience (impact factor: 7.11). 03/2008; 28(6):1385-97. DOI:10.1523/JNEUROSCI.4033-07.2008 pp.1385-97
Source: PubMed

ABSTRACT Drugs that increase GABA levels in the brain reduce cocaine seeking in rodents and humans, suggesting that GABAergic inhibition regulates cocaine-seeking behavior. We previously reported that repeated cocaine exposure in vivo facilitates long-term potentiation by reducing the strength of GABAergic inhibition in dopamine neurons of the ventral tegmental area (VTA). Selective blockade of cocaine-induced reduction of GABAergic inhibition in the VTA might diminish cocaine-induced aberrant synaptic plasticity and addictive behavior. Here, we investigated the mechanism for cocaine-induced reduction of GABAergic inhibition. We show that a pathophysiologically relevant concentration of cocaine enables a normally ineffective stimulus to induce long-term depression (LTD) of IPSCs (I-LTD) in VTA dopamine neurons of midbrain slices. Activation of D2 dopamine receptors and group I metabotropic glutamate receptors and subsequent recruitment of endocannabinoid signaling are required for I-LTD induction. We further demonstrate that in vivo pretreatment with antagonists to these receptors blocks cocaine-induced reduction of GABAergic inhibition and that repeated cocaine exposure in vivo occludes the subsequent induction of I-LTD ex vivo. Together, these results suggest that repeated cocaine exposure reduces the strength of GABAergic inhibition in dopamine neurons by inducing I-LTD-like modification in vivo.

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Keywords

cocaine-induced aberrant synaptic plasticity
 
cocaine-induced reduction
 
D2 dopamine receptors
 
dopamine neurons
 
GABAergic inhibition
 
I-LTD
 
I-LTD ex vivo
 
I-LTD induction
 
increase GABA levels
 
induce long-term depression
 
inducing I-LTD-like modification
 
ineffective stimulus
 
pathophysiologically relevant concentration
 
receptors blocks cocaine-induced reduction
 
repeated cocaine exposure
 
subsequent recruitment
 
ventral tegmental area
 
vivo facilitates long-term potentiation
 
vivo pretreatment
 
VTA dopamine neurons