glyceryl-2-arachidonate and Huntington-Disease

Huntington's disease (HD) is an inherited neurodegenerative disease affecting predominantly striatum and cortex that results in motor and cognitive disorders. Before a motor phenotype, animal models of HD show aberrant cortical-striatal glutamate signaling. Here, we tested synaptic plasticity of cortical excitatory synapses onto striatal spiny projection neurons (SPNs) early in the YAC128 mouse model of HD. High-frequency stimulation-induced long-term depression, mediated by the endocannabinoid anandamide and cannabinoid receptor 1 (CB1), was significantly attenuated in male and female YAC128 SPNs. Indirect pathway SPNs, which are more vulnerable in HD, were most affected. Our experiments show metabotropic glutamate receptor and endocannabinoid 2-arachidonoylglycerol-dependent plasticity, as well as direct CB1 activation by agonists, was similar in YAC128 and FVB/N wild-type SPNs suggesting that presynaptic CB1 is functioning normally. These results are consistent with a specific impairment in postsynaptic anandamide synthesis in YAC128 SPN. Strikingly, although suppression of degradation of anandamide was not effective, elevating 2-arachidonoylglycerol levels restored long-term depression in YAC128 striatal neurons. Together, these results have potential implications for neuroprotection and ameliorating early cognitive and motor deficits in HD.

Topics: Animals; Arachidonic Acids; Corpus Striatum; Disease Models, Animal; Endocannabinoids; Female; Glycerides; Huntington Disease; Male; Mice; Mice, Transgenic; Neuronal Plasticity; Neurons; Polyunsaturated Alkamides

Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression. Whether changes in dopamine and eCB systems are associated with specific behavioral impairments in HD and whether these deficits are amenable to viable treatments is unknown. Here, we show that dopaminergic encoding of effortful drive progressively declines with age in an HD mouse model, and is restored by elevating tissue levels of the eCB 2-arachidonoylglycerol (2-AG) through targeted inhibition of its enzymatic degradation. This work supports aberrant dopaminergic encoding of reward as a neurobiological correlate of apathy in HD, and indicates that cannabinoid receptor-based therapies may benefit neuropsychiatric care for HD.

Topics: Aging; Animals; Apathy; Arachidonic Acids; Benzodioxoles; Conditioning, Operant; Disease Progression; Dopamine; Endocannabinoids; Glycerides; Huntington Disease; Male; Mice; Motivation; Piperidines; Pyrazoles; Reward

In this study, we analyzed the components of the endocannabinoid system (ECS) in R6/2 mice, a widely used model of Huntington's disease (HD). We measured the endogenous content of N-arachidonoylethanolamine and 2-arachidonoylglycerol and the activity of their biosynthetic enzymes (N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and diacylglycerol lipase, respectively) and hydrolytic enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively] and of their target receptors (type 1 cannabinoid receptor, type 2 cannabinoid receptor, and transient receptor potential vanilloid-1) in the brains of wild-type and R6/2 mice of different ages, as well as in the striatum and cortex of 12-week-old animals. In addition, we measured FAAH activity in lymphocytes of R6/2 mice. In the whole brains of 12-week-old R6/2 mice, we found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity and cannabinoid receptor binding, mostly associated with changes in the striatum but not in the cortex, as well as an increase in 2-arachidonoylglycerol content as compared with wild-type littermates, without any other change in ECS elements. Then, our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and noninduced conditions, we demonstrated a fully functional ECS. Overall, our data suggest that the ECS is differently affected in mouse and human HD, and that HD43 cells are suitable for high-throughput screening of FAAH-oriented drugs affecting HD progression.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Cannabinoid Receptor Agonists; Cell Line; Cerebral Cortex; Disease Models, Animal; Endocannabinoids; Glycerides; Humans; Huntington Disease; Kinetics; Lymphocytes; Mice; Mice, Transgenic; Neostriatum; Polyunsaturated Alkamides; Rats

Huntington's disease (HD) is an inherited neurodegenerative disease characterised by cell dysfunction and death in the basal ganglia and cortex. Currently there are no effective pharmacological treatments available. Loss of cannabinoid CB1 receptor ligand binding in key brain regions is detected early in HD in human postmortem tissue [Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington's disease. Neuroscience 97:505-519]. In HD transgenic mice environmental enrichment upregulates the CB1 receptors and slows disease progression [Glass M, van Dellen A, Blakemore C, Hannan AJ, Faull RL (2004) Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors. Neuroscience 123:207-212]. These findings, combined with data from lesion studies have led to the suggestion that activation of cannabinoid receptors may be protective. However, studies suggest that CB1 mRNA may be decreased early in the disease progression in HD mice, making this a poor drug target. We have therefore performed a detailed analysis of CB1 receptor ligand binding, protein, gene expression and levels of endocannabinoids just prior to motor symptom onset (12 weeks of age) in R6/1 transgenic mice. We demonstrate that R6/1 mice exhibit a 27% decrease in CB1 mRNA in the striatum compared to wild type (WT). Total protein levels, determined by immunohistochemistry, are not significantly different to WT in the striatum or globus pallidus, but are significantly decreased by 19% in the substantia nigra. CB1 receptor ligand binding demonstrates significant but small decreases (<20%) in all basal ganglia regions evaluated. The levels of the endocannabinoid 2-arachidonoyl glycerol are significantly increased in the cortex (147%) while anandamide is significantly decreased in the hippocampus to 67% of WT. Decreases are also apparent in the ligand binding of neuronal D1 and D2 dopamine receptors co-located with CB1, while there is no change in GABA(A) receptor ligand binding. These results suggest that in this R6/1 mouse colony at 12 weeks there are only very small changes in CB1 protein and receptors and thus this would be an appropriate time point to evaluate therapeutic interventions.

Topics: Animals; Arachidonic Acids; Binding, Competitive; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Corpus Striatum; Disease Models, Animal; Down-Regulation; Dyskinesias; Endocannabinoids; Glycerides; Hippocampus; Huntington Disease; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptors, Dopamine; RNA, Messenger; Substantia Nigra