The endocannabinoid system and drug-associated contextual memories

Abstract

Drug abuse and addiction can be initiated and reinstated by contextual stimuli previously paired with the drug use. The influence exerted by the context on drug-seeking behaviour can be modelled in experimental animals with place-conditioning protocols. Here, we review the effects of cannabinoids in place conditioning and the therapeutic potential of the endocannabinoid system for interfering with drug-related memories. The phytocannabinoid Δ9-tetrahydrocannabinol (THC) tends to induce conditioned place preference (CPP) at low doses and conditioned place aversion at high doses; cannabidiol is devoid of any effect, yet it inhibits CPP induced by some drugs. Synthetic CB1 receptor agonists tend to recapitulate the biphasic profile observed with THC, whereas selective antagonists/inverse agonists inhibit CPP induced by cocaine, nicotine, alcohol and opioids. However, their therapeutic use is limited by potential psychiatric side effects. The CB2 receptor has also attracted attention, because selective CB2 receptor agonists inhibit cocaine-induced CPP. Inhibitors of endocannabinoid membrane transport and hydrolysis yield mixed results. In targeting the endocannabinoid system for developing new treatments for drug addiction, future research should focus on ‘neutral’ CB1 receptor antagonists and CB2 receptor agonists. Such compounds may offer a well-tolerated pharmacological profile and curb addiction by preventing drug-seeking triggered by conditioned contextual cues.

Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction

“…Among these new potential targets is the endocannabinoid system (eCBS). The eCBS may be involved in various aspects of drug addiction, including reward, contextual memories precipitating drug seeking, drug tolerance, and withdrawal effects [ 8 , 9 ]. The eCBS comprises two main cannabinoid receptor subtypes (CB 1 R and CB 2 R), their endogenous ligands, termed endocannabinoids, and the proteins and enzymes responsible for endocannabinoid transport, biosynthesis, and degradation [ 10 ].…”

The endocannabinoid system as a putative target for the development of novel drugs for the treatment of psychiatric illnesses

“…To conclude, the eCB system is clearly involved in the mechanism by which a range of substances produce their reinforcing effects. CB1R antagonists directly attenuate the positive subjective effects of cannabis, but also reduce the rewarding and reinforcing effects of non-cannabinoid substances, likely by blocking eCBs from disinhibiting dopaminergic neurons in the ventral tegmental area (Asth et al, 2022;Soyka et al, 2008). Studies by Mantsch and colleagues suggest that another potential use for CB1R antagonists could be in the prevention of stress-induced relapse to drug taking (McReynolds et al, 2018(McReynolds et al, , 2016.…”

“…Although it was not surprising that rimonabant reduced the subjective effects of cannabis, evidence that this medication also reduces the reinforcing effects of nicotine was one of many clues that targeting the eCB may have potential to treat a range of SUDs. To start preclinically, CB1R antagonists reduce nicotine reinforcement [see (Saravia, Ten-Blanco, Pereda-Pérez, & Berrendero, 2021 ; Spanagel, 2020 )], presumably by blocking eCBs from disinhibiting dopaminergic neurons in the ventral tegmental area [see (Asth, Santos, & Moreira, 2022 ; Butler & Le Foll, 2020 )]. These findings appear consistent with human imaging data [summarized by (Hirvonen et al, 2018 )] – with cannabis, THC acts on CB1Rs directly and thereby downregulates CB1Rs in neocortical brain regions but not in the basal ganglia, midbrain, or cerebellum.…”

Biomarkers of the Endocannabinoid System in Substance Use Disorders

“…In addition, ECS components are expressed in the brain regions that make up the mesocorticolimbic pathway, including the VTA, NAcc, or PFC. Notably, the dopaminergic neurons of this brain reward circuitry are controlled by excitatory and inhibitory inputs that are, in turn, modulated by the ECS [31][32][33].…”