title: Dissociation of μ-opioid receptor and CRF-R1 antagonist effects on escalated ethanol consumption and mPFC serotonin in C57BL/6J mice.
abstract: Both the opioid antagonist naltrexone and corticotropin-releasing factor type-1 receptor (CRF-R1) antagonists have been investigated for the treatment of alcoholism. The current study examines the combination of naltrexone and CP154526 to reduce intermittent access ethanol drinking [intermittent access to alcohol (IAA)] in C57BL/6J male mice, and if these compounds reduce drinking via serotonergic mechanisms in the dorsal raphe nucleus (DRN). Systemic injections and chronic intracerebroventricular infusions of naltrexone, CP154526 or CP376395 transiently decreased IAA drinking. Immunohistochemistry revealed CRF-R1 or μ-opioid receptor immunoreactivity was co-localized in tryptophan hydroxylase (TPH)-immunoreactive neurons as well as non-TPH neurons in the DRN. Mice with a history of IAA or continuous access to alcohol were microinjected with artificial cerebral spinal fluid, naltrexone, CP154526 or the combination into the DRN or the median raphe nucleus (MRN). Either intra-DRN naltrexone or CP154526 reduced IAA in the initial 2 hours of fluid access, but the combination did not additively suppress IAA, suggesting a common mechanism via which these two compounds affect intermittent drinking. These alcohol-reducing effects were localized to the DRN of IAA drinkers, as intra-MRN injections only significantly suppressed water drinking, and continuous access drinkers were not affected by CRF-R1 antagonism. Extracellular serotonin was measured in the medial prefrontal cortex (mPFC) using in vivo microdialysis after intra-DRN microinjections in another group of mice. Intra-DRN CP154526 increased serotonin impulse flow to the mPFC while naltrexone did not. This suggests the mPFC may not be an essential location to intermittent drinking, as evidenced by different effects on serotonin signaling to the forebrain yet similar behavioral findings.
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Hwa
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamoto
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Tala
authors.initials: T
authors.lastname: Kayyali
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Norman
authors.affiliation: Division of Stress Neurobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Valentino
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: DeBold
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.|Department of Neuroscience, Tufts University, Medford, MA, USA.
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Miczek
mesh_terms: D000428:Alcohol Drinking; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D065847:Dorsal Raphe Nucleus; D000431:Ethanol / Q000008:administration & dosage*; D007150:Immunohistochemistry; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: C529296:(3,6-dimethyl-2-(2,4,6-trimethylphenoxy)pyridin-4-yl)(1-ethylpropyl)amine; D000631:Aminopyridines; C101628:CP 154526; D002492:Central Nervous System Depressants; D009292:Narcotic Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D017450:Receptors, Opioid, mu; D012701:Serotonin; D000431:Ethanol; D000099052:CRF Receptor, Type 1; D009271:Naltrexone; D014365:Tryptophan Hydroxylase
keywords: CRF-R1; dorsal raphe nucleus; intermittent alcohol; naltrexone