title: Gq-DREADD Selectively Initiates Glial Glutamate Release and Inhibits Cue-induced Cocaine Seeking.
abstract: 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.
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina. Electronic address: scofield@musc.edu.
authors: Michael D
authors: MD
authors: Scofield
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
authors: Heather A
authors: HA
authors: Boger
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
authors: Rachel J
authors: RJ
authors: Smith
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
authors: Hao
authors: H
authors: Li
authors: Department of Neurosciences, Tufts University, Boston, Massachusetts.
authors: Philip G
authors: PG
authors: Haydon
authors: Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
authors: Peter W
authors: PW
authors: Kalivas
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000503:physiopathology* / Q000628:therapy*; D003463:Cues; D019422:Dietary Sucrose / Q000008:administration & dosage; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects; D015316:Genetic Therapy; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D050600:SNARE Proteins / Q000235:genetics / Q000378:metabolism; D012646:Self Administration
chemical_list: D020864:Calcium Channels, N-Type; D002491:Central Nervous System Agents; D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D050600:SNARE Proteins; D018698:Glutamic Acid; D003042:Cocaine; D003024:Clozapine; C079149:clozapine N-oxide
keywords: Astrocytes; Biosensor; Cocaine; DREADD; Glutamate; Reinstatement