title: A sustained depressive state promotes a guanfacine reversible susceptibility to alcohol seeking in rats.
abstract: High rates of comorbidity between alcohol use disorder (AUD) and major depressive disorder (MDD) are reported. Preclinical models examining effects of primary depression on secondary AUD are currently absent, preventing adequate testing of drug treatment. Here, we combined social defeat-induced persistent stress (SDPS) and operant alcohol self-administration (SA) paradigms to assess causality between these two neuropsychiatric disorders. We then exploited guanfacine, an FDA-approved adrenergic agent reported to reduce drug craving in humans, against SDPS-induced modulation of operant alcohol SA. Wistar rats were socially defeated and isolated for a period of ≥9 weeks, during which depression-like symptomatology (cognitive and social behavioral symptoms) was assessed. Subsequently, animals were subjected to a 5-month operant alcohol SA paradigm, examining acquisition, motivation, extinction, and cue-induced reinstatement of alcohol seeking. The effects of guanfacine on motivation and relapse were measured at >6 months following defeat. SDPS rats exhibited significant disruption of social and cognitive behavior, including short-term spatial and long-term social memory, several months following defeat. Notably, SDPS increased motivation to obtain alcohol, and cue-induced relapse vulnerability. Guanfacine reversed the SDPS-induced effects on motivation and relapse. Together, our model mimics core symptomatology of a sustained depressive-like state and a subsequent vulnerability to alcohol abuse. We show that SDPS is strongly associated with an enhanced motivation for alcohol intake and relapse. Finally, we show that the clinically employed drug guanfacine has potential as a novel treatment option in comorbid patients, as it effectively reduced the enhanced sensitivity to alcohol and alcohol-associated stimuli.
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Danai
authors.initials: D
authors.lastname: Riga
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Leanne J M
authors.initials: LJ
authors.lastname: Schmitz
authors.affiliation: Delta Phenomics BV, Utrecht, The Netherlands.
authors.forename: Johanneke E
authors.initials: JE
authors.lastname: van der Harst
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Yvar
authors.initials: Y
authors.lastname: van Mourik
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Witte J G
authors.initials: WJ
authors.lastname: Hoogendijk
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: 1] Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands [2] Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Taco J
authors.initials: TJ
authors.lastname: De Vries
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000503:physiopathology / Q000517:prevention & control*; D000437:Alcoholism / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D003866:Depressive Disorder / Q000150:complications* / Q000503:physiopathology; D004291:Dominance-Subordination; D000431:Ethanol / Q000008:administration & dosage; D005108:Extinction, Psychological / Q000187:drug effects; D016316:Guanfacine / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D009042:Motivation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration; D012919:Social Behavior; D013315:Stress, Psychological
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D002492:Central Nervous System Depressants; D016316:Guanfacine; D000431:Ethanol