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.
Highlights
The administration of delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in Cannabis sativa, induces numerous behavioral responses related to undesirable effects, including memory impairments [1,2], anxiogenic effects [3], and dependence [4,5]
Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals
We showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other
Summary
The administration of delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in Cannabis sativa, induces numerous behavioral responses related to undesirable effects, including memory impairments [1,2], anxiogenic effects [3], and dependence [4,5]. The activation of 5-HT2AR expressed in cells stimulates the formation and release of the endocannabinoid, 2-arachidonoylglycerol (2-AG) [13,14] Both 5-HT2AR and CB1R are expressed in brain structures involved in regulating emotions, learning, and memory, including the amygdala, cerebral cortex, and hippocampus [15,16,17]. 5-HT2AR is involved in different psychotic manifestations [28,29], while adolescent consumption of cannabis enhances the incidence of psychotic symptoms [30,31] These data suggest possible bidirectional interactions between CB1R- and 5-HT2AR-mediated pharmacological responses, a cellular mechanism for this cross talk has yet to be discovered. Using a variety of in vivo and in vitro assays, we reveal a new molecular mechanism by which the cognitive deficits of THC can be dissociated from its beneficial antinociceptive properties
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