Original Article

Neuropsychopharmacology (2014) 39, 2835–2845; doi:10.1038/npp.2014.135; published online 2 July 2014

Rat Nucleus Accumbens Core Astrocytes Modulate Reward and the Motivation to Self-Administer Ethanol after Abstinence

Cecilia Bull1, Kelen CC Freitas2, Shiping Zou3, Ryan S Poland1, Wahab A Syed1, Daniel J Urban4, Sabrina C Minter1, Keith L Shelton2, Kurt F Hauser2, S Stevens Negus2, Pamela E Knapp2,3 and M Scott Bowers1,2

  1. 1Department of Psychiatry, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, USA
  2. 2Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
  3. 3Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, USA
  4. 4Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

Correspondence: Dr MS Bowers, Virginia Commonwealth University, Virginia Institute for Psychiatric and Behavioral Genetics, PO Box 980126, Richmond, VA 23298-0126, USA, Tel: +804 628 7646, Fax: +804 828 1471, E-mail: msbowers@vcu.edu

Received 25 November 2013; Revised 3 May 2014; Accepted 3 June 2014
Accepted article preview online 6 June 2014; Advance online publication 2 July 2014



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.

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