title: Synaptic neurotransmission depression in ventral tegmental dopamine neurons and cannabinoid-associated addictive learning.
abstract: Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.
authors.affiliation: College of Life Sciences, Shaanxi Normal University, Xian, People's Republic of China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Lintao
authors.initials: L
authors.lastname: Jia
authors.forename: Jean-Christian
authors.initials: JC
authors.lastname: Maillet
authors.forename: Guang
authors.initials: G
authors.lastname: Bai
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Jia
authors.forename: Qiaohua
authors.initials: Q
authors.lastname: Zheng
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
authors.forename: Robert
authors.initials: R
authors.lastname: Monette
authors.forename: Zul
authors.initials: Z
authors.lastname: Merali
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Ren
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D002186:Cannabinoids / Q000378:metabolism*; D004594:Electrophysiology / Q000379:methods; D004705:Endocytosis; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000473:pathology*
chemical_list: D002186:Cannabinoids; D043884:Receptor, Cannabinoid, CB1; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2