Synaptic changes induced by cannabinoid drugs and cannabis use disorder

Abstract

The legalization of cannabis in many countries, as well as the decrease in perceived risks of cannabis, have contributed to the increase in cannabis use medicinally and recreationally. Like many drugs of abuse, cannabis and cannabis-derived drugs are prone to misuse, and long-term usage can lead to drug tolerance and the development of Cannabis Use Disorder (CUD). These drugs signal through cannabinoid receptors, which are expressed in brain regions involved in the neural processing of reward, habit formation, and cognition. Despite the widespread use of cannabis and cannabinoids as therapeutic agents, little is known about the neurobiological mechanisms associated with CUD and cannabinoid drug use. In this article, we discuss the advances in research spanning animal models to humans on cannabis and synthetic cannabinoid actions on synaptic transmission, highlighting the neurobiological mechanisms following acute and chronic drug exposure. This article also highlights the need for more research elucidating the neurobiological mechanisms associated with CUD and cannabinoid drug use.

Keywords: Cannabinoid 1 receptor; Cannabis sativa; Delta-9 tetrahydrocannabinol; Endocannabinoid; Long-term depression; Long-term potentiation; Synaptic Modulation.

Fig. 1.

Mechanisms involved in presynaptic depression induced by acute CB1 agonist exposure. A) Receptor activation inhibits presynaptic VGCCs implicated in excitation-secretion coupling through actions of the Gβ/γ G protein subunit. B) Receptor activation inhibits vesicle fusion directly, presumably via Gβ/γ subunit interactions with proteins that are part of the fusion/release machinery. C) Receptor activation inhibits release via Gα G protein subunit inhibition of Adenylyl cyclase (AC) leading to decreased protein kinase A (PKA)-mediated phosphorylation of proteins that regulate vesicle fusion. This mechanism is implicated in LTD.

Fig. 2.

Presynaptic alterations in CB1 desensitization. A) Following prolonged CB1 agonist exposure receptors are internalized and uncoupled from Gβ/γ G protein subunit. B) Receptor/G-protein signaling may also be uncoupled from AC inhibition, leading to loss of LTD-inducing mechanisms. Increased cyclic AMP levels and PKA activity might also occur under this condition.