Chronic intermittent ethanol exposure reduces presynaptic dopamine neurotransmission in the mouse nucleus accumbens

Karkhanis, Anushree N.; Rose, Jamie H.; Huggins, Kimberly N.; Konstantopoulos, Joanne K.

doi:10.1016/j.drugalcdep.2015.01.019

Cited by 73 publications

(80 citation statements)

References 65 publications

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“…The increased uptake of DA observed in the NAc core and shell of SI rats in the current study and in the NAc core in a previous report suggests that SI leads to augmented DAT levels in this brain region (Yorgason et al, 2015). Interestingly, other forms of chronic stress, such as repeated restraint stress, have also been shown to enhance DA uptake in the striatum (Copeland et al, 2005) and chronic ethanol exposure increases DA uptake in adult mouse, rat, and monkey models (Budygin et al, 2003;Karkhanis et al, 2015). An increase in DAT function would be expected to decrease overall extracellular DA levels.…”

Section: Adolescent Si Disrupts Da Transmission In the Nacmentioning

confidence: 64%

“…Many studies have demonstrated that chronic stress, particularly during adolescence, results in a dysfunctional DA system (Broom and Yamamoto, 2005;Lucas et al, 2007;Karkhanis et al, 2015), which may result in a hypodopaminergic state. A hypodopaminergic state is classically characterized by reduced extracellular DA levels (tonic) but increased electrically stimulated DA release (phasic) and uptake rates (Mathews et al, 2009).…”

Section: Adolescent Si Disrupts Da Transmission In the Nacmentioning

confidence: 99%

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Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Karkhanis¹,

Rose

Weiner³

et al. 2016

Neuropsychopharmacol

113

107

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Chronic early-life stress increases vulnerability to alcoholism and anxiety disorders during adulthood. Similarly, rats reared in social isolation (SI) during adolescence exhibit augmented ethanol intake and anxiety-like behaviors compared with group housed (GH) rats. Prior studies suggest that disruption of dopamine (DA) signaling contributes to SI-associated behaviors, although the mechanisms underlying these alterations are not fully understood. Kappa opioid receptors (KORs) have an important role in regulating mesolimbic DA signaling, and other kinds of stressors have been shown to augment KOR function. Therefore, we tested the hypothesis that SI-induced increases in KOR function contribute to the dysregulation of NAc DA and the escalation in ethanol intake associated with SI. Our ex vivo voltammetry experiments showed that the inhibitory effects of the kappa agonist U50,488 on DA release were significantly enhanced in the NAc core and shell of SI rats. Dynorphin levels in NAc tissue were observed to be lower in SI rats. Microdialysis in freely moving rats revealed that SI was also associated with reduced baseline DA levels, and pretreatment with the KOR antagonist nor-binaltorphimine (nor-BNI) increased DA levels selectively in SI subjects. Acute ethanol elevated DA in SI and GH rats and nor-BNI pretreatment augmented this effect in SI subjects, while having no effect on ethanol-stimulated DA release in GH rats. Together, these data suggest that KORs may have increased responsiveness following SI, which could lead to hypodopaminergia and contribute to an increased drive to consume ethanol. Indeed, SI rats exhibited greater ethanol intake and preference and KOR blockade selectively attenuated ethanol intake in SI rats. Collectively, the findings that nor-BNI reversed SI-mediated hypodopaminergic state and escalated ethanol intake suggest that KOR antagonists may represent a promising therapeutic strategy for the treatment of alcohol use disorders, particularly in cases linked to chronic early-life stress.

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Section: Adolescent Si Disrupts Da Transmission In the Nacmentioning

confidence: 64%

Section: Adolescent Si Disrupts Da Transmission In the Nacmentioning

confidence: 99%

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Karkhanis¹,

Rose

Weiner³

et al. 2016

Neuropsychopharmacol

113

107

View full text Add to dashboard Cite

show abstract

“…Further, dysphoric states during withdrawal are mediated by changes in Acb neurotransmission, with alcohol-induced reductions in monoaminergic function theorized to contribute to the depressive effects of alcohol withdrawal. [23, 74, 75], Moreover, we know that a chronic history of binge drinking elevates indices of glutamatergic signaling within the Acb [15, 73]. Thus, we hypothesized at the outset of this study that a history of binge drinking would augment Acb cellular activity, particularly within the AchSh, and this increased activity would correlate with behavioral indices of negative affect.…”

Section: Discussionmentioning

confidence: 98%

Binge alcohol drinking elicits persistent negative affect in mice

Lee

Coehlo

McGregor

et al. 2015

Behavioural Brain Research

148

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Cessation from chronic alcohol abuse often produces a dysphoric state that can persist into protracted withdrawal. This dysphoric state is theorized to function as a negative reinforcer that maintains excessive alcohol consumption and/or precipitates relapse in those struggling to abstain from alcohol. However, we know relatively little regarding the impact of cessation from binge drinking on behavioral measures of negative affect and related neurobiology. Male C57BL/6J mice were given access to unsweetened 20% alcohol for 6 weeks under modified Drinking-in-the-Dark procedures, followed by behavioral testing beginning either 1 or 21 days into withdrawal. Mice were administered a behavioral test battery consisting of: the elevated plus maze, light/dark box, novel object test, marble burying test, Porsolt forced swim test and sucrose preference test to assess anxiogenic and depressive signs. Egr1 immunostaining was used to quantify cellular activity within the central nucleus of the amygdala (CEA), basolateral amygdala (BLA), bed nucleus of the stria terminalis (BNST), and the nucleus accumbens (Acb) shell (AcbSh) and core (AcbC). Compared to water controls, alcohol-drinking mice exhibited higher indices of emotionality in the majority of behavioral assays. The hyper-emotionality exhibited by binge drinking mice was apparent at both withdrawal time-points and correlated with higher Egr1+ cell counts in the CEA and BNST, compared to controls. These data show that affective symptoms emerge very early after cessation of binge drinking and persist into protracted withdrawal. A history of binge drinking is capable of producing enduring neuroadaptations within brain circuits mediating emotional arousal.

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“…Thus these differences may also be due to exposure length or strain; future studies will aim to systematically examine the hypothesis that these differences are due to sex. A second issue that should be addressed in future studies is differences in dopamine release changes induced by ethanol between these findings and rodent models, which have shown decreased dopamine release following chronic intermittent ethanol exposure via vapor inhalation (Karkhanis et al, 2015). These differences may be due to exposure length or route of administration; however, in all three studies (Siciliano et al, 2015a; Karkhanis et al, 2015; current study) dopamine uptake rate was increased by ethanol exposure, suggesting that alterations to the dopamine transporter may be a critical neurochemical adaptation induced by ethanol.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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Chronic intermittent ethanol exposure reduces presynaptic dopamine neurotransmission in the mouse nucleus accumbens

Cited by 73 publications

References 65 publications

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

Binge alcohol drinking elicits persistent negative affect in mice

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

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