title: Voluntary ethanol intake predicts κ-opioid receptor supersensitivity and regionally distinct dopaminergic adaptations in macaques.
abstract: The dopaminergic projections from the ventral midbrain to the striatum have long been implicated in mediating motivated behaviors and addiction. Previously it was demonstrated that κ-opioid receptor (KOR) signaling in the striatum plays a critical role in the increased reinforcing efficacy of ethanol following ethanol vapor exposure in rodent models. Although rodents have been used extensively to determine the neurochemical consequences of chronic ethanol exposure, establishing high levels of voluntary drinking in these models has proven difficult. Conversely, nonhuman primates exhibit similar intake and pattern to humans in regard to drinking. Here we examine the effects of chronic voluntary ethanol self-administration on dopamine neurotransmission and the ability of KORs to regulate dopamine release in the dorsolateral caudate (DLC) and nucleus accumbens (NAc) core. Using voltammetry in brain slices from cynomolgus macaques after 6 months of ad libitum ethanol drinking, we found increased KOR sensitivity in both the DLC and NAc. The magnitude of ethanol intake predicted increases in KOR sensitivity in the NAc core, but not the DLC. Additionally, ethanol drinking increased dopamine release and uptake in the NAc, but decreased both of these measures in the DLC. These data suggest that chronic daily drinking may result in regionally distinct disruptions of striatal outputs. In concert with previous reports showing increased KOR regulation of drinking behaviors induced by ethanol exposure, the strong relationship between KOR activity and voluntary ethanol intake observed here gives further support to the hypothesis that KORs may provide a promising pharmacotherapeutic target in the treatment of alcoholism.
authors: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors: Cody A
authors: CA
authors: Siciliano
authors: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors: Erin S
authors: ES
authors: Calipari
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, and.
authors: Verginia C
authors: VC
authors: Cuzon Carlson
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, and.
authors: Christa M
authors: CM
authors: Helms
authors: Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland 20832.
authors: David M
authors: DM
authors: Lovinger
authors: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, and.
authors: Kathleen A
authors: http://orcid.org/0000-0002-0380-7219
authors: KA
authors: Grant
authors: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, srjones@wakehealth.edu.
authors: Sara R
authors: http://orcid.org/0000-0002-3424-7576
authors: SR
authors: Jones
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002421:Caudate Nucleus / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage* / Q000097:blood; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood; D008252:Macaca fascicularis; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D012646:Self Administration; D018709:Statistics, Nonparametric
chemical_list: D002492:Central Nervous System Depressants; D017473:Receptors, Opioid, kappa; D000431:Ethanol; D004298:Dopamine
keywords: caudate; dopamine; nonhuman primate; nucleus accumbens; voltammetry; κ-opioid receptor