Few preclinical approaches are available to study the health impact of voluntary consumption of edibles containing the psychoactive drug Δ 9-tetrahydrocannabinol (THC). We developed and validated such approach by measuring voluntary oral consumption of THC-containing gelatin by rats and used it to study if and how THC consumption during adolescence impacts adult behavior. We found that adolescent rats of both sexes consumed enough THC to trigger acute hypothermia, analgesic, and locomotor responses, and that 15 days of access to THC-gelatin in adolescence resulted in the down-regulation of cannabinoid 1 receptors (CB 1 Rs) in adulthood in a sex and brain area specific manner. Remarkably, THC consumption by adolescent male rats and not female rats led to impaired Pavlovian reward-predictive cue behaviors in adulthood consistent with a male-specific loss of CB 1 Rexpressing vGlut-1 synaptic terminals in the ventral tegmental area (VTA). Thus, voluntary oral consumption of THC during adolescence is associated with sex-dependent behavioral impairment in adulthood.

Background Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark -1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are two of the seven diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking. Methods To determine other traits genetically correlated with high DID, we compared naive animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits. Results Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their 3rd daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2 and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment. Conclusions These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to ethanol responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.

Association studies implicate multiple PDZ domain protein (MPDZ/MUPP1) sequence and/or expression in risk for alcoholism in humans and ethanol withdrawal (EW) in mice, but confirmation has been hindered by the dearth of targeted genetic models. We report the creation of transgenic (MPDZ-TG) and knockout heterozygote (Mpdz+/−) mice, with increased (2.9-fold) and decreased (47%) target expression, respectively. Both models differ in EW compared to wild type littermates (p≤0.03), providing compelling evidence for an inverse relationship between Mpdz expression and EW severity. Additionally, ethanol consumption is reduced up to 18% (p=0.006) in Mpdz+/−, providing the first evidence implicating Mpdz in ethanol self-administration.

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