A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking

Next Section Abstract Increases in mesolimbic dopamine transmission are observed when animals are treated with all known drugs of abuse, including cannabis, and to conditioned stimuli predicting their availability. In contrast, decreases in mesolimbic dopamine function are observed during drug withdrawal, including cannabis-withdrawal syndrome. Thus, despite general misconceptions that cannabis is unique from other drugs of abuse, cannabis exerts identical effects on the mesolimbic dopamine system. The recent discovery that endogenous cannabinoids modulate the mesolimbic dopamine system, however, might be exploited for the development of potential pharmacotherapies designed to treat disorders of motivation. Indeed, disrupting endocannabinoid signaling decreases drug-induced increases in dopamine release in addition to dopamine concentrations evoked by conditioned stimuli during reward seeking.

All known drugs of abuse, including Δ9-tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, increase dopamine concentrations in terminal regions of the mesolimbic dopamine system (Di Chiara and Imperato 1988; Pierce and Kumaresan 2006). The mesolimbic dopamine system is a neural pathway that originates from A10 dopamine neurons in the ventral tegmental area of the midbrain and projects to limbic structures, most prominently the nucleus accumbens (Table 1) (Spanagel and Weiss 1999). Increases in nucleus accumbens dopamine are theorized to mediate the primary positive reinforcing and rewarding properties of all known drugs of abuse (Roberts et al. 1977; Wise and Bozarth 1985; Ritz et al. 1987). In addition, when animals are presented with conditioned stimuli that predict drug availability, transient dopamine events that are theorized to mediate the secondary reinforcing effects of drugs of abuse and initiate drug seeking are also observed in the nucleus accumbens (Phillips et al. 2003; Owesson-White et al. 2009). In contrast, the negative affective state that occurs during drug withdrawal is associated with a decrease in mesolimbic dopamine function, which might lead to compulsive drug seeking (Weiss et al. 2001; Koob 2009). This article reviews studies addressing the effects of cannabinoids and cannabinoid withdrawal on dopamine release, in addition to the effects of manipulating the endogenous cannabinoid system on drug- and cue-evoked dopamine release.

View this table: Table 1. Terminology and definitions used in text

Previous Section Next Section TONIC AND PHASIC DOPAMINE OVERVIEW Before delving into the interaction between cannabinoids and the dopamine system, it is important first to develop a general understanding of the patterns of dopamine signaling and the common methods used to monitor dopamine transmission in vivo. Two distinct patterns of dopamine neural activity occur in the behaving animal. Midbrain dopamine neurons typically fire at low frequencies of 1–5 Hz, which is thought to produce a tone on high-affinity dopamine D2 receptors in terminal regions of the mesolimbic dopamine system, including the nucleus accumbens (Grace 1991; Dreyer et al. 2010). These tonic dopamine levels are detectable using techniques, such as in vivo microdialysis, that allow for neurochemical collection on a timescale of minutes. In contrast, when animals are presented with motivationally salient stimuli, such as conditioned cues that predict drug availability, midbrain dopamine neurons fire in high-frequency bursts (≥20 Hz), thereby producing transient increases in nucleus accumbens dopamine concentration that are sufficiently high to occupy low-affinity dopamine D1 receptors (Grace 1991; Phillips et al. 2003; Dreyer et al. 2010). These phasic dopamine events are detectable in vivo at the level of the dopamine neuron using single-unit electrophysiological recording techniques or at the neurochemical level within terminal fields of the mesolimbic dopamine system using fast-scan cyclic voltammetry, an electrochemical technique that allows for the detection of dopamine on the millisecond timescale.

Previous Section Next Section CONCLUDING REMARKS Based on the evidence presented herein, commonly abused cannabinoids, such as Δ9-tetrahydrocannabinol, affect the mesolimbic dopamine system similarly to other common drugs of abuse. It is very likely that repeated exposures to Δ9-tetrahydrocannabinol might result in neuroadaptations, not only to the mesolimbic dopamine system, but also to downstream targets that are critically involved in the development of drug addiction. Regarding the endocannabinoid system, we are still in a discovery phase. Little is known concerning the relative contributions of specific endocannabinoids or their exact signaling mechanisms. We are, however, aware of compelling new evidence showing that the endocannabinoid system is capable of modulating the mesolimbic dopamine system and its potential impact in disorders of motivation. Future studies must be conducted to dissect the precise roles of endocannabinoids in this modulation to minimize side effects and how they influence dopamine transmission in animal models.