Regulation of ethanol intake under chronic mild stress: roles of dopamine receptors and transporters

Abstract

Studies have shown that exposure to chronic mild stress decreases ethanol intake and preference in dopamine D2 receptor wild-type mice (Drd2+/+), while it increases intake in heterozygous (Drd2+/−) and knockout (Drd2−/−) mice. Dopaminergic neurotransmission in the basal forebrain plays a major role in the reinforcing actions of ethanol as well as in brain responses to stress. In order to identify neurochemical changes associated with the regulation of ethanol intake, we used in vitro receptor autoradiography to measure the levels and distribution of dopamine D1 and D2 receptors and dopamine transporters (DAT). Receptor levels were measured in the basal forebrain of Drd2+/+, Drd2+/−, and Drd2−/− mice belonging to one of four groups: control (C), ethanol intake (E), chronic mild stress exposure (S), and ethanol intake under chronic mild stress (ES). D2 receptor levels were higher in the lateral and medial striatum of Drd2+/+ ES mice, compared with Drd2+/+ E mice. Ethanol intake in Drd2+/+ mice was negatively correlated with striatal D2 receptor levels. D2 receptor levels in Drd2+/− mice were the same among the four treatment groups. DAT levels were lower in Drd2+/− C and Drd2−/− C mice, compared with Drd2+/+ C mice. Among Drd2+/− mice, S and ES groups had higher DAT levels compared with C and E groups in most regions examined. In Drd2−/− mice, ethanol intake was positively correlated with DAT levels in all regions studied. D1 receptor levels were lower in Drd2+/− and Drd2−/− mice, compared with Drd2+/+, in all regions examined and remained unaffected by all treatments. The results suggest that in normal mice, ethanol intake is associated with D2 receptor-mediated neurotransmission, which exerts a protective effect against ethanol overconsumption under stress. In mice with low Drd2 expression, where DRD2 levels are not further modulated, ethanol intake is associated with DAT function which is upregulated under stress leading to ethanol overconsumption.

Maternal separation affects expression of stress response genes and increases vulnerability to ethanol consumption

“…Interestingly, overexpression of Drd2 has been previously associated with a significant decrease i n ethanol consumption in rats (Thanos et al., ), which suggests that ethanol effects could be mediated by Drd2 . Our results are in accordance with previous studies linking excessive ethanol consumption to an increase in Drd1 and Drd2 expression and to an imbalance between the subunits of GABA B receptors (Delis et al., ; Ribeiro et al., ). This, together with the differential regulation of the reward system in these animals, confirms our hypothesis that mice from the MS group consume ethanol to alleviate stress.…”

Roux‐en‐Y gastric bypass surgery normalizes dopamine D1, D2, and DAT levels

“…Binding was performed as previously described to quantify dopamine type 2‐like receptor (D2R) expression (Delis et al, ; Thanos et al, ). Briefly, slides were pre‐incubated for 60 min at room temperature in 50mM Tris 7 HCl buffer.…”

“…Binding was performed as previously described for dopamine transporter (DAT) expression (Delis et al, ). Briefly, slides were pre‐incubated for 10 minutes at 4°C in 30mM sodium phosphate buffer (pH = 7.4).…”

“…Binding was performed as previously described to quantify dopamine type 2-like receptor (D2R) expression (Delis et al, 2015;Thanos et al, 2002). Briefly, slides were pre-incubatedfor60minatroomtemperaturein50mMTris7HClbuffer.Then,0.5nM[ 3 H] Spiperone (specific activ-ity=16.2Ci/mmol)and40nMketanserinwasaddedtothepre-incubation buffer and slides were incubated for an additional 60 min at room temperature.…”

Estudos epigenéticos em dependentes de crack e cocaína: investigação da metilação global do genoma

“…, gene envolvido na modulação da locomoção, reforço, memória e aprendizagem e têm sido associado à diversas patologias psiquiátricas na literatura como, por exemplo, esquizofrenia (Lencz et al, 2015;Yao et al, 2015), depressão (Savitz et al, 2013;Pearson-Fuhrhop et al, 2014); jogo patológico (Hillemacher et al, 2015) e dependência de álcool (Delis et al, 2015), nicotina (Ahrens et al, 2015;Ma et al, 2015), opiáceos (Nelson et al, 2014;Levran et al, 2015), maconha (Colizzi et al, 2015;DiNieri et al, 2015) e cocaína (Noble et al, 1993). A relação entre o gene DRD2 e o abuso/dependência de cocaína têm sido investigada em diversos estudos em animais (Lee et al, 2006;Bertran-Gonzalez et al, 2008;Lawhorn et al, 2013) e humanos.…”