Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking

Biol Psychiatry. 2015 Oct 1;78(7):441-51. doi: 10.1016/j.biopsych.2015.02.016. Epub 2015 Feb 24.


Background: Glial cells of the central nervous system directly influence neuronal activity by releasing neuroactive small molecules, including glutamate. Long-lasting cocaine-induced reductions in extracellular glutamate in the nucleus accumbens core (NAcore) affect synaptic plasticity responsible for relapse vulnerability.

Methods: We transduced NAcore astrocytes with an adeno-associated virus vector expressing hM3D designer receptor exclusively activated by a designer drug (DREADD) under control of the glial fibrillary acidic protein promoter in 62 male Sprague Dawley rats, 4 dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor mice, and 4 wild-type littermates. Using glutamate biosensors, we measured NAcore glutamate levels following intracranial or systemic administration of clozapine N-oxide (CNO) and tested the ability of systemic CNO to inhibit reinstated cocaine or sucrose seeking following self-administration and extinction training.

Results: Administration of CNO in glial fibrillary acidic protein-hM3D-DREADD transfected animals increased NAcore extracellular glutamate levels in vivo. The glial origin of released glutamate was validated by an absence of CNO-mediated release in mice expressing a dominant-negative soluble N-ethylmaleimide-sensitive factor attachment protein receptor variant in glia. Also, CNO-mediated release was relatively insensitive to N-type calcium channel blockade. Systemic administration of CNO inhibited cue-induced reinstatement of cocaine seeking in rats extinguished from cocaine but not sucrose self-administration. The capacity to inhibit reinstated cocaine seeking was prevented by systemic administration of the group II metabotropic glutamate receptor antagonist LY341495.

Conclusions: DREADD-mediated glutamate gliotransmission inhibited cue-induced reinstatement of cocaine seeking by stimulating release-regulating group II metabotropic glutamate receptor autoreceptors to inhibit cue-induced synaptic glutamate spillover.

Keywords: Astrocytes; Biosensor; Cocaine; DREADD; Glutamate; Reinstatement.

Publication types

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

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Calcium Channels, N-Type / metabolism
  • Central Nervous System Agents / pharmacology
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / physiopathology*
  • Cocaine-Related Disorders / therapy*
  • Cues
  • Dietary Sucrose / administration & dosage
  • Disease Models, Animal
  • Dopamine Uptake Inhibitors / administration & dosage
  • Drug-Seeking Behavior / drug effects
  • Drug-Seeking Behavior / physiology*
  • Extinction, Psychological / drug effects
  • Genetic Therapy
  • Glutamic Acid / metabolism*
  • Male
  • Mice, Transgenic
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism*
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / metabolism
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Self Administration


  • Calcium Channels, N-Type
  • Central Nervous System Agents
  • Dietary Sucrose
  • Dopamine Uptake Inhibitors
  • Receptors, G-Protein-Coupled
  • Receptors, Metabotropic Glutamate
  • SNARE Proteins
  • Glutamic Acid
  • Cocaine
  • Clozapine
  • clozapine N-oxide