title: Rat nucleus accumbens core astrocytes modulate reward and the motivation to self-administer ethanol after abstinence.
abstract: Our understanding of the active role that astrocytes play in modulating neuronal function and behavior is rapidly expanding, but little is known about the role that astrocytes may play in drug-seeking behavior for commonly abused substances. Given that the nucleus accumbens is critically involved in substance abuse and motivation, we sought to determine whether nucleus accumbens astrocytes influence the motivation to self-administer ethanol following abstinence. We found that the packing density of astrocytes that were expressing glial fibrillary acidic protein increased in the nucleus accumbens core (NAcore) during abstinence from EtOH self-administration. No change was observed in the nucleus accumbens shell. This increased NAcore astrocyte density positively correlated with the motivation for ethanol. Astrocytes can communicate with one another and influence neuronal activity through gap-junction hemichannels. Because of this, the effect of blocking gap-junction hemichannels on the motivation for ethanol was examined. The motivation to self-administer ethanol after 3 weeks abstinence was increased following microinjection of gap-junction hemichannel blockers into the NAcore at doses that block both neuronal and astrocytic channels. In contrast, no effect was observed following microinjection of doses that are not thought to block astrocytic channels or following microinjection of either dose into the nucleus accumbens shell. Additionally, the motivation for sucrose after 3 weeks abstinence was unaffected by NAcore gap-junction hemichannel blockers. Next, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were selectively expressed in NAcore astrocytes to test the effect of astrocyte stimulation. DREADD activation increased cytosolic calcium in primary astrocytes, facilitated responding for rewarding brain stimulation, and reduced the motivation for ethanol after 3 weeks abstinence. This is the first work to modulate drug-seeking behavior with astrocyte-specific DREADDs. Taken together, our findings demonstrate that NAcore astrocytes can shape the motivation to self-administer ethanol; suggesting that the development of ligands which selectively stimulate astrocytes may be a successful strategy to abate ethanol-seeking behavior.
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bull
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Kelen C C
authors.initials: KC
authors.lastname: Freitas
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Poland
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
authors.forename: Wahab A
authors.initials: WA
authors.lastname: Syed
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Urban
authors.affiliation: Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA.
authors.forename: Sabrina C
authors.initials: SC
authors.lastname: Minter
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Shelton
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.affiliation: 1] Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA [2] Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: 1] Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA [2] Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: M Scott
authors.initials: MS
authors.lastname: Bowers
mesh_terms: D000428:Alcohol Drinking / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D009042:Motivation; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration
chemical_list: D002492:Central Nervous System Depressants; D005904:Glial Fibrillary Acidic Protein; D000431:Ethanol; D002118:Calcium