The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement

Gonzales, Rueben A.; Job, Martin O.; Doyon, William M.

doi:10.1016/j.pharmthera.2004.06.002

Cited by 268 publications

(247 citation statements)

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“…Ethanol's ability to change local cellular levels of 3a,5a-THP in the NAc and CeA is particularly interesting, as these regions are strongly associated with ethanol reinforcement and consumption (Gonzales et al, 2004;McBride, 2002), and exogenous 3a,5a-THP has been shown to modulate ethanol self-administration. For example, several studies have shown that 3a,5a-THP alters ethanol consumption (Ford et al, 2007;Ford et al, 2005;Morrow et al, 2001) and reinforcement (Janak and Michael Gill, 2003;Janak et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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The neuroactive steroid (3a,5a)-3-hydroxypregnan-20-one (3a,5a-THP or allopregnanolone) is a positive modulator of GABA A receptors synthesized in the brain, adrenal glands, and gonads. In rats, ethanol activates the hypothalamic-pituitary-adrenal axis and elevates 3a,5a-THP in plasma, cerebral cortex, and hippocampus. In vivo, these effects are dependent on both the pituitary and adrenal glands. In vitro, however, ethanol locally increases 3a,5a-THP in hippocampal slices, in the absence of adrenal influence. Therefore, it is not known whether ethanol can change local brain levels of 3a,5a-THP in vivo, independent of the adrenals. To directly address this controversy, we administered ethanol (2 g/kg) or saline to rats that underwent adrenalectomy (ADX) or received sham surgery and performed immunohistochemistry for 3a,5a-THP. In the medial prefrontal cortex (mPFC), ethanol increased 3a,5a-THP after sham surgery, compared with saline controls, with no ethanol-induced change in 3a,5a-THP following ADX. In subcortical regions, 3a,5a-THP was increased independent of adrenals in the CA1 pyramidal cell layer, dentate gyrus polymorphic layer, bed nucleus of the stria terminalis, and paraventricular nucleus of the hypothalamus. Furthermore, ethanol decreased 3a,5a-THP labeling in the nucleus accumbens shore and central nucleus of the amygdala, independent of the adrenal glands. These data indicate that ethanol dynamically regulates local 3a,5a-THP levels in several subcortical regions; however, the adrenal glands contribute to 3a,5a-THP elevations in the mPFC. Using double immunofluorescent labeling we determined that adrenal dependence of 3a,5a-THP induction by ethanol is not due to a lack of colocalization of 3a,5a-THP with the cholesterol transporters steroidogenic acute regulatory protein (StAR) or translocator protein (TSPO).

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Section: Discussionmentioning

confidence: 99%

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Cook

Nelli

Neighbors

et al. 2014

Neuropsychopharmacol

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“…In addition to metabolic cross-tolerance a variety of factors including genetic factors may contribute to the dependence on both nicotine and ethanol (Bierut et al, 2004;Goldman et al, 2005;Swan et al, 1997;True et al, 1999;Tyndale, 2003). Additionally, other physiological mechanisms could include the ability of nicotine and ethanol to induce dopamine release in the mesolimbic dopamine system, thereby potentiating each other's rewarding effects (Corrigall et al, 1994;Gonzales et al, 2004), as well as a possible role of activation of nicotinic acetylcholine receptors (Blomqvist et al, 1996;Le et al, 2000). Our study demonstrates that the higher levels of hepatic CYP2E1 after chronic nicotine pretreatment and ethanol self-administration were accompanied by an increase in ethanol consumption and it remains to be tested whether metabolic crosstolerance directly contributes to this.…”

