Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh) or mutant huntingtin protein (STHdh). Signaling bias was assessed using the Black and Leff operational model. Relative activity [DlogR (t/KA)] and system bias (DDlogR) were calculated relative to the reference compound WIN55,212-2 for Gai/o, Gas, Gaq, Gbg, and b-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, D-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC1CBD (1:1), and compared between wild-type and HD cells. The Emax of Gai/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gai/o/Gbg bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed b-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC1CBD). Therefore, enhancing Gai/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are b-arrestin-biased—such as THC found at high levels in modern varieties of marijuana—may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced.