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.
journal_name
Psychopharmacology (Berl)journal_title
Psychopharmacologyauthors
Siciliano CA,Calipari ES,Yorgason JT,Lovinger DM,Mateo Y,Jimenez VA,Helms CM,Grant KA,Jones SRdoi
10.1007/s00213-016-4239-4subject
Has Abstractpub_date
2016-04-01 00:00:00pages
1435-43issue
8eissn
0033-3158issn
1432-2072pii
10.1007/s00213-016-4239-4journal_volume
233pub_type
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