title: The endocannabinoid 2-arachidonoylglycerol inhibits long-term potentiation of glutamatergic synapses onto ventral tegmental area dopamine neurons in mice.
abstract: Drugs of abuse cause changes in the mesocorticolimbic dopamine (DA) system, such as a long-term potentiation (LTP)-like phenomenon at glutamatergic synapses onto ventral tegmental area (VTA) DA neurons. Abolishing this LTP interferes with drug-seeking behavior. Endocannabinoids (ECs) can be released by DA neurons in response to repetitive activation, which can inhibit glutamate release. Therefore, we hypothesized that ECs may act as negative regulators of LTP. Here we tested the induction of LTP in DA neurons of the VTA in mice expressing enhanced green fluorescent protein under the control of the tyrosine hydroxylase promoter. Immunohistochemistry showed colocalization of CB1 receptors with vesicular glutamate transporter (VGLUT)1 in terminals near DA neuron dendrites, with less extensive colocalization with VGLUT2. In addition, a CB1 receptor agonist, as well as trains of stimulation leading to EC production, decreased glutamate release onto DA neurons. We found that blocking CB1 receptors or synthesis of the EC 2-arachidonoylglycerol (2-AG) was without effect on basal excitatory postsynaptic potential amplitude; however, it facilitated the induction of LTP. As previously reported, antagonizing γ-aminobutyric acid (GABA)(A) transmission also facilitated LTP induction. Combining GABA(A) and CB1 receptor antagonists did not lead to larger LTP. LTP induced in the presence of CB1 receptor blockade was prevented by an N-methyl-d-aspartate receptor antagonist. Our observations argue in favor of the hypothesis that 2-AG acts as a negative regulator of LTP in the VTA. Understanding the factors that regulate long-term synaptic plasticity in this circuit is critical to aid our comprehension of drug addiction in humans.
authors.affiliation: Department of Pharmacology, Université de Montréal, 2900 Boulevard Édouard-Montpetit, Montréal, QC, Canada H3T 1J4.
authors.forename: Christian
authors.initials: C
authors.lastname: Kortleven
authors.forename: Caroline
authors.initials: C
authors.lastname: Fasano
authors.forename: Dominic
authors.initials: D
authors.lastname: Thibault
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.forename: Louis-Eric
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D063388:Endocannabinoids; D018698:Glutamic Acid / Q000378:metabolism*; D005989:Glycerides / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D004298:Dopamine