title: CRF-R2 and the heterosynaptic regulation of VTA glutamate during reinstatement of cocaine seeking.
abstract: Stress can reinstate cocaine seeking through an interaction between the stress hormone corticotropin releasing factor (CRF) and glutamate release onto dopamine neurons in the ventral tegmental area (VTA). To better understand the underlying causes, synaptic mechanisms were investigated in brain slices from rats. In control tissue, EPSCs displayed concentration-dependent, bimodal responses to CRF potentiation at low concentrations (3-100 nm) and attenuation at higher concentrations (300 nm). EPSC potentiation and attenuation were mediated by CRF-R1 and CRF-R2 receptor subtypes, respectively, localized to presynaptic terminals. The CRF-R2 attenuation was blocked by the GABA-B receptor antagonist CGP55843. Additional recordings of GABA-A IPSCs showed CRF-R2 activation-facilitated presynaptic release of GABA, suggesting that CRF-R2 may regulate glutamate release via heterosynaptic facilitation of GABA synapses. After chronic cocaine self-administration and extinction training, the sensitivity of glutamate and GABA receptors was unchanged. However, the ability of CRF-R2 agonists to depress EPSCs and potentiate IPSCs was diminished. After yohimbine plus cue reinstatement, the actions of CRF-R2 on GABA and glutamate release were reversed. CRF-R2 activation increased EPSCs as a result of a reduction of tonic GABA-dependent inhibition. After reinstatement, application of the A1 adenosine antagonist 1,3-dipropyl-8-cyclopentylxanthine increased GABA tone to inhibit the CRF-R2 action. Blockade of GABA-B receptors prevented both the CRF-R2 increase in EPSCs and the attenuation produced by 1,3-dipropyl-8-cyclopentylxanthine. These studies demonstrate that presynaptic CRF-R1/R2 tightly regulate glutamate transmission in the VTA via a concerted, heterosynaptic manner that may become altered by stress-related pathologies, such as addiction.
authors: Medical University of South Carolina, Charleston, South Carolina 29425.
authors: Courtney L
authors: CL
authors: Williams
authors: Medical University of South Carolina, Charleston, South Carolina 29425.
authors: William C
authors: WC
authors: Buchta
authors: Medical University of South Carolina, Charleston, South Carolina 29425 Riegel@musc.edu.
authors: Arthur C
authors: http://orcid.org/0000-0001-7758-4436
authors: AC
authors: Riegel
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012646:Self Administration; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000502:physiology; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D018377:Neurotransmitter Agents; D011480:Protease Inhibitors; D018019:Receptors, Corticotropin-Releasing Hormone; D018698:Glutamic Acid; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D003042:Cocaine
keywords: CRF; GABA; addiction; dopamine; glutamate; stress