Enantiomer-specific positive allosteric modulation of CB$_1$ signaling in autaptic hippocampal neurons

Abstract

The cannabinoid signaling system is found throughout the CNS and its involvement in several pathological processes makes it an attractive therapeutic target. Because orthosteric CB$_1$ cannabinoid receptor ligands have undesirable adverse effects there has been great interest in the development of allosteric modulators – both negative (NAMs) and positive (PAMs) – of these receptors. NAMs of CB$_1$ appeared first on the scene, followed more recently by PAMs. Because allosteric modulation can vary depending on the orthosteric ligand it is important to study their function in a system that employs endogenous cannabinoids. We have recently surveyed first generation NAMs using cultured autaptic hippocampal neurons. These neurons ex depolarization induced suppression of excitation (DSE), a form of synaptic plasticity that is mediated by CB$_1$ and 2-arachidonoyl glycerol (2-AG); they are therefore an excellent neuronal model of endogenous cannabinoid signaling in which to test CB$_1$ modulators.