Loss of mRNA levels, binding and activation of GTP-binding proteins for cannabinoid CB 1 receptors in the basal ganglia of a transgenic model of Huntington’s disease

Abstract

Data obtained from the basal ganglia of postmortem Huntington’s disease (HD) brains have revealed that the level of cannabinoid CB 1 receptors in striatal efferent neurons decreases in parallel to the dysfunction and subsequent degeneration of these neurons. These findings, and others from rat models of HD generated by lesions with mitochondrial toxins, suggest that the loss of CB 1 receptors may be involved in the pathogenesis of the disease. To explore further the changes in the endocannabinoid system, as well as the potential of endocannabinoid-related compounds, we examined the status of CB 1 receptors in the HD94 transgenic mouse model of HD. These mice express huntingtin exon 1 with a polyglutamine tract of 94 repeats in a tissue-specific and conditional manner using the tet regulatable system. They develop many features of HD, such as striatal atrophy, intraneuronal aggregates and progressive dystonia. In these animals, we analyzed mRNA levels for the CB 1 receptor, in addition to the number of specific binding sites and the activation of GTP-binding proteins by CB 1 receptor agonists. mRNA transcripts of the CB 1 receptor were significantly decreased in the caudate-putamen of HD transgenic mice compared to age-matched littermate controls. The decrease concurred with a marked reduction in receptor density in both the caudate-putamen and its projection areas such as the globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata. Furthermore, the efficacy of CB 1 receptor activation was reduced in the globus pallidus, as determined by agonist-induced [ 35S]GTPγS binding, and tended towards a decrease in the substantia nigra. None of these changes was seen in the cerebral cortex and hippocampus, despite high levels of expression of the mutant protein in these regions. The decrease in CB 1 receptor levels was accompanied by a decrease in the proenkephalin-mRNA levels but not in substance P-mRNA levels. Taken together, these results suggest that the loss of CB 1 receptor might be preferential to the enkephalinergic CB 1 receptor-containing striatopallidal neurons, and further implicate the CB 1 receptor to the subsequent HD symptomatology and neuropathology.