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

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

Author information

1
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina. Electronic address: scofield@musc.edu.
2
Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina.
3
Department of Neurosciences, Tufts University, Boston, Massachusetts.

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.

KEYWORDS:

Astrocytes; Biosensor; Cocaine; DREADD; Glutamate; Reinstatement

PMID:
25861696
PMCID:
PMC4547911
DOI:
10.1016/j.biopsych.2015.02.016
[Indexed for MEDLINE]
Free PMC Article

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