Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors

Abstract

Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) produces a variety of negative effects with major consequences in cannabis users that constitute important drawbacks for the use of cannabinoids as therapeutic agents. For this reason, there is a tremendous medical interest in harnessing the beneficial effects of THC. Behavioral studies carried out in mice lacking 5-HT2A receptors (5-HT2AR) revealed a remarkable 5-HT2AR-dependent dissociation in the beneficial antinociceptive effects of THC and its detrimental amnesic properties. We found that specific effects of THC such as memory deficits, anxiolytic-like effects, and social interaction are under the control of 5-HT2AR, but its acute hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects are not. In biochemical studies, we show that CB1R and 5-HT2AR form heteromers that are expressed and functionally active in specific brain regions involved in memory impairment. Remarkably, our functional data shows that costimulation of both receptors by agonists reduces cell signaling, antagonist binding to one receptor blocks signaling of the interacting receptor, and heteromer formation leads to a switch in G-protein coupling for 5-HT2AR from Gq to Gi proteins. Synthetic peptides with the sequence of transmembrane helices 5 and 6 of CB1R, fused to a cell-penetrating peptide, were able to disrupt receptor heteromerization in vivo, leading to a selective abrogation of memory impairments caused by exposure to THC. These data reveal a novel molecular mechanism for the functional interaction between CB1R and 5-HT2AR mediating cognitive impairment. CB1R-5-HT2AR heteromers are thus good targets to dissociate the cognitive deficits induced by THC from its beneficial antinociceptive properties.

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

“…Specifically, we showed that TM5 and TM6 of D 1 R are implicated in the heteromerization of D 1 R and D 3 R [11]. Likewise, TM5 and TM6 of CB 1 Rs were found to be involved in the 5-HT 2A R-CB 1 R heteromer interface [52]. However, TM5 and TM1 of OX 1 R were involved in the CRF 1 R-OX 1 R heteromer interface [51].…”

“…This technique is useful for determining which TMs are involved in the heterotetrameric interfaces. Recently, we successfully used this method to demonstrate the involvement of specific TM domains in the heteromerization of A 2A R and D 2 R [21], D 1 R and D 3 R [11], corticotropin-releasing factor CRF 1 (CRF 1 R) and orexin OX 1 receptors (OX 1 R) [51] and serotonin 5-HT 2A (5-HT 2A R) and cannabinoid CB 1 receptors (CB 1 R) [52]. In these studies, TMs of the receptors were fused to the HIV transactivator of transcription (TAT) peptide, allowing their effective insertion and orientation in the plasma membrane due to its capacity to penetrate it [11,21,51,53].…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Evidence points also to ⌬ 9 -THC modulation of behaviors typically mediated by 5-HT 2A receptor activation (178, 305). Both in vitro and in vivo CB1 and 5-HT 2A receptors seem to form functionally active heteromers in specific brain regions, which seem to be required for some cognitive and anxiolitic effects of ⌬ 9 -THC, but not for antinociception and hypolocomotion (884).…”

Drug development: The treasure chest

“…And it turns out that the receptor missing in McCormick's mice, 5-HT 2A , also interacts with CB 1 . When the team used a small peptide molecule to impede the 5-HT 2A and CB 1 interaction in normal mice, the same effect was seen 3 . He suggests that this could be a way to target the effects of cannabinoids more precisely.…”