Abstract
Cannabinoid receptor 1 activation by the major psychoactive component in cannabis, Δ9-tetrahydrocannabinol (THC), produces motor impairments, hypothermia, and analgesia upon acute exposure. In previous work, we demonstrated significant sex and strain differences in acute responses to THC following administration of a single dose (10 mg/kg, i.p.) in C57BL/6J (B6) and DBA/2J (D2) inbred mice. To determine the extent to which these differences are heritable, we quantified acute responses to a single dose of THC (10 mg/kg, i.p.) in males and females from 20 members of the BXD family of inbred strains derived by crossing and inbreeding B6 and D2 mice. Acute THC responses (initial sensitivity) were quantified as changes from baseline for: 1. spontaneous activity in the open field (mobility), 2. body temperature (hypothermia), and 3. tail withdrawal latency to a thermal stimulus (antinociception). Initial sensitivity to the immobilizing, hypothermic, and antinociceptive effects of THC varied substantially across the BXD family. Heritability was highest for mobility and hypothermia traits, indicating that segregating genetic variants modulate initial sensitivity to THC. We identified genomic loci and candidate genes, including Ndufs2, Scp2, Rps6kb1 or P70S6K, Pde4d, and Pten, that may control variation in THC initial sensitivity. We also detected strong correlations between initial responses to THC and legacy phenotypes related to intake or response to other drugs of abuse (cocaine, ethanol, and morphine). Our study demonstrates the feasibility of mapping genes and variants modulating THC responses in the BXDs to systematically define biological processes and liabilities associated with drug use and abuse.
Highlights
Recombinant inbred (RI) rodent populations are a valuable resource for forward genetic mapping and systems genetics analysis
We found that treatment had significant and moderate to large main effects on mobility, hypothermia, and antinociception in our BXD cohort
Genetic mapping of THC response traits in the BXD family will lead to the identification of genomic loci, including variants and genes, that modulate response to cannabinoids
Summary
Recombinant inbred (RI) rodent populations are a valuable resource for forward genetic mapping and systems genetics analysis. Since its inception in the late 1970s, the BXD RI panel continues to be a valuable resource for characterization of the genetic architecture of addiction-related behavior and identification of genes and variants modulating the response to drugs of abuse (Phillips et al, 1991; Rodriguez et al, 1994, 1995; Hitzemann et al, 2003; Philip et al, 2010; Jackson et al, 2011; Dickson et al, 2016). The BXD family has been deeply phenotyped for molecular, behavioral, physiological, and pharmacological traits since the late 1970’s and includes data related to cognitive function, anxiety and stress, social interactions, and response to drugs of abuse (Philip et al, 2010; Laughlin et al, 2011; Newbury and Rosen, 2012; Harenza et al, 2014; Loos et al, 2014; Neuner et al, 2016; Ashbrook et al, 2018; Knoll et al, 2018)
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