Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats

Benjamin, Daniel; Grant, Elfrida R.; Pohorecky, Larissa A.

doi:10.1016/0006-8993(93)90309-b

Cited by 224 publications

(135 citation statements)

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“…These increases are fully blocked after treatment with naltrexone suggesting mesolimbic and nigrostriatal circuits as important systems that correlate with decreased intake of ethanol. Previous studies have suggested that naltrexone reduced the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens (Benjamin et al, 1993;Gonzales and Weiss, 1998;Middaugh et al, 2003) or dopamine neuronal firing rates activated by ethanol (Inoue, 2000). It is important to note that in these reports the release of dopamine was blocked by acute naltrexone administration.…”

Section: Discussionmentioning

confidence: 91%

“…The results of scalable doses of naltrexone 0.7 mg/kg for 4 days followed by an additional period of 4 days at 1.4 mg/kg revealed a significant decrease in the consumption of ethanol, in particular, in the last days of treatment (approximately 50%). The decrease of ethanol consumption after treatment with naltrexone has been shown by different Naltrexone and ethanol intake JM Oliva and J Manzanares laboratories although the magnitude of the reduction in consumption is variable and may depend of the experimental design, the strain of the rat, the duration of the treatment, and the dose employed or the length of the period that rats have been drinking ethanol before initiating the treatment (Benjamin et al, 1993;Myers and Lankford, 1996;Davidson and Amit, 1997;Phillips et al, 1997;Bienkowski et al, 1999;Goodwin et al, 2001;Stromberg et al, 2001Stromberg et al, , 2002. In this study, the prolonged consumption of ethanol in rats selected by its preference produced a significant decrease in the functional activity of m-opioid receptors in Cg, CPu, Acb C, and Acb S. The reduction in m-opioid-stimulated [ 35 S]GTPg binding in prefrontal cortex induced by voluntary ethanol intake was reported previously (Sim-Selley et al, 2002), although no differences were found in Cg, CPu, or nucleus accumbens.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Indeed, the blockade of opioid receptors induced by naltrexone represents probably the initial mechanism that triggers a variety of 'neuroplastic adaptations' underlying the reduction of ethanol intake. A few reports indicated that the administration of naltrexone reverted the ethanol-induced increases in extracellular dopamine (Benjamin et al, 1993;Gonzales and Weiss, 1998;Inoue, 2000;Middaugh et al, 2003), or tyrosine hydroxylase (TH) gene expression in the VTA , decreased the dopaminergic neuronal firing rates activated by ethanol (Inoue, 2000), induced changes in opioid receptor density (Parkes and Sinclair, 2000), and in proenkephalin (PENK) gene expression (Cowen and Lawrence, 2001).The search of what enzymes or receptors are altered in animals made preferring for ethanol and, in particular, in those with significant decreased ethanol consumption after treatment with drugs as naltrexone may allow to find out potential pharmacological targets to treat more effectively ethanol dependence.The purpose of this study was to identify what changes in the expression of a number of genes involved in the initiation or the maintenance of ethanol dependence are modified after treatment with naltrexone and in which specific brain regions of the rat are these alterations occurring. To this aim, TH, PENK, corticotropin releasing factor (CRF), cannabinoid CB 1 receptor (CB 1 -R), and serotonin transporter (5-HTT) gene expression and mopioid receptor functional autoradiography were examined in selected brain regions after naltrexone treatment in rats made preferring to ethanol.…”

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confidence: 99%

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Gene Transcription Alterations Associated with Decrease of Ethanol Intake Induced by Naltrexone in the Brain of Wistar Rats

