Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques

Cody A. Siciliano, Erin S. Calipari, Jordan T. Yorgason, David M. Lovinger, Yolanda Mateo, Vanessa A. Jimenez, Christa Helms, Kathleen (Kathy) Grant, Sara R. Jones

    Research output: Contribution to journalArticle

    18 Citations (Scopus)

    Abstract

    Rationale: 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.

    Original languageEnglish (US)
    Pages (from-to)1-9
    Number of pages9
    JournalPsychopharmacology
    DOIs
    StateAccepted/In press - Feb 19 2016

    Fingerprint

    Self Administration
    Nucleus Accumbens
    Macaca
    Synaptic Transmission
    Dopamine
    Ethanol
    kappa Opioid Receptor
    Autoreceptors
    Alcohols
    Quinpirole
    Corpus Striatum
    Dynorphins
    Dopamine Agonists
    Macaca mulatta
    Primates
    Alcoholism
    Drinking

    Keywords

    • Autoreceptor
    • Drinking
    • Kappa opioid receptor
    • Monkey
    • Nonhuman primate
    • Voltammetry

    ASJC Scopus subject areas

    • Pharmacology

    Cite this

    Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques. / Siciliano, Cody A.; Calipari, Erin S.; Yorgason, Jordan T.; Lovinger, David M.; Mateo, Yolanda; Jimenez, Vanessa A.; Helms, Christa; Grant, Kathleen (Kathy); Jones, Sara R.

    In: Psychopharmacology, 19.02.2016, p. 1-9.

    Research output: Contribution to journalArticle

    Siciliano, Cody A. ; Calipari, Erin S. ; Yorgason, Jordan T. ; Lovinger, David M. ; Mateo, Yolanda ; Jimenez, Vanessa A. ; Helms, Christa ; Grant, Kathleen (Kathy) ; Jones, Sara R. / Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques. In: Psychopharmacology. 2016 ; pp. 1-9.
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    abstract = "Rationale: 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.",
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    AU - Siciliano, Cody A.

    AU - Calipari, Erin S.

    AU - Yorgason, Jordan T.

    AU - Lovinger, David M.

    AU - Mateo, Yolanda

    AU - Jimenez, Vanessa A.

    AU - Helms, Christa

    AU - Grant, Kathleen (Kathy)

    AU - Jones, Sara R.

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    KW - Drinking

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    KW - Monkey

    KW - Nonhuman primate

    KW - Voltammetry

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