title: Ethanol Disinhibits Dorsolateral Striatal Medium Spiny Neurons Through Activation of A Presynaptic Delta Opioid Receptor.
abstract: The dorsolateral striatum mediates habit formation, which is expedited by exposure to alcohol. Across species, alcohol exposure disinhibits the DLS by dampening GABAergic transmission onto this structure's principal medium spiny projection neurons (MSNs), providing a potential mechanistic basis for habitual alcohol drinking. However, the molecular and circuit components underlying this disinhibition remain unknown. To examine this, we used a combination of whole-cell patch-clamp recordings and optogenetics to demonstrate that ethanol potently depresses both MSN- and fast-spiking interneuron (FSI)-MSN GABAergic synaptic transmission in the DLS. Concentrating on the powerfully inhibitory FSI-MSN synapse, we further show that acute exposure of ethanol (50 mM) to striatal slices activates delta opioid receptors that reside on FSI axon terminals and negatively couple to adenylyl cyclase to induce a long-term depression of GABA release onto both direct and indirect pathway MSNs. These findings elucidate a mechanism through which ethanol may globally disinhibit the DLS.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Mary H
authors.initials: MH
authors.lastname: Patton
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Bradley M
authors.initials: BM
authors.lastname: Roberts
authors.affiliation: Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, Division of Intramural Clinical and Biological Research, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Bethesda, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Mathur
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D000075402:Channelrhodopsins / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology*; D000431:Ethanol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D010320:Parvalbumins; D020710:RGS Proteins; D043884:Receptor, Cannabinoid, CB1; D017465:Receptors, Opioid, delta; D013873:Thionucleotides; C116925:regulator of g-protein signaling 9; D006153:Guanosine Diphosphate; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; C023427:guanosine 5'-O-(2-thiodiphosphate)