title: Reverse pharmacogenetic modulation of the nucleus accumbens reduces ethanol consumption in a limited access paradigm.
abstract: Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.
authors.affiliation: 1] Department of Psychiatry, NYU School of Medicine, New York, NY, USA [2] Department of Neuroscience and Physiology, Smilow Neuroscience Program, NYU Neuroscience Institute, New York, NY, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cassataro
authors.affiliation: 1] Department of Neuroscience and Physiology, Smilow Neuroscience Program, NYU Neuroscience Institute, New York, NY, USA [2] Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Daniella
authors.initials: D
authors.lastname: Bergfeldt
authors.affiliation: 1] Department of Neuroscience and Physiology, Smilow Neuroscience Program, NYU Neuroscience Institute, New York, NY, USA [2] Department of Medicine, Uppsala Biomedicinska Centrum, Uppsala University, Polacksbacken, Sweden.
authors.forename: Cariz
authors.initials: C
authors.lastname: Malekian
authors.affiliation: Department of Psychiatry, Division of Translational Imaging, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: Jared X
authors.initials: JX
authors.lastname: Van Snellenberg
authors.affiliation: 1] Neuroimaging Laboratory, NIAAA Intramural Program, NIH, Bethesda, MD, USA [2] Department of Medicine, Behavioral Pharmacology and Neuroimaging Laboratory, Brookhaven National Laboratory, Upton, NY, USA.
authors.forename: Panayotis K
authors.initials: PK
authors.lastname: Thanos
authors.affiliation: Department of Neuroscience and Physiology, Smilow Neuroscience Program, NYU Neuroscience Institute, New York, NY, USA.
authors.forename: Gord
authors.initials: G
authors.lastname: Fishell
authors.affiliation: 1] Department of Psychiatry, NYU School of Medicine, New York, NY, USA [2] Department of Neuroscience and Physiology, Smilow Neuroscience Program, NYU Neuroscience Institute, New York, NY, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Sjulson
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control*; D000818:Animals; D015198:Designer Drugs / Q000008:administration & dosage*; D005822:Genetic Vectors / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D010597:Pharmacogenetics / Q000379:methods*
chemical_list: D015198:Designer Drugs
references.citation: Front Hum Neurosci. 2009 Sep 02;3:22
references.pmid: 19750197
references.citation: World Neurosurg. 2013 Sep-Oct;80(3-4):S28.e21-31
references.pmid: 22824557
references.citation: Front Neuroanat. 2010 Dec 29;4:150
references.pmid: 21228905
references.citation: Alcohol. 2006 Feb;38(2):73-9
references.pmid: 16839853
references.citation: Chem Rev. 2008 May;108(5):1588-602
references.pmid: 18447399
references.citation: Stereotact Funct Neurosurg. 2008;86(5):320-9
references.pmid: 18841037
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8
references.pmid: 17360345
references.citation: Neurosci Lett. 2010 Apr 5;473(2):77-81
references.pmid: 20156524
references.citation: Alcohol. 2011 Feb;45(1):19-32
references.pmid: 20843634
references.citation: Science. 2011 Jul 29;333(6042):637-42
references.pmid: 21798952
references.citation: Annu Rev Neurosci. 2011;34:389-412
references.pmid: 21692661
references.citation: Addict Biol. 2011 Oct;16(4):620-3
references.pmid: 21762290
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1998 Jul;22(5):723-39
references.pmid: 9723115
references.citation: Addict Biol. 2009 Jan;14(1):108-18
references.pmid: 18855799
references.citation: Life Sci. 2005 May 27;77(2):130-9
references.pmid: 15862598
references.citation: J Neurosurg Pediatr. 2010 Aug;6(2):115-22
references.pmid: 20672930
references.citation: Q J Stud Alcohol. 1962 Mar;23:26-33
references.pmid: 14493106
references.citation: Alcohol. 2011 Feb;45(1):33-44
references.pmid: 20843635
references.citation: Physiol Behav. 2005 Jan 31;84(1):53-63
references.pmid: 15642607
references.citation: J Neurochem. 2001 Sep;78(5):1094-103
references.pmid: 11553683
references.citation: Lancet Neurol. 2011 Apr;10(4):309-19
references.pmid: 21419704
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references.pmid: 19710631
references.citation: Pharmacol Rev. 2011 Jun;63(2):291-315
references.pmid: 21415127
references.citation: Alcohol. 1995 Sep-Oct;12(5):397-402
references.pmid: 8519433
references.citation: Neuron. 2009 Jul 16;63(1):27-39
references.pmid: 19607790
references.citation: Neurology. 2009 Nov 17;73(20):1662-9
references.pmid: 19828868
references.citation: Pharmacol Biochem Behav. 2009 Apr;92(2):335-42
references.pmid: 19353807
references.citation: Neuropsychopharmacology. 2010 Feb;35(3):783-91
references.pmid: 19924113
references.citation: Am J Prev Med. 2011 Nov;41(5):516-24
references.pmid: 22011424
references.citation: Physiol Behav. 2000 Sep 15;70(5):453-63
references.pmid: 11110998
references.citation: J Clin Invest. 2011 Apr;121(4):1424-8
references.pmid: 21364278
references.citation: Alcohol Clin Exp Res. 2004 May;28(5):720-8
references.pmid: 15166646
references.citation: J Neurosci. 2008 Jan 30;28(5):1076-84
references.pmid: 18234886
references.citation: Front Neuroanat. 2011 Jul 18;5:41
references.pmid: 21811439
references.citation: Proc Natl Acad Sci U S A. 1984 Jun;81(11):3543-6
references.pmid: 6587369