Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Jul;46(8):1432-1441.
doi: 10.1038/s41386-020-00938-8. Epub 2021 Jan 15.

Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques

Armando G Salinas  1   2 , Yolanda Mateo  2 , Verginia C Cuzon Carlson  3 , Gwen S Stinnett  4 , Guoxiang Luo  2 , Audrey F Seasholtz  4   5 , Kathleen A Grant  3 , David M Lovinger  6
Affiliations

Long-term alcohol consumption alters dorsal striatal dopamine release and regulation by D2 dopamine receptors in rhesus macaques

Armando G Salinas et al. Neuropsychopharmacology. 2021 Jul.

Abstract

The dorsal striatum (DS) is implicated in behavioral and neural processes including action control and reinforcement. Alcohol alters these processes in rodents, and it is believed that the development of alcohol use disorder involves changes in DS dopamine signaling. In nonhuman primates, the DS can be divided into caudate and putamen subregions. As part of a collaborative effort examining the effects of long-term alcohol self-administration in rhesus macaques, we examined DS dopamine signaling using fast-scan cyclic voltammetry. We found that chronic alcohol self-administration resulted in several dopamine system adaptations. Most notably, dopamine release was altered in a sex- and region-dependent manner. Following long-term alcohol consumption, male macaques, regardless of abstinence status, had reduced dopamine release in putamen, while only male macaques in abstinence had reduced dopamine release in caudate. In contrast, female macaques had enhanced dopamine release in the caudate, but not putamen. Dopamine uptake was also enhanced in females, but not males (regardless of abstinence state). We also found that dopamine D2/3 autoreceptor function was reduced in male, but not female, alcohol drinkers relative to control groups. Finally, we found that blockade of nicotinic acetylcholine receptors inhibited evoked dopamine release in nonhuman primates. Altogether, our findings demonstrate that long-term alcohol consumption can sex-dependently alter dopamine release, as well as its feedback control mechanisms in both DS subregions.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1. Overview of experimental design and alcohol consumption measures for all cohorts.
A Experimental design and timelines used in this study. Cohort 1 (red) consisted of females with 1 year of ad libitum alcohol open access necropsied during the active drinking time. Cohort 2 (blue) consisted of males treated identically to the females in Cohort 1. Cohort 3 (green) consisted of males that underwent an extended ad libitum alcohol open access with intermittent forced abstinent periods and were necropsied following 1 month of abstinence. B Example of the brain section obtained with the caudate (Cd) and putamen (Pt) outlined and the typical FSCV recording configuration. Image obtained from www.brainmaps.org. C The average alcohol intake at blood sampling (7 h after session onset) positively correlated with blood ethanol concentrations for each cohort. D The average lifetime alcohol intake was similar between the active drinking female and male cohorts (cohorts 1 and 2, respectively), but both were lower than the multiple abstinence males (Cohort 3). E Alcohol-consuming monkeys were categorized according to their alcohol consumption and intoxication patterns during the open access period. These categories are stable throughout the first open access period but currently we demonstrate that multiple abstinence periods push animals toward more severe drinking phenotypes. **p < 0.01. Error bars represent the SEM.
Fig. 2
Fig. 2. Dopamine release is altered in subjects with long-term alcohol consumption in both active drinking status and after multiple abstinences.
Representative color plots depicting dopamine oxidation and reduction potentials during FSCV recordings (+0.6 V and −0.2 V, respectively) across time are shown along with representative dopamine transients for each cohort, treatment group, and region (A–F). Evoked dopamine release was increased in the caudate (A), but not putamen (D), of female macaques following long-term alcohol consumption. In male macaques, 1 year of long-term alcohol consumption did not significantly alter evoked dopamine release in the caudate; however, dopamine release was decreased in the putamen of alcohol subjects relative to controls (B, E). In male macaques with long-term alcohol consumption and multiple abstinence periods, dopamine release was significantly reduced relative to control subjects in the caudate and putamen (C, F). *p < 0.05, ***p < 0.001. Error bars represent the SEM.
Fig. 3
Fig. 3. The dopamine uptake rate (Vmax) was assessed for each cohort.
In female macaques, Vmax was significantly increased in caudate and putamen following long-term alcohol consumption (A). The Vmax for alcohol-consuming male macaques, however, was similar to control subjects in both male cohorts (B, C). *p < 0.05. Error bars represent the SEM.
Fig. 4
Fig. 4. Presynaptic D2/3 dopamine receptor sensitivity is decreased following long-term alcohol consumption in a sex-dependent manner.
The D2/3 dopamine receptor agonist, quinpirole (30 nM), decreased stimulated dopamine release and this effect was partially reversed by the D2/3 dopamine receptor antagonist, sulpiride (2 µM), during washout. Data shown were collected after 30 min in quinpirole and after 15 min in sulpiride solutions. In female macaques, there was no alcohol effect on D2 dopamine receptor sensitivity in the caudate (A) or putamen (D). In both groups of male macaques, however, D2/3 dopamine receptor-mediated inhibition of dopamine release was decreased following long-term alcohol consumption in the caudate (B, E) and putamen (C, F) relative to control subjects. *p < 0.05, **p < 0.01. Error bars represent the SEM.
Fig. 5
Fig. 5. nAChR antagonism decreases dopamine release.
The β2 subunit-containing nAChR antagonist DHβE (1 µM) depressed dopamine release in caudate and putamen of control and ethanol subjects (A). Dopamine release was compared across varying train stimulations (6 pulses at the indicated frequencies) before and after nAChR blockade with DHβE (1 µM) in caudate and putamen (B, C; values normalized to single-pulse values before DHβE application). Gene expression of cholinergic interneuron markers and several nAChR subunits was not changed following chronic alcohol consumption and abstinence (D, E). Error bars represent the SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. WHO. Global status report on alcohol and health 2014. World Health Organization; 2014. https://apps.who.int/iris/bitstream/handle/10665/112736/9789240692763_en.... Accessed 22 December 2020.
    1. Sacks JJ, Gonzales KR, Bouchery EE, Tomedi LE, Brewer RD. 2010 national and state costs of excessive alcohol consumption. Am J Prev Med. 2015;49:e73–9. - PubMed
    1. Centers for Disease Control and Prevention. Alcohol and public health: Alcohol-Related Disease Impact (ARDI). Average for United States 2006–2010 alcohol-attributable deaths due to excessive alcohol use. Centers for Disease Control and Prevention; 2017. https://nccd.cdc.gov/DPH_ARDI/default/default.aspx. Accessed 9 May 2018.
    1. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA. 1988;85:5274–8. - PMC - PubMed
    1. Jimenez VA, Grant KA. Studies using macaque monkeys to address excessive alcohol drinking and stress interactions. Neuropharmacology. 2017;122:127–35.. - PMC - PubMed

Publication types