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

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 unknown. 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 one year of daily (22 hr/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, were 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 pharmcotherapeutic targets in the treatment of alcohol use disorders.

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…Increased uptake rates have been reported in the NAc of mice (Rose et al 2016), rats (Budygin et al 2007) and monkeys (Siciliano et al 2016) following chronic ethanol exposure, and these findings are supported by increased DAT protein tissue expression (Healey et al 2008). Here we add to the consensus by showing increased uptake rates in the NAc core following a CIE vapor exposure paradigm.…”

Age-dependent regulation of GABA transmission by kappa opioid receptors in the basolateral amygdala of Sprague-Dawley rats

“…While numerous studies have shown that KORs are G i/o coupled [reviewed by (Bruchas and Chavkin, 2010)], which ultimately reduces neuronal excitability and/or neurotransmitter release in various brain structures (Chen et al, 2015; Crowley et al, 2016; Gilpin et al, 2014; Kang-Park et al, 2013; Karkhanis et al, 2016; Lemos et al, 2012; Li et al, 2012; Rose et al, 2015; Siciliano et al, 2016), studies have also shown that KORs can couple to G s in various cellular models (Baraban et al, 1995; Hampson et al, 2000; Shen and Crain, 1990a, b, 1994) which can increase action potential duration (Shen and Crain, 1990a, b, 1994) and neuronal excitability in dentate granule cells (McDermott and Schrader, 2011). While we have not yet directly investigated these coupling mechanisms, our findings could be explained by a KOR-dependent increase in action potential duration of local GABAergic interneurons, resulting in the observed increase in sIPSC frequency.…”

“…Alterations in kappa opioid receptor (KOR) expression and function associated with changes in emotional states have been found in many brain regions implicated in anxiety and reward, including the central amygdala (CeA) (Kissler et al, 2014; Kissler and Walker, 2016), the nucleus accumbens (Karkhanis et al, 2016; Rose et al, 2015; Siciliano et al, 2016), and the bed nucleus of the stria terminalis (BNST) (Crowley et al, 2016). However, the role of KORs in the BLA is not well understood despite it being a brain structure with high levels of KOR expression (Gackenheimer et al, 2005; Slowe et al, 1999).…”

Dopamine synthesis in alcohol drinking-prone and -resistant mouse strains

“…Given that C57 mice show greater autoreceptor sensitivity in the ventral striatum, a trait that is associated with ethanol use (Siciliano, Calipari, Yorgason, Lovinger, et al, 2016), we next sought to determine the effects of a history of ethanol exposure on dopamine synthesis and autoreceptor sensitivity in C57 mice. Following exposure to one cycle of ethanol (4 days of 16 h ethanol vapor/8 h of withdrawal followed by 3 days of withdrawal), we found that there was no change in dopamine synthesis in the ventral striatum (Fig.…”

“…Previous work from our lab and others has highlighted changes in dopamine release as well as the ability of presynaptic dopamine D2-type autoreceptors to regulate dopamine release as neuroadaptations induced by chronic ethanol exposure, and important factors in the development of excessive drinking behaviors (Dutton, Chen, You, Brodie, & Lasek, 2016; Karkhanis, Rose, Huggins, Konstantopoulos, & Jones, 2015; Narita, Soma, Tamaki, Narita, & Suzuki, 2002; Rossetti, Melis, Carboni, Diana, & Gessa, 1992; Siciliano, Calipri, Yorgason, Mateo, et al, 2016). One possible explanation for altered dopamine release following ethanol exposure is that ethanol dysregulates the dopamine synthesis process.…”