Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons

Nat Commun. 2016 Jul 22:7:12199. doi: 10.1038/ncomms12199.

Abstract

Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Arachidonic Acids / metabolism
  • Cocaine / adverse effects*
  • Conditioning, Classical
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Endocannabinoids / metabolism*
  • Excitatory Postsynaptic Potentials / drug effects
  • Glycerides / metabolism
  • Hypothalamic Area, Lateral / drug effects
  • Hypothalamic Area, Lateral / metabolism
  • Inhibitory Postsynaptic Potentials / drug effects
  • Male
  • Mice, Inbred C57BL
  • Models, Biological
  • Neural Inhibition* / drug effects
  • Orexin Receptors / metabolism
  • Orexins / metabolism*
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism
  • Recurrence
  • Restraint, Physical*
  • Signal Transduction / drug effects
  • Stress, Physiological*
  • Synaptic Transmission / drug effects
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Arachidonic Acids
  • CNR1 protein, mouse
  • Endocannabinoids
  • Glycerides
  • Orexin Receptors
  • Orexins
  • Receptor, Cannabinoid, CB1
  • gamma-Aminobutyric Acid
  • glyceryl 2-arachidonate
  • Cocaine