Martínez

Manzanares

2006

Neuropsychopharmacol

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Preclinical and clinical studies suggest that the administration of the opioid antagonist naltrexone decreases the intake of ethanol. However, the neuroplastic adaptations in the brain associated to reduction of ethanol consumption remains to be elucidated. The aim of the study was to identify gene transcription alterations underlying the attenuation of voluntary ethanol intake by administration of naltrexone in rats. Increasing doses of naltrexone (0.7 mg/kg, 4 days and 1.4 mg/kg/day, 4 days) to rats with acquired high preferring ethanol consumption (43.5 g of ethanol/kg/day) decreased voluntary ethanol intake (50%). Voluntary ethanol consumption altered mopioid receptor function in the cingulate cortex, caudate-putamen (CPu), nucleus accumbens core (Acb C) and shell (Acb S), the expression of tyrosine hydroxylase (TH) in the ventral tegmental area and substantia nigra, proenkephalin (PENK) in the piriform cortex, olfactory tubercle, CPu, Acb C and Acb S, ventromedial nucleus (VMN) and paraventricular nucleus (PVN) of the hypothalamus, corticotropin releasing factor (CRF) in PVN, cannabinoid CB 1 receptor (CB 1 -R) in the CPu, hippocampus and VMN, and serotonin transporter (5-HTT) in the dorsal and median raphe nuclei. The reduction of ethanol intake induced by naltrexone was associated with a blockade or significant reduction of the changes produced by ethanol in the expression of these genes in key regions related to drug dependence. These results point to a role for the m-opioid receptor, TH, PENK, CRF, CB 1 -R, and 5-HTT genes in specific brain regions in the modulation of neuroadaptative mechanisms associated to the decrease of ethanol intake induced by naltrexone. INTRODUCTIONAlcoholism is a serious health, social, and familiar problem of difficult solution produced by the conjunction of different complex causes that reflect the interaction of genetic, environmental, socio-cultural, and personal factors (Saatcioglu et al, 2006). In general, the main objective in the treatment of alcohol dependence is the maintenance of the abstinence and the reduction of seeking behavior to avoid relapse. The development of alcohol dependence is a slow process produced by continuous and repeated consumption of ethanol that results specially damaging to subjects presenting high impulsivity, low self-esteem, and sensation-seeking behavior. The vulnerability to develop any kind of problems related to ethanol becomes even higher in patients with certain psychiatric disorders such as phobias, attention-deficit hyperactive disorder or affective disorders (anxiety, depression, or bipolar disorder) (Hines et al, 2005). The reinforcing actions of ethanol are enhanced in these situations facilitating the progression to ethanol dependence. It has been proposed that consumption of ethanol stimulates dopamine neurons by acting directly on the nucleus accumbens and by disinhibiting GABA mesencephalic neurons projecting into the dopamine tegmental area (Spanagel and Weiss, 1999;Kienast and Heinz, 2006). Alterations in dopamine neurons ...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Gene Transcription Alterations Associated with Decrease of Ethanol Intake Induced by Naltrexone in the Brain of Wistar Rats

Martínez

Manzanares

2006

Neuropsychopharmacol

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“…Preclinical data suggest that μ‐opioid receptor activation indirectly promotes dopamine release in the nucleus accumbens via a pathway involving GABAergic and dopaminergic neurons in the ventral tegmental area (Heilig et al , 2011). Conversely, μ‐opioid blockade blunts alcohol‐related dopamine release in the nucleus accumbens (Benjamin et al , 1993; Di Chiara et al , 1996; Spanagel et al , 1992), presumably contributing to reductions in alcohol reward and self‐administration (SA) (Gonzales and Weiss, 1998). These findings complement clinical evidence concerning reductions in craving and event‐level consumption as potential mechanisms for naltrexone's efficacy (Pettinati et al , 2006; Sinclair, 2001).…”

Section: Introductionmentioning

confidence: 99%

Effects of naltrexone on alcohol self‐administration and craving: meta‐analysis of human laboratory studies

et al. 2016

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Randomized clinical trials have established the efficacy of naltrexone for reducing quantity of alcohol consumption and incidence of relapse to heavy drinking. To evaluate putative treatment mechanisms, human laboratory studies have examined naltrexone's effects on alcohol responses and self‐administration during short‐term medication protocols. Results from these studies are inconsistent and have yet to be examined in aggregate. This meta‐analysis aimed to quantify naltrexone's effects on alcohol self‐administration and craving in the context of placebo‐controlled human laboratory trials. Potential moderators of medication effects were also examined. Meta‐analyses of alcohol self‐administration (k = 9, N = 490) and craving (k = 16, N = 748) confirmed that, under controlled experimental conditions, naltrexone reduces the quantity of consumption (Hedges' g = −.277, SE = .074, 95 percent CI = −.421, −.133, p < .001) and magnitude of self‐reported craving (g = −.286, SE = .066, 95 percent CI = −.416, −.156, p < .001) relative to placebo. Subgroup and moderation analyses found no evidence that effect sizes differed by study population (dependent versus non‐dependent drinkers), laboratory paradigm or duration of medication exposure. These results substantiate prior evidence for reductions in event‐level craving and consumption as potential treatment mediators, also establishing effect sizes to inform future human laboratory trials. From a clinical perspective, these results may provide additional evidence regarding naltrexone's efficacy in the context of acute or subacute dosing regimens.

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Family History of Alcoholism and Hypothalamic Opioidergic Activity

Wand¹,

Mangold²,

Deiry³

et al. 1998

Arch Gen Psychiatry

116

112

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Background: This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered endogenous central nervous system opioid activity. Naloxone hydrochloride stimulates plasma cortisol by blocking opioidergic input on the corticotropinreleasing factor neuron, thereby providing a noninvasive method for measuring hypothalamic opioid tone.

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Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats

Cited by 224 publications

References 25 publications

Gene Transcription Alterations Associated with Decrease of Ethanol Intake Induced by Naltrexone in the Brain of Wistar Rats

Gene Transcription Alterations Associated with Decrease of Ethanol Intake Induced by Naltrexone in the Brain of Wistar Rats

Effects of naltrexone on alcohol self‐administration and craving: meta‐analysis of human laboratory studies

Family History of Alcoholism and Hypothalamic Opioidergic Activity

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