Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future

Abstract

Over the last decades, the endocannabinoid system has been implicated in a large variety of functions, including a crucial modulation of brain-reward circuits and the regulation of motivational processes. Importantly, behavioral studies have shown that cannabinoid compounds activate brain reward mechanisms and circuits in a similar manner to other drugs of abuse, such as nicotine, alcohol, cocaine, and heroin, although the conditions under which cannabinoids exert their rewarding effects may be more limited. Furthermore, there is evidence on the involvement of the endocannabinoid system in the regulation of cue- and drug-induced relapsing phenomena in animal models. The aim of this review is to briefly present the available data obtained using diverse behavioral experimental approaches in experimental animals, namely, the intracranial self-stimulation paradigm, the self-administration procedure, the conditioned place preference procedure, and the reinstatement of drug-seeking behavior procedure, to provide a comprehensive picture of the current status of what is known about the endocannabinoid system mechanisms that underlie modification of brain-reward processes. Emphasis is placed on the effects of cannabinoid 1 (CB1) receptor agonists, antagonists, and endocannabinoid modulators. Further, the role of CB1 receptors in reward processes is investigated through presentation of respective genetic ablation studies in mice. The vast majority of studies in the existing literature suggest that the endocannabinoid system plays a major role in modulating motivation and reward processes. However, much remains to be done before we fully understand these interactions. Further research in the future will shed more light on these processes and, thus, could lead to the development of potential pharmacotherapies designed to treat reward-dysfunction-related disorders.

The Brain on Drugs: From Reward to Addiction

“…Endogenous opioids and cannabinoids have been also implicated in drug reward responses, in part through the opioid regulation of the mesolimbic DA pathway (Box 2) and through studies of the role of cannabinoids in adaptations that occur with repeated drug exposures (for reviews, see Covey et al, 2014;Panagis et al, 2014).…”

Biased Agonism of Three Different Cannabinoid Receptor Agonists in Mouse Brain Cortex

“…In this context, a considerable amount of studies have been performed in order to elucidate the effects of cannabinoids (natural or synthetics) in the development of mental alterations, such as addiction, cognitive deficits, anxiety or psychosis. Importantly, different or opposite behavioral effects have been observed after the administration of Δ 9 -THC or synthetic cannabinoid ligands (Fattore et al, 2003; Panagis et al, 2014; Rubino and Parolaro, 2016). It has been demonstrated that for most G protein-coupled receptors, distinct agonists can differentially regulate several signaling pathways through the same receptor by a selective activation of different intracellular effectors.…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…202 The CB2 receptors has been shown to modulate ventral tegmental dopamine neuron activity, circuitry considered pivotal in the addictive process. 203 …”