Genetic association of nucleus accumbens 5-hydroxyindoleacetic acid level and alcohol preference drinking in a quasi-congenic male mice: Potential modulation by Grm7 gene polymorphism

Abstract

Objective: To test the hypothesis that predisposition to high alcohol drinking behavior is genetically associated with hypoactive serotonergic function in the Nucleus Accumbens (NAc).

Method: Alcohol avoiding C5A3 and alcohol preferring I5B25A mice of the Quasi-congenic Recombinant QTL Introgression (RQI) mouse strains were subjected to in vivo microdialysis in the NAc. Neurotransmitter and metabolite contents were analyzed by HPLC and samples were collected in three phases: Baseline, Control, and Alcohol. Samples were collected with 20 min intervals.

Results: Between-strain differences restricted to small chromosome segments significantly affected both alcohol preference drinking and NAc 5-HIAA levels [F_{1, 13} = 5.569 p=.035 (General Linear Model Repeated Measures ANOVA and Tests of Between-Subjects Effects)]. Whole genome biallelic DNA marker genotyping allowed the identification of 16 differential microsatellite markers associated with low 5-HIAA levels and excessive alcohol drinking. Chromosome 6 markers were linked to Grm7 (51.19 centimorgan), a reported candidate gene for modulation of addiction. The results are consistent with earlier reports of association of low 5-HIAA and high alcohol consumption in rats and primates, including Homo sapiens.

Conclusion: Low NAc 5-HIAA and high alcohol consumption are genetically associated in a quasi-congenic mouse model carrying variants of the Grm7 gene. We propose that constitutional polymorphism in Grm7 may modulate CRF neuron activity via altered mGluR7 expression thus targeting CRF pathways to substance use circuits. This raises the possibility of modulation of DRN 5-HT neurons leading to hypo- or hyper-serotonergic condition in NAc and higher or lower alcohol preference drinking.

Keywords: 5-HIAA; Addiction; Alcohol; Genetics; Grm7; Serotonin; mGluR7.

Fig. 1.

Genetic differences in NAc 5-HIAA levels determined by in vivo microdialysis. GLM RM ANOVA with13 sampling intervals (−60 min to 180 min) were used as levels of within-subject factor. Between-subjects factor was strain (C5A3 n = 8, I5B25A n = 7). Mauchly's Test of Sphericity rejected the null hypothesis, Greenhouse-Geisser (GG) correction (Epsilon GG=0.351) was applied. After GG correction the within-subjects effects of time (F_4.211 = 2.295 p=.068) and WS time*strain interaction (p=.477) were not significant sources of 5-HIAA level variation. Tests of WS contrasts for time or time*strain interaction showed no significant change from baseline (−60 min sample). Tests of Between-Subjects Effects showed significant effects F_1,13 = 5.569 p=.035).