Section: Discussionmentioning

confidence: 99%

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Yue

Khokhar

Miksys

et al. 2009

European Journal of Pharmacology

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Alcohol and nicotine are frequently co-used and co-abused, and use of both drugs alone can affect hepatic drug metabolism. We investigated the influences of chronic nicotine treatment and voluntary ethanol intake on the induction of rat hepatic cytochrome P450 (CYP) enzymes that metabolize ethanol and nicotine. Rats were trained to voluntarily drink ethanol (6% v/v, 1 h) with nicotine pretreatment for 10 days. Another group of rats were treated with the same nicotine doses alone. Hepatic CYP2E1, CYP2B1/2 and CYP2D1 proteins were assessed by immunoblotting. Nicotine pretreatment (0.4, 0.8 and 1.2 mg/kg) increased voluntary ethanol intake on day 10 by 1.8, 2.0, and 1.4 fold respectively compared to saline pretreatment (P<0.01-0.3). CYP2E1 was increased 1.7, 1.8, and 1.4 fold by the three doses of nicotine alone (P<0.02-0.21); CYP2E1 levels were increased by voluntary ethanol intake alone and a further 2.4, 2.2, and 1.8 fold by 0.4, 0.8, and 1.2 mg/kg nicotine respectively versus saline pretreatment (P<0.002-0.06). CYP2B1/2 proteins were not induced by nicotine alone, but were increased by 2.2-2.5 fold by ethanol drinking (P<0.05). CYP2E1 (r=0.67, P<0.001) and CYP2B1/2 levels (r=0.49, P=0.007) correlated with alcohol consumption on day 10. There was no change in CYP2D1. Chronic nicotine increased voluntary ethanol intake thereby enhancing CYP2E1 and CYP2B1/2 levels. Thus CYPs are regulated not only directly by nicotine and ethanol, but also indirectly via an increase in the ethanol consumption in the presence of nicotine pretreatment. Together this may contribute to the co-abuse of these drugs and alter the metabolism of clinical drugs and endogenous substrates.

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“…Surprisingly, the D1R partial agonist ((+/−)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7, 8-diol hydrochloride) (SKF-38393) also decreased alcohol intake in both rats (Cohen et al 1999;Dyr et al 1993;Silvestre et al 1996) and mice (Ng and George 1994). We are focusing on D1 receptors expressed in medium spiny neurons, because they are expressed at high levels in the ventral striatum (Caille et al 1996;Matamales et al 2009;Muly et al 2010;Podda et al 2010) and are thought to be major regulators of dopaminergic neurons originating from the ventral tegmental area (VTA) that provide innervation to the NAc (Altier and Stewart 1999;Arias-Carrion et al 2010;Cooper 2002;Gonzales et al 2004;Herz 1997;McBride et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice

Bahí

Dreyer

2012

Psychopharmacology

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Rationale Dopamine D1 receptor (D1R) signaling has been associated to ethanol consumption and reward in laboratory animals. Objectives Here, we hypothesize that this receptor, which is located within the nucleus accumbens (NAc) neurons, modulates alcohol reward mechanisms. Methods To test this hypothesis, we measured alcohol consumption and ethanol-induced psychomotor sensitization and conditioned place preference (CPP) in mice that received bilateral microinjections of small interference RNA (siRNA)-expressing lentiviral vectors (LV-siD1R) producing D1R knock-down. The other group received control (LV-Mock) viral vectors into the NAc. Results There were no differences in the total fluid consumed and also no differences in the amount of ethanol consumed between groups prior to surgery. However, after surgery, the LV-siD1R group consumed less ethanol than the control group. This difference was not associated to taste neophobia. In addition, results have shown that downregulation of endogenous D1R using viral-mediated siRNA in the NAc significantly decreased ethanol-induced behavioral sensitization as well as acquisition, but not expression, of ethanol-induced place preference.Conclusions We conclude that decreased D1R expression into the NAc led to reduced ethanol rewarding properties, thereby leading to lower voluntary ethanol consumption. Together, these findings demonstrate that the D1 receptor pathway within the NAc controls ethanol reward and intake.

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The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement

Cited by 268 publications

References 267 publications

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

Differential induction of ethanol-metabolizing CYP2E1 and nicotine-metabolizing CYP2B1/2 in rat liver by chronic nicotine treatment and voluntary ethanol intake

Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice

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