Cocaine-Induced Sensitization is Linked to Distal Chromosome 6 Region in Congenic Mouse Model

Abstract

Objective: Previously we mapped QTL Eac2 to mouse Chr6 and identified the first gene (Grm7) as accounting for alcohol consumption in a mammalian model. Despite the central role of glutamate receptors in addiction, the effects of Grm7 gene variants are not well known. Here we test the hypothesis that genetic variation of the distal mouse Chr6 Eac2 region, location of Grm7, controls cocaine-induced locomotor sensitization.

Method: C57BL/6By background and B6.C6.327.54 congenic mice were subjected to whole-genome SNP genotyping. Isogeneic (C57BL/6ByXB6.C6.327.54)F2 mice homozygous for SNPs in the BALB/c-type Eac2 region were selected to create a subcongenic strain (B6By.C6.108-120). In a 2-strain x 2-sex 2-treatment factorial design (n = 6-10) C57BL/6By and B6By.C6.108-120 mice received repeated daily cocaine or saline intraperitoneal injections, and locomotor activity was recorded for 90 minutes immediately after injection.

Results: C57BL/6By females with the G/G genotype of SNP rs3723352 of Grm7 responded to cocaine with significantly higher activity and greater cocaine-induced sensitization than those with the BALB/cJ-type T/T genotype in the congenic strain.

Conclusion: The results are consistent with a large body of accumulated mechanistic evidence for a role of the mGlu7 receptor in the control of neurobiological responses to cocaine, and are consistent with the hypotheses that (1) natural variants of the Grm7 gene show pleiotropy and can modulate cocaine-induced behaviors in addition to alcohol consumption, (2) interactions between mGluR7 expression, estrogen receptors, and estradiol may explain phenotypic variation in females. Heritable variation of GRM7 may affect vulnerability to substance abuse in women.

Keywords: Eac2Grm7mGluR7; cocaine; rs3723352; sensitization; sex.