Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments

Abstract

The cannabinoid type 1 (CB 1) receptor and the dopamine type 2 (D 2) receptor are co-localized on medium spiny neuron terminals in the globus pallidus where they modulate neural circuits involved in voluntary movement. Physical interactions between the two receptors have been shown to alter receptor signaling in cell culture. The objectives of the current study were to identify the presence of CB 1 /D 2 heteromers in the globus pallidus of C57BL/6J male mice, define how CB 1 /D 2 heteromer levels are altered following treatment with cannabinoids and/or antipsychotics, and determine if fluctuating levels of CB 1 /D 2 heteromers have functional consequences. Using in situ proximity ligation assays, we observed CB 1 /D 2 heteromers in the globus pallidus of C57BL/6J mice. The abundance of the heteromers increased following treatment with the nonselective cannabinoid receptor agonist, CP55,940. In contrast, treatment with the typical antipsychotic haloperidol reduced the number of CB 1 /D 2 heteromers, whereas the atypical antipsychotic olanzapine treatment had no effect. Co-treatment with CP55,940 and haloperidol had similar effects to haloperidol alone, whereas co-treatment with CP55,940 and olanzapine had similar effects to CP55,940. The observed changes were found to have functional consequences as the differential effects of haloperidol and olanzapine also applied to γ-aminobutyric acid release in STHdh Q7/Q7 cells and motor function in C57BL/6J male mice. This work highlights the clinical relevance of co-exposure to cannabinoids and different antipsychotics over acute and prolonged time periods.

G Protein-Coupled Receptor Heteromers as Putative Pharmacotherapeutic Targets in Autism

“…The presence of the CB1R-D2R heteromer has been recently reported in the globus pallidus in mice (Bagher et al, 2020). The heteromer activation is characterized by an antagonistic interaction between the protomers, with CB1R agonists reducing the affinity and hyper-locomotor activity exerted by D2R agonists (Marcellino et al, 2008).…”

The Dynamic Role of Microglia and the Endocannabinoid System in Neuroinflammation

“…CB 2 -A 2A , CB 2 -5HT 1A , and CB 2 -CB 1 heteromers have been observed within microglia and fundamentally alter the microglial response to cannabinoids (Navarro et al, 2018;Franco et al, 2019a;Franco et al, 2019b). Furthermore, these heteromers have been found in different quantities under conditions of neuroinflammation and in response to different cannabinoid treatments (Navarro et al, 2018;Bagher et al, 2020). Currently, there are several established heteromer-dependent mechanisms that can result in either enhanced or diminished CB 2 receptor-mediated signaling (Figure 2).…”

Disrupting GPCR Complexes with Smart Drug-like Peptides

“…The human genome encodes nearly 1000 different GPCRs, each one highly specific to a signaling pathway [18]. However, growing evidence indicates that many GPCRs can form active higher-order oligomers constituted by equal (homo) or different (hetero) monomers [19][20][21][22][23][24][25][26], with functional properties distinct from their protomer components [27] and generally involved in both healthy and pathological processes [28], thus making them ideal targets for the development and screening of novel drugs [29,30].…”