Activation of cannabinoid CB1 receptors (CB1R) by delta9-tetrahydrocannabinol (THC) causes negative effects including memory deficits, limiting therapeutic use. Behavioral studies in mice lacking 5-HT2A receptors (5-HT2AR) showed a dissociation: THC's antinociceptive effects remained, but its amnesic, anxiolytic-like, and social interaction effects depended on 5-HT2AR, while hypolocomotor, hypothermic, anxiogenic, and antinociceptive effects did not. Biochemical studies revealed CB1R and 5-HT2AR form heteromers in brain regions involved in memory, altering cell signaling and G-protein coupling. Synthetic peptides disrupting heteromerization selectively prevented THC-induced memory impairments, identifying CB1R-5-HT2AR heteromers as targets to separate cognitive deficits from beneficial pain relief.
Repeated high doses of MDMA (30 mg/kg) given to mice impaired working memory and cognitive flexibility, with deficits in recalling learned alternation behavior persisting five days after the last dose. The high dose also increased perseveration errors in an attentional set-shifting task, indicating reduced cognitive flexibility. These behavioral effects were not due to anhedonia, as saccharin preference remained unchanged. Although baseline dopamine levels in the striatum were unaffected, an acute MDMA challenge failed to increase dopamine outflow in mice that had received the high dose, suggesting reduced dopamine transporter function. Dopamine outflow recovered seven days later. The findings suggest that neurotoxic MDMA doses cause lasting impairments in recall and cognitive flexibility in mice.