The Sobering Sting: Oleoyl Serotonin Is a Novel Stephanoconus Snail Venom-Derived Antagonist of Cannabinoid Receptors That Counteracts Learning and Memory Deficits.

Cannabinoid receptors (CB1 and CB2) are promising targets for a better understanding of neurological diseases. Nevertheless, only a few ligands of CB have reached clinical application so far. Venoms are considered as interesting sources of novel biologically active compounds. Here, we describe an endocannabinoid-like molecule, oleoyl serotonin (OS), present in the venom of Stephanoconus snails. Using electrophysiological assays, it was shown that OS inhibits CB1 and CB2. Structure-activity relationship studies using a chimeric CB1/2 revealed that the domain encompassing the transmembrane helix V (TMHV)- intracellular loop 3 (ICL3)-TMHVI of the CB2 is critical for the binding and function of OS. We concluded that OS binds to sites of the CB2 that are different from the binding sites of the non-selective CB agonist WIN55,212-2. Behavioral assays in mice showed that OS counteracted learning and memory deficits caused by WIN55,212-2. Furthermore, a selectivity screening of OS showed high selectivity for CB over various ion channels and receptors. Overall, OS may represent a new approach to the prevention and treatment of learning and memory cognition impairment in neurological diseases.

Maternal deprivation impairs memory and cognitive flexibility, effect that is avoided by environmental enrichment.

Maternal deprivation (MD) causes cognitive deficits that persist until adulthood. Thereby, the environmental enrichment (EE) is widely used to increase brain plasticity. Here, pregnant female rats were used and their offspring were submitted to neonatal MD from post-natal day 1-10; after weaning the rats were submitted to EE. MD caused deficits on short and long-term aversive and recognition memory and on cognitive flexibility tested on reversed Morris Water Maze test. MD also promoted the decrease of hippocampal Brain-Derived Neurotropic Factor (BDNF) protein expression. The EE was able to protect against the cognitive deficits, avoiding the memory and the cognitive flexibility disrupting, and normalizing hippocampal BDNF expression of rats submitted to MD. These data confirms that MD promotes long-life memory deficits and demonstrates that MD causes cognitive flexibility disruption; the mechanisms seem involve the decrease of BDNF. We also demonstrate that EE, which improves BDNF, is able to avoid memory deficits and cognitive flexibility disrupts.