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

• Published in: Biological psychiatry (1969) Vol. 78; no. 7; pp. 441 - 451
• Main Authors: Scofield, Michael D, Boger, Heather A, Smith, Rachel J, Li, Hao, Haydon, Philip G, Kalivas, Peter W
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015
• Subjects: Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Biosensor; Calcium Channels, N-Type - metabolism; Central Nervous System Agents - pharmacology; Clozapine - analogs & derivatives; Clozapine - pharmacology; Cocaine; Cocaine - administration & dosage; Cocaine-Related Disorders - physiopathology; Cocaine-Related Disorders - therapy; Cues; Dietary Sucrose - administration & dosage; Disease Models, Animal; Dopamine Uptake Inhibitors - administration & dosage; DREADD; Drug-Seeking Behavior - drug effects; Drug-Seeking Behavior - physiology; Extinction, Psychological - drug effects; Genetic Therapy; Glutamate; Glutamic Acid - metabolism; Male; Mice, Transgenic; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Psychiatry; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - metabolism; Reinstatement; Self Administration; SNARE Proteins - genetics; SNARE Proteins - metabolism; Cocaine; Glutamate; Astrocytes; Biosensor; Reinstatement; DREADD
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2015.02.016

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.