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 (analgesia/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.

中文翻译：

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BXD小鼠家族中对Δ9-四氢大麻酚（THC）的初始敏感性的遗传调控

大麻中的主要精神活性成分Δ9-四氢大麻酚（THC）激活大麻素受体1，在急性暴露后会产生运动障碍，体温过低和镇痛作用。在以前的工作中，我们证明了在C57BL / 6J（B6）和DBA / 2J（D2）近交小鼠中单剂量（10 mg / kg，ip）给药后，对THC的急性反应存在明显的性别和品系差异。为了确定这些差异可遗传的程度，我们对BXD和B6D的近交系BXD家族的20个成员的雄性和雌性中单剂量THC（10 mg / kg，ip）的急性反应进行了定量。 D2小鼠。急性THC反应（初始敏感性）被量化为相对于基线的变化：1.在旷野中的自发活动（运动），2。体温（体温过低）和3。尾巴退缩对热刺激的潜伏期（镇痛/镇痛）。在整个BXD家族中，对THC的固定，低温和镇痛作用的初始敏感性差异很大。流动性和低温性状的遗传力最高，表明分离的遗传变异体可调节对THC的初始敏感性。我们确定了基因组基因座和候选基因，包括Ndufs2，Scp2，Rps6kb1或P70S6K，Pde4d和Pten，它们可以控制THC初始灵敏度的变化。我们还发现，对THC的初始反应与与摄入或对其他滥用药物（可卡因，乙醇和吗啡）的反应相关的传统表型之间存在很强的相关性。