Endocannabinoid signaling mediates cocaine-induced inhibitory synaptic plasticity in midbrain dopamine neurons.
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.
Pan
Bin
B
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Hillard
Cecilia J
CJ
Liu
Qing-song
QS
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D004298:Dopamine / Q000502:physiology*; D063388:Endocannabinoids; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D003042:Cocaine; D004298:Dopamine