Cannabinoid modulation of drug reward and the implications of marijuana legalization

Abstract

Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana’s illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana’s psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.

Amphetamine elevates nucleus accumbens dopamine via an action potential‐dependent mechanism that is modulated by endocannabinoids

“…RIMO therefore enabled us to directly compare the present results with previous work and demonstrate a similar regulatory mechanism for AMPH‐evoked elevations in NAc dopamine. Moreover, the effects of RIMO on dopamine signalling associated with abused drugs and reward‐related stimuli (Oleson et al ., ) are consistent with other pharmacological or genetic manipulations of CB1 receptor function that alter dopamine‐dependent, brain reinforcement mechanisms (Lupica & Riegel, ; Covey et al ., ; Parsons & Hurd, ).…”

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…Acute treatment with Δ 9 -THC or synthetic CB1 agonists produce well-characterized signs of intoxication and anti-nociception in humans and laboratory animals through CB1 activation (Wiley and Martin, 2003). Presynaptic CB1 receptors present on GABAergic terminals in the midbrain reduce inhibition of dopaminergic neurons (for additional discussion see Wang and Lupica, 2014; Covey et al, 2015). This mechanism is thought to account for the rewarding effects of Δ 9 -THC and other cannabinoid drugs, and is also likely to be a prominent mechanism through which eCBs contribute to brain mechanisms of reward.…”

“…The eCB system is strongly implicated in the rewarding effects of a variety of abused drugs (Table 2; Justinova et al, 2009; Covey et al, 2015). Antagonists of CB1 impair acquisition or reinstatement of CPP for cocaine, morphine, and nicotine (Chaperon et al, 1998; Le Foll and Goldberg, 2004; Forget et al, 2005; Biala et al, 2009; Fang et al, 2011), but not ethanol (Pina and Cunningham, 2014).…”

Contrasting Regulation of Catecholamine Neurotransmission in the Behaving Brain: Pharmacological Insights from an Electrochemical Perspective

“…Cannabanoids. Emerging evidence supports cannabinoid modulation of dopamine signaling and drug reward (Cheer et al, 2007b;Loewinger et al, 2012;Hernandez et al, 2014), and cannabinoid's effects on the dopaminergic system have been recently reviewed in detail (Oleson and Cheer, 2012;Covey et al, 2015). Despite reports that cannabinoids increase LC norepinephrine activity (Oropeza et al, 2005;Page et al, 2007), how cannabinoid receptor activation influences phasic norepinephrine release has not been investigated.…”