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Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol.
Neuropsychopharmacology. 2018 09; 43(10):2064-2074.N

Abstract

Dopamine neurons in the ventral tegmental area (VTA) influence learned behaviors and neuropsychiatric diseases including addiction. The stress peptide corticotrophin-releasing factor (CRF) contributes to relapse to drug and alcohol seeking following withdrawal, although the cellular actions are poorly understood. In this study, we show that presynaptic CRF type 1 receptors (CRF-R1) potentiate GABA release onto mouse VTA dopamine neurons via a PKC-Ca2+ signaling mechanism. In naive animals, activation of CRF-R1 by bath application of CRF or ethanol enhanced GABAA inhibitory postsynaptic currents (IPSCs). Following 3 days of withdrawal from four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure, spontaneous IPSC frequency was enhanced while CRF and ethanol potentiation of IPSCs was intact. However, withdrawal for 3 weeks or more was associated with reduced spontaneous IPSC frequency and diminished CRF and ethanol responses. Long-term withdrawal was also accompanied by decreased sensitivity to the CB1 receptor agonist WIN55212 as well as greatly enhanced sensitivity to the CB1 antagonist AM251. Inclusion of BAPTA in the internal recording solution restored the responsiveness to CRF or ethanol and reduced the potentiating actions of AM251. Together, these data suggest that GABAA inhibition of VTA dopamine neurons is regulated by presynaptic actions of CRF and endocannabinoids and that long-term withdrawal from CIE treatment enhances endocannabinoid-mediated inhibition, thereby suppressing CRF facilitation of GABA release. Such findings have implications for understanding the impact of chronic alcohol on stress-related, dopamine-mediated alcohol-seeking behaviors.

Authors+Show Affiliations

Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina & RHJ Department of Veterans Affairs, Charleston, SC, USA. Charleston Alcohol Research Center, Charleston, SC, USA.Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. Charleston Alcohol Research Center, Charleston, SC, USA.Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA. Riegel@musc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29946104

Citation

Harlan, Benjamin A., et al. "Opposing Actions of CRF-R1 and CB1 Receptors On VTA-GABAergic Plasticity Following Chronic Exposure to Ethanol." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 43, no. 10, 2018, pp. 2064-2074.
Harlan BA, Becker HC, Woodward JJ, et al. Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol. Neuropsychopharmacology. 2018;43(10):2064-2074.
Harlan, B. A., Becker, H. C., Woodward, J. J., & Riegel, A. C. (2018). Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 43(10), 2064-2074. https://doi.org/10.1038/s41386-018-0106-9
Harlan BA, et al. Opposing Actions of CRF-R1 and CB1 Receptors On VTA-GABAergic Plasticity Following Chronic Exposure to Ethanol. Neuropsychopharmacology. 2018;43(10):2064-2074. PubMed PMID: 29946104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol. AU - Harlan,Benjamin A, AU - Becker,Howard C, AU - Woodward,John J, AU - Riegel,Arthur C, Y1 - 2018/06/09/ PY - 2018/01/18/received PY - 2018/05/22/accepted PY - 2018/05/17/revised PY - 2018/6/28/pubmed PY - 2019/2/23/medline PY - 2018/6/28/entrez SP - 2064 EP - 2074 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 43 IS - 10 N2 - Dopamine neurons in the ventral tegmental area (VTA) influence learned behaviors and neuropsychiatric diseases including addiction. The stress peptide corticotrophin-releasing factor (CRF) contributes to relapse to drug and alcohol seeking following withdrawal, although the cellular actions are poorly understood. In this study, we show that presynaptic CRF type 1 receptors (CRF-R1) potentiate GABA release onto mouse VTA dopamine neurons via a PKC-Ca2+ signaling mechanism. In naive animals, activation of CRF-R1 by bath application of CRF or ethanol enhanced GABAA inhibitory postsynaptic currents (IPSCs). Following 3 days of withdrawal from four weekly cycles of chronic intermittent ethanol (CIE) vapor exposure, spontaneous IPSC frequency was enhanced while CRF and ethanol potentiation of IPSCs was intact. However, withdrawal for 3 weeks or more was associated with reduced spontaneous IPSC frequency and diminished CRF and ethanol responses. Long-term withdrawal was also accompanied by decreased sensitivity to the CB1 receptor agonist WIN55212 as well as greatly enhanced sensitivity to the CB1 antagonist AM251. Inclusion of BAPTA in the internal recording solution restored the responsiveness to CRF or ethanol and reduced the potentiating actions of AM251. Together, these data suggest that GABAA inhibition of VTA dopamine neurons is regulated by presynaptic actions of CRF and endocannabinoids and that long-term withdrawal from CIE treatment enhances endocannabinoid-mediated inhibition, thereby suppressing CRF facilitation of GABA release. Such findings have implications for understanding the impact of chronic alcohol on stress-related, dopamine-mediated alcohol-seeking behaviors. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/29946104/Opposing_actions_of_CRF_R1_and_CB1_receptors_on_VTA_GABAergic_plasticity_following_chronic_exposure_to_ethanol_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29946104/ DB - PRIME DP - Unbound Medicine ER -