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INTRODUCTION: Activation of cannabinoid 1 receptors (CB(1)Rs) by endocannabinoids (eCBs) is controlled by both eCB production and eCB inactivation. Accordingly, inhibition of eCB hydrolyzing enzymes, monoacylglycerol lipase (MAGL) and α/β-hydrolase domain containing 6 (ABHD6), enhances eCB accumulation and CB(1)R activation. It is known that inhibition of MAGL regulates select CB(1)R-dependent behaviors in mice, including locomotor behaviors and their modulation by psychostimulants, but much less is known about the effect of inhibiting ABHD6 activity on such behaviors. METHODS: We report a new mouse line that carries a genetic deletion of Abhd6 and evaluated its effect on spontaneous locomotion measured in a home cage monitoring system, motor coordination measured on a Rotarod, and amphetamine-stimulated hyperlocomotion and amphetamine sensitization (AS) measured in an open-field chamber. RESULTS: ABHD6 knockout (KO) mice reached adulthood without exhibiting overt behavioral impairment, and we measured only mild reduction in spontaneous locomotion and motor coordination in adult ABHD6 KO mice compared to wild-type (WT) mice. Significantly, amphetamine-stimulated hyperlocomotion was enhanced by twofold in ABHD6 KO mice compared to WT mice and yet ABHD6 KO mice expressed AS to the same extent as WT mice. A twofold increase in amphetamine-stimulated hyperlocomotion was also measured in ABHD6 heterozygote mice and in WT mice treated with the ABHD6 inhibitor KT-182. It is known that amphetamine-stimulated hyperlocomotion is not affected by the CB(1)R antagonist, SR141617, and we discovered that the enhanced amphetamine-stimulated hyperlocomotion resulting from ABHD6 inhibition is blocked by SR141617. CONCLUSIONS: Our study suggests that ABHD6 controls amphetamine-stimulated hyperlocomotion by a mechanistic switch to a CB(1)R-dependent mechanism.

Activation of cannabinoid 1 receptors (CB(1)R) modulates multiple behaviors, including exploration, motor coordination and response to psychostimulants. It is known that CB(1)R expressed by either excitatory or inhibitory neurons mediates different behavioral responses to CB(1)R activation, yet the involvement of CB(1)R expressed by medium spiny neurons (MSNs), the neuronal subpopulation that expresses the highest level of CB(1)R in the CNS, remains unknown. We report a new genetically modified mouse line that expresses functional CB(1)R in MSN on a CB(1)R knockout (KO) background (CB(1)R((MSN)) mice). The absence of cannabimimetic responses measured in CB(1)R KO mice was not rescued in CB(1)R((MSN)) mice, nor was decreased spontaneous locomotion, impaired instrumental behavior, or reduced amphetamine-triggered hyperlocomotion measured in CB(1)R KO mice. Significantly, reduced novel environment exploration of an open field and absence of amphetamine sensitization (AS) measured in CB(1)R KO mice were fully rescued in CB(1)R((MSN)) mice. Impaired motor coordination in CB(1)R-KO mice measured on the Rotarod was partially rescued in CB(1)R((MSN)) mice. Thus, CB(1)R expressed by MSN control exploration, motor coordination, and AS, demonstrating new functional roles for cell specific CB(1)R expression at the systems level and their causal link in the control of specific behaviors.

Huntington's Disease (HD) is a fatal neurodegenerative disease characterized by severe loss of medium spiny neuron (MSN) function and striatal-dependent behaviors. We report that female HdhQ200/200 mice display an earlier onset and more robust deterioration in spontaneous locomotion and motor coordination measured at 8 months of age compared to male HdhQ200/200 mice. Remarkably, HdhQ200/200 mice of both sexes exhibit comparable impaired spontaneous locomotion and motor coordination at 10 months of age and reach moribund stage by 12 months of age, demonstrating reduced life span in this model system. Histopathological analysis revealed enhanced mutant huntingtin protein aggregation in male HdhQ200/200 striatal tissue at 8 months of age compared to female HdhQ200/200. Functional analysis of calcium dynamics in MSNs of female HdhQ200/200 mice using GCaMP6m imaging revealed elevated responses to excitatory cortical-striatal stimulation suggesting increased MSN excitability. Although there was no down-regulation of the expression of common HD biomarkers (DARPP-32, enkephalin and CB1R), we measured a sex-dependent reduction of the astrocytic glutamate transporter, GLT-1, in female HdhQ200/200 mice that was not detected in male HdhQ200/200 mice when compared to respective wild-type littermates. Our study outlines a sex-dependent rapid deterioration of striatal-dependent behaviors occurring in the HdhQ200/200 mouse line that does not involve alterations in the expression of common HD biomarkers and yet includes impaired MSN function.

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)R-expressing 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.