title: Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects.
abstract: Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation (LTP) in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning, and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I-LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I-LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg; four pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB(1) antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB(1) and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.forename: Peng
authors.initials: P
authors.lastname: Zhong
authors.forename: Dalong
authors.initials: D
authors.lastname: Sun
authors.forename: Qing-song
authors.initials: QS
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D048588:Benzoxazines / Q000494:pharmacology; D001703:Biophysics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases; D018756:GABA Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010852:Picrotoxin; D010880:Piperidines; D011720:Pyrazoles; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone