Elsevier

Drug and Alcohol Dependence

Volume 158, 1 January 2016, Pages 159-163
Drug and Alcohol Dependence

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Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core

https://doi.org/10.1016/j.drugalcdep.2015.10.031Get rights and content

Highlights

Abstract

Background

Given the high level of homology between nonhuman primates and humans in regard to anatomy, physiology and ethanol drinking patterns, nonhuman primates represent an unparalleled preclinical model for examining the neurobiological basis of ethanol abuse.

Methods

Here we examined the neurochemical consequences of chronic daily ethanol use using fast-scan cyclic voltammetry in brain slices containing the nucleus accumbens core or dorsolateral caudate taken from male cynomolgus macaques following ethanol drinking.

Results

We found that in both regions the ability of ethanol to decrease dopamine release was unchanged, indicating that ethanol self-administration does not produce tolerance or sensitization to ethanol effects on dopamine release at the dopamine terminal at this time point. We also found that in the nucleus accumbens core, autoregulation of dopamine release was shifted from equal D2 and D3 receptor involvement in control animals to primarily D2 receptor-mediated in drinkers. Specifically, the effect quinpirole, a D2/D3 receptor agonist, on dopamine release was equal across groups; however, dopamine signals were reversed to a greater extent by the selective D3 receptor antagonist SB-277,011A in control animals, indicating a greater contribution of D2 receptors in quinpirole-induced inhibition following ethanol self-administration. In the dorsolateral caudate, the effects of quinpirole and reversal with SB-277,011A was not different between ethanol and control slices.

Conclusions

This work provides novel insight into the dopaminergic adaptations resulting from chronic ethanol use in nonhuman primates and indicates that alterations in D2/D3 dopamine autoreceptor signaling may be an important neurochemical adaptation to ethanol consumption during early use.

Introduction

Alcohol use disorders are a major public health concern and, as such, determining the neurobiological basis of alcoholism in search of pharmacotherapeutic targets has been an area of much research. Due to the physiological, genetic and behavioral similarities between nonhuman primates and humans, nonhuman primate models of human disease states are thought to possess high translational validity (Grant et al., 2014). Similarities between nonhuman primates and humans are particularly relevant in the study of voluntary ethanol drinking as nonhuman primates consume ethanol with similar daily intake to human alcoholics (Grant et al., 2008, Majchrowicz and Mendelson, 1970).

Alcohol abuse and addiction are thought to be mediated in part by ethanol-induced adaptations to dopaminergic signaling in the striatum (Koob, 2013). The striatum is composed of multiple distinct subregions that exert divergent control over behavioral outputs. Specifically, ventral regions of the striatum, such as the nucleus accumbens (NAc), encode associations between discrete cues, drug availability and previously learned contingencies. Conversely, dorsal regions, such as the putamen and dorsolateral caudate (DLC), mediate habitual and compulsive behaviors that emerge after repeated drug use (Porrino et al., 2004, Graybiel, 1995, Graybiel, 2008, Everitt and Robbins, 2013). The NAc and DLC both express D2 and D3 dopamine receptors, though distribution of these receptors is differential with the DLC preferentially expressing D2 and the NAc preferentially expressing D3 receptors (Murray et al., 1994). It is hypothesized that alterations to dopamine receptors contribute to pathological drinking behaviors, and in both rodents and humans, chronic ethanol exposure has been associated with decreased sensitivity of dopamine D2/D3 receptors in striatal regions (Volkow et al., 1996, Lucchi et al., 1988). However, the majority of these studies have not differentiated between post synaptic dopamine receptors located on striatal medium spiny neurons and presynaptic dopamine autoreceptors located on dopamine terminals originating from the ventral midbrain (Ford, 2014).

Here we sought to examine the effects of daily ethanol self-administration in male cynomolgus macaques on two important facets of dopamine terminal function: (1) the sensitivity of D2 and D3 autoreceptors and (2) the ability of ethanol to decrease dopamine release. These measures were assessed using fast scan cyclic voltammetry (FSCV), which allows for the isolated assessment of presynaptic dopamine autoreceptors, in brain slices containing the NAc core or the DLC.

Section snippets

Subjects

All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Oregon National Primate Research Center Institutional Animal Care and Use Committee. Eleven male cynomolgus monkeys (Macaca fascicularis) between the ages of 5.9–6.9 years were used for the current study (Daunais et al., 2014).

Drinking procedure

Monkeys (8 ethanol and 3 control) were trained to obtain fluids and their meals from an operant panel that replaced one of the walls of their home

Autoregulation of dopamine release shifts from D2/D3-mediated to primarily D2-mediated following ethanol exposure

Dopamine release and uptake kinetics as well as behavioral data from these animals were previously published in Siciliano et al. (2015a). The average amounts of ethanol consumed daily varied across individuals and ranged from 0.7 to 3.0 g/kg (Fig. 1A; group average: 1.79 ± 0.27 g/kg/day). Average BECs ranged from 6 to 144 mg/dl (Fig. 1B; group average: 62.38 ± 16.59). Ethanol self-administration increased dopamine release (control: 0.49 ± 0.16 μM, drinkers: 0.97 ± 0.11 μM) and uptake (control: 1.74 ± 0.16 

Discussion

We found that following free-access ethanol self-administration in male cynomolgus macaques there is a marked shift in the relative contribution of D2 versus D3 type autoreceptors in regulating dopamine release from presynaptic terminals in the nucleus accumbens core. Indeed, in control animals, autoregulation of dopamine release was roughly equally D2 and D3 receptor mediated, while in ethanol self-administration animals autoregulation was primarily D2 receptor mediated. Additionally, we found

Role of funding source

Nothing declared.

Conflict of interest statement

The authors have no conflicts to report.

Contributors

Cody Siciliano: designed and performed experiments, analyzed data, wrote manuscript.

Erin Calipari: designed and performed experiments, analyzed data.

Jordan Yorgason: provided equipment/reagents.

Yolanda Mateo: provided equipment/reagents.

Christa Helms: performed experiments.

David Lovinger: provided equipment/reagents.

Kathleen Grant: designed experiments, provided equipment/reagents.

Sara Jones: designed experiments, provided equipment/reagents, edited manuscript.

All authors have approved the

Acknowledgements

This work was funded by NIH grants U01 AA014091, P01 AA021099 (SRJ), F31 DA031533 (ESC), F31 DA037710, T32 AA007565 (CAS), F31 AA020439 (JTY), U01 OD011092, R24 AA019431, P60 AA10760 (KAG), Division of Intramural Clinical and Biomedical Research NIAAA (DML), Integrative Neuroscience Initiative on Alcoholism AA 13510 (KAG) and OHSU Administration Core AA 13641 (KAG).

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