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.

This study was supported by grants from the Spanish ‘Ministerio de Ciencia e Innovación’ (SAF2011-29864) to RM, SAF2010-18472) to PJM and (SAF2011-23813) to EC. ‘Ministerio de Economía y Competitividad’ (SAF2014-59648-P) to RM. The Spanish ‘Instituto de Salud Carlos III’ (P1070709 and PI14/00210) to PR and (RD06/001/ 001) to RM, the Catalan government (SGR2009- 00131) to RM. PJM was supported by a Ramon y Cajal Fellow and internal funds from UEA, and PJM and LP participate in the European COST Action CM 1207 (GLISTEN). FEDER funds partial support is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.