Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area

Cell Rep. 2015 Sep 29;12(12):1997-2008. doi: 10.1016/j.celrep.2015.08.041. Epub 2015 Sep 10.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arachidonic Acids / biosynthesis
  • Arachidonic Acids / metabolism*
  • Biological Transport
  • Calcium / metabolism
  • Cocaine / pharmacology*
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / pharmacology*
  • Dopaminergic Neurons / cytology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / metabolism
  • Endocannabinoids / biosynthesis
  • Endocannabinoids / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Expression Regulation
  • Glycerides / biosynthesis
  • Glycerides / metabolism*
  • Male
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / metabolism
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Adrenergic, alpha-1 / genetics
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, GABA / genetics
  • Receptors, GABA / metabolism
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Reward
  • Synaptic Transmission
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Arachidonic Acids
  • Dopamine Uptake Inhibitors
  • Endocannabinoids
  • Glycerides
  • Receptor, Cannabinoid, CB1
  • Receptors, Adrenergic, alpha-1
  • Receptors, GABA
  • Receptors, Metabotropic Glutamate
  • gamma-Aminobutyric Acid
  • glyceryl 2-arachidonate
  • Type C Phospholipases
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Cocaine
  • Calcium
  • Dopamine
  • Norepinephrine