Synaptic Targets of  9-Tetrahydrocannabinol in the Central Nervous System

Abstract

The availability of potent synthetic agonists for cannabinoid receptors has facilitated our understanding of cannabinoid actions on synaptic transmission in the central nervous system. Moreover, the ability of these compounds to inhibit neurotransmitter release at many central synapses is thought to underlie most of the behavioral effects of cannabinoid agonists. However, despite the widespread use and misuse of marijuana, and recognition of its potential adverse psychological effects in humans, comparatively few studies have examined the actions of its primary psychoactive constituent, D 9-tetrahydrocannabinol (THC), at well-defined synaptic pathways. Here we examine the recent literature describing the effects of acute and repeated THC exposure on synaptic function in several brain regions and explore the importance of these neurobiological actions of THC in drug addiction.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Stimulating CB1 receptors can affect neurotransmission and interestingly augment signaling of many types of neurotransmitters (Szabo and Schlicker, 2005). When secreted, eCBs originate from the postsynaptic neuron and travel retrogradely to the presynaptic terminal, activate CB1 receptors, and cause a decrease in glutamate release probability (Lupica and Riegel, 2005;Szabo and Schlicker, 2005;Hoffman and Lupica, 2013). Recent studies also support a role for astroglial CB1 receptors in the enhancement of glial glutamate release, which can modulate plasticity in adjacent synapses (Navarrete and Araque, 2008;Rossi, 2012;Hwang et al, 2014).…”

“…This inhibition is, as described above, due to a presynaptic mechanism (although for a possible postsynaptic mechanism, see Hoffman and Lupica, 2001) since the frequency of mEPSCs is decreased and the PPR is increased (Robbe et al, 2001(Robbe et al, , 2003Hoffman and Lupica, 2013). More specifically, eCBs activate a cAMP/PKA cascade in the presynaptic terminal (Mato et al, 2008) by binding to the CB1 receptor.…”

“…Endocannabinoid-dependent long-term depression. Marijuana is a drug that acts in the brain by activating cannabinoid (CB) 1 receptors (Lupica and Riegel, 2005; The Nucleus Accumbens: Mechanisms of Addiction Fratta and Fattore, 2013;Hoffman and Lupica, 2013), which are also activated by endogenous cannabinoids (eCBs). Stimulating CB1 receptors can affect neurotransmission and interestingly augment signaling of many types of neurotransmitters (Szabo and Schlicker, 2005).…”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

“…The selection of these markers was based on previous evidence about the role of cannabinoids in modulating synaptic signaling and function [21,22]. In contrast to what happened when 9 -THC and CBD were administered at early stages [13], the combination of these natural cannabinoids fails to modify the levels of the redox protein Txn2 and the signaling molecule Wnt16 in the somatosensory cortex of aged A␤PP/PS1 mice.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The CB 1 receptor is predominantly expressed in the brain and plays a role in regulation of mood and appetite, in processes of pain, in addiction, and in synaptic plasticity in response to eCB-induced activation ( Fig. 12) (for reviews, see Witkin et al, 2005;Katona et al, 2006;Katona and Freund, 2008;Heifets and Castillo, 2009;Hoffman and Lupica, 2013). CB 2 receptors are found predominantly in peripheral tissues, such as T and B cells, keratinocytes, and peripheral nervous system, and have so far remained a target for preclinical investigations related to immunomodulation (Dhopeshwarkar and Mackie, 2014;Malfitano et al, 2014).…”