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^Q7/Q7) or mutant huntingtin protein (STHdh^Q111/Q111). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/K_A)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gα_i/o, Gα_s, Gα_q, Gβγ, and β-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The E_max of Gα_i/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gα_i/o/Gβγ bias and normalized CB₁ protein levels and improved cell viability, whereas CP55,940 and THC displayed β-arrestin1 bias and reduced CB₁ protein levels and cell viability in HD cells. CBD was not a CB₁ agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gα_i/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are β-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.