Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats

Marinelli, Peter W.; Kiianmaa, Kalervo; Gianoulakis, Christina

doi:10.1016/s0024-3205(00)00517-8

Cited by 87 publications

(69 citation statements)

References 29 publications

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“…Consistent with these results, a previous report showed decreases in PENK gene expression in the nucleus accumbens and olfactory Tu and increases in the amygdala after several weeks of ethanol consumption (Cowen and Lawrence, 2001). The relevance of the role of this opioid gene in ethanol dependence is also strengthened by the fact that basal lower PENK gene expression has been related to high vulnerability for ethanol consumption (Gianoulakis et al, 1996;Fadda et al, 1999;Marinelli et al, 2000;Cowen and Lawrence, 2001;Manzanares et al, 2005). Treatment with naltrexone tended to 'normalize' the decreases found in the reward circuit regions whereas no effects were observed in the PVN.…”

Section: Discussionsupporting

confidence: 80%

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: Discussionsupporting

confidence: 80%

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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“…Consistent with the proposed role of m-and d-ORs in modulating alcohol reinforcement and consumption, numerous studies have demonstrated that alcohol preferring rodent strains show differences in m-and d-OR density (de Waele et al, 1995;Marinelli et al, 2000;McBride et al, 1998;Soini et al, 1998) and basal levels of b-endorphin and enkephalins (Blum et al, 1987;De Waele and Gianoulakis, 1994;De Waele et al, 1992;Gianoulakis et al, 1992;Nylander et al, 1994) when compared with nonpreferring strains. Similarly, m-OR knockout mice self-administer alcohol at lower levels when compared with wild-type controls (Becker et al, 2002;Hall et al, 2001;Roberts et al, 2000).…”

Section: Introductionmentioning

confidence: 79%

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Weerts

Kim

Wand

et al. 2007

Neuropsychopharmacol

138

147

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Blockade of brain m-opioid receptor (m-OR) and d-opioid receptor (d-OR) was investigated in recently abstinent alcohol-dependent subjects (N ¼ 21) maintained on naltrexone. Subjects completed a 19-day inpatient protocol, which included alcohol abstinence followed by naltrexone treatment (50 mg) on days 15-19. Blood samples were collected after the first administration of naltrexone to evaluate serum levels of naltrexone and 6-b-naltrexol. Regional brain m-OR binding potential (BP) and d-OR K i was measured using [ 11 C]carfentanil (CAR) positron emission tomography (PET) and [11 C]methyl naltrindole ([ 11 C]MeNTI) PET, respectively, before (day 5) and during naltrexone treatment (day 18). Naltrexone inhibition of [ 11 C]CAR BP was near maximal across all brain regions of interest with little variability across subjects (mean + SD% inhibition ¼ 94.9 + 4.9%). Naltrexone only partially inhibited the [ 11 C]MeNTI K i and there was more variability across subjects (mean + SD% inhibition ¼ 21.1 + 14.49%). Peak serum levels of naltrexone were positively correlated with % inhibition of d-OR K i in neocortex and basal ganglia. Peak serum levels of naltrexone were not correlated with % inhibition of m-OR BP. Peak levels of 6-b-naltrexol were not significantly correlated with % inhibition of m-OR BP or d-OR K i . Thus, the FDA recommended therapeutic dose of naltrexone was sufficient to produce near complete inhibition of the m-OR in recently abstinent alcohol dependent subjects. The lower percent inhibition of d-OR and greater variability in d-OR blockade by naltrexone across subjects may contribute to individual differences in treatment outcomes to naltrexone. Further investigations on the relationship between individual differences in d-OR blockade by naltrexone and clinical outcomes should be explored.

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“…67 Similar results were also described in rats: the density of KOR in the ventromedial hypothalamus was much lower in alcohol-avoiding AA rats than in alcohol-preferring ANA rats. 35 Difference in basal amount of KOR mRNA could lead to differences in KOR activity and subsequently to behavioral differences between the strains of animals in alcohol preferences. The application of a KOR-specific agonist U50,488H dosedependently decreased voluntary ethanol intake in AA rat.…”

Section: Discussionmentioning

confidence: 99%

“…32 Evidence from animal models also suggests a possible relationship between the opioid system and alcohol preference. [33][34][35][36] The dynorphin/KOR system may serve as a novel target for therapeutic treatment of alcohol and drug dependence. A selective KOR agonist U50,488H attenuates voluntary ethanol intake in rats.…”

Section: Introductionmentioning

confidence: 99%

Association of the κ-opioid system with alcohol dependence

et al. 2006

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Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the j-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the j-opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3 0 end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the j-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the j-opioid system.

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Opioid propeptide mRNA content and receptor density in the brains of AA and ANA rats

Cited by 87 publications

References 29 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

Differences in δ- and μ-Opioid Receptor Blockade Measured by Positron Emission Tomography in Naltrexone-Treated Recently Abstinent Alcohol-Dependent Subjects

Association of the κ-opioid system with alcohol dependence

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