title: Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.
abstract: Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine.
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, USA.
authors.forename: Huikun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Treadway
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Covey
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
authors.affiliation: Electrophysiology Research Section, Cellular Neurobiology Research Branch, National Institute on Drug Abuse, 251 Bayview Boulevard, Suite 200, Baltimore, MD 21224, USA. Electronic address: clupica@mail.nih.gov.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000378:metabolism*; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D063388:Endocannabinoids / Q000096:biosynthesis / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005989:Glycerides / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism; D012201:Reward; D009435:Synaptic Transmission; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D018765:Dopamine Uptake Inhibitors; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D018340:Receptors, Adrenergic, alpha-1; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D003042:Cocaine; D002118:Calcium; D004298:Dopamine; D009638:Norepinephrine