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Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

ABSTRACT: BACKGROUND AND PURPOSE:The aim of this study was to explore if the administration of naltrexone together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately. EXPERIMENTAL APPROACH:The effects of low doses of naltrexone (0.7 mg·kg-1 , p.o.) and/or CBD (20 mg·kg-1 ·day-1 , s.c.) on ethanol consumption and motivation to drink were evaluated in the oral-ethanol self-administration paradigm in C57BL/6 mice. Gene expression analyses of the opioid ? receptor (Oprm1) in the nucleus accumbens (NAc), tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and the 5-HT1A receptor in the dorsal raphe nucleus (DR) were carried out by real-time PCR. The role of 5-HT1A receptors in the ethanol reduction induced by the administration of CBD + naltrexone was analysed by using the 5-HT1A receptor antagonist WAY100635 (0.3 mg·kg-1 , i.p.). KEY RESULTS:The administration of CBD + naltrexone significantly reduced motivation and ethanol intake in the oral self-administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced Oprm1, TH and 5-HT1A gene expressions in the NAc, VTA and DR respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD + naltrexone but had no effects by itself. CONCLUSION AND IMPLICATIONS:The combination of low doses of CBD plus naltrexone were more effective than either CBD or naltrexone alone at reducing ethanol consumption and the motivation to drink. These effects appear to be mediated, at least in part, by 5-HT1A receptors.

SUBMITTER: Viudez-Martinez A

PROVIDER: S-EPMC6057893 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

Viudez-Martínez Adrián A García-Gutiérrez María S MS Fraguas-Sánchez Ana Isabel AI Torres-Suárez Ana Isabel AI Manzanares Jorge J

British journal of pharmacology 20180701 16

<h4>Background and purpose</h4>The aim of this study was to explore if the administration of naltrexone together with cannabidiol (CBD) may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.<h4>Experimental approach</h4>The effects of low doses of naltrexone (0.7 mg·kg<sup>-1</sup> , p.o.) and/or CBD (20 mg·kg<sup>-1</sup> ·day<sup>-1</sup> , s.c.) on ethanol consumption and motivation to drink were evaluated in the oral-ethanol sel ...[more]

PMID: 29859012

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Project description:Data from C57BL/6J (B6) × DBA/2J (D2) F2 intercrosses (B6xD2 F2 ), standard and recombinant inbred strains, and heterogeneous stock mice indicate that a reciprocal (or inverse) genetic relationship exists between alcohol consumption and withdrawal severity. Furthermore, some genetic studies have detected reciprocal quantitative trait loci (QTLs) for these traits. We used a novel mouse model developed by simultaneous selection for both high alcohol consumption/low withdrawal and low alcohol consumption/high withdrawal and analyzed the gene expression and genome-wide genotypic differences.Randomly chosen third selected generation (S3 ) mice (N = 24/sex/line), bred from a B6xD2 F2 , were genotyped using the Mouse Universal Genotyping Array, which provided 2,760 informative markers. QTL analysis used a marker-by-marker strategy with the threshold for a significant log of the odds (LOD) set at 10. Gene expression in the ventral striatum was measured using the Illumina Mouse 8.2 array. Differential gene expression and the weighted gene co-expression network analysis (WGCNA) were implemented.Significant QTLs for consumption/withdrawal were detected on chromosomes (Chr) 2, 4, 9, and 12. A suggestive QTL mapped to Chr 6. Some of the QTLs overlapped with known QTLs mapped for 1 of the traits individually. One thousand seven hundred and forty-five transcripts were detected as being differentially expressed between the lines; there was some overlap with known withdrawal genes (e.g., Mpdz) located within QTL regions. WGCNA revealed several modules of co-expressed genes showing significant effects in both differential expression and intramodular connectivity; a module richly annotated with kinase-related annotations was most affected.Marked effects of selection on expression and network structure were detected. QTLs overlapping with differentially expressed genes on Chr 2 (distal) and 4 suggest that these are cis-eQTLs (Chr 2: Kif3b, Kcnq2; Chr 4: Mpdz, Snapc3). Other QTLs identified were on Chr 2 (proximal), 9, and 12. Network results point to involvement of kinase-related mechanisms and outline the need for further efforts such as interrogation of noncoding RNAs.

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Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

Publications

Effects of cannabidiol plus naltrexone on motivation and ethanol consumption.

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