title: Evaluation of guanfacine as a potential medication for alcohol use disorder in long-term drinking rats: behavioral and electrophysiological findings.
abstract: One of the main treatment challenges in alcohol use disorder (AUD) is the high rate of craving in combination with decreased cognitive functioning including impaired decision making and impulse control that often lead to relapse. Recent studies show that guanfacine, an α-2-adrenoceptor agonist and FDA-approved ADHD medication, attenuates stress-induced relapse of several drugs of abuse including alcohol. Here we evaluated guanfacine's effects on voluntary alcohol intake, the alcohol deprivation effect (ADE), alcohol seeking behavior, and cue/priming-induced reinstatement in Wistar rats that had voluntarily consumed alcohol for at least 2 months before treatment. In addition, guanfacine's ability to regulate glutamatergic neurotransmission was evaluated through electrophysiological recordings in medial prefrontal cortex (mPFC) slices prepared from long-term drinking rats (and alcohol-naive controls) that had received three daily guanfacine (0.6 mg/kg/day) or vehicle injections in vivo. Guanfacine decreased alcohol intake in high, but not low, alcohol-consuming rats and the effects were generally more long lasting than that of the AUD medication naltrexone. Repeated guanfacine treatment induced a long-lasting decrease in alcohol intake, persistent up to five drinking sessions after the last injection. In addition, guanfacine attenuated the ADE as well as alcohol seeking and cue/priming-induced reinstatement of alcohol seeking. Finally, subchronic guanfacine treatment normalized an alcohol-induced dysregulated glutamatergic neurotransmission in the mPFC. These results support previous studies showing that guanfacine has the ability to improve prefrontal connectivity through modulation of the glutamatergic system. Together with the fact that guanfacine appears to be clinically safe, these results merit evaluation of guanfacine's clinical efficacy in AUD individuals.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ida
authors.initials: I
authors.lastname: Fredriksson
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nitya
authors.initials: N
authors.lastname: Jayaram-Lindström
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Wirf
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Nylander
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erica
authors.initials: E
authors.lastname: Nyström
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Jardemark
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Steensland
mesh_terms: D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy / Q000503:physiopathology; D019973:Alcohol-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage; D018698:Glutamic Acid / Q000378:metabolism; D016316:Guanfacine / Q000494:pharmacology*; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D046509:Tissue Culture Techniques; D016896:Treatment Outcome
chemical_list: D000427:Alcohol Deterrents; D002492:Central Nervous System Depressants; D016316:Guanfacine; D000431:Ethanol; D018698:Glutamic Acid; D009271:Naltrexone