title: Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques.
abstract: BACKGROUND
  Hypofunction of striatal dopamine neurotransmission, or hypodopaminergia, is a consequence of excessive ethanol use and is hypothesized to be a critical component of alcoholism, driving alcohol intake in an attempt to restore dopamine levels; however, the neurochemical mechanisms involved in these dopaminergic deficiencies are not fully understood.
  
  
  OBJECTIVE
  Here we examined the specific dopaminergic adaptations that produce hypodopaminergia and contribute to alcohol use disorders using direct, sub-second measurements of dopamine signaling in nonhuman primates following chronic ethanol self-administration.
  
  
  METHODS
  Female rhesus macaques completed 1 year of daily (22 h/day) ethanol self-administration. Subsequently, fast-scan cyclic voltammetry was used in nucleus accumbens core brain slices to determine alterations in dopamine terminal function, including release and uptake kinetics, and sensitivity to quinpirole (D2/D3 dopamine receptor agonist) and U50,488 (kappa opioid receptor agonist) induced inhibition of dopamine release.
  
  
  RESULTS
  Ethanol drinking greatly increased uptake rates, which were positively correlated with lifetime ethanol intake. Furthermore, the sensitivity of dopamine D2/D3 autoreceptors and kappa opioid receptors, which both act as negative regulators of presynaptic dopamine release, was moderately and robustly enhanced in ethanol drinkers.
  
  
  CONCLUSIONS
  Greater uptake rates and sensitivity to D2-type autoreceptor and kappa opioid receptor agonists could converge to drive a hypodopaminergic state, characterized by reduced basal dopamine and an inability to mount appropriate dopaminergic responses to salient stimuli. Together, we outline the specific alterations to dopamine signaling that may drive ethanol-induced hypofunction of the dopamine system and suggest that the dopamine and dynorphin/kappa opioid receptor systems may be efficacious pharmacotherapeutic targets in the treatment of alcohol use disorders.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Siciliano
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.|Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Calipari
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Yorgason
authors.affiliation: Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lovinger
authors.affiliation: Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD, USA.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Mateo
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: Jimenez
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
authors.forename: Christa M
authors.initials: CM
authors.lastname: Helms
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Grant
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA. srjones@wakehealth.edu.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D008253:Macaca mulatta; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D017660:Autoreceptors; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D000431:Ethanol; D004298:Dopamine
keywords: Autoreceptor; Drinking; Kappa opioid receptor; Monkey; Nonhuman primate; Voltammetry