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