Tales from the dark side: Do neuromodulators of drug withdrawal require changes in endocannabinoid tone?

Abstract

Environmental and interoceptive cues are theorized to serve as ‘signals’ that motivate drug seeking, effects that may be augmented in the withdrawn state. Phasic dopamine release events are observed in the nucleus accumbens in response to such motivational salient stimuli and are thought to be necessary for drug-associated cues to trigger craving. We recently demonstrated how dopamine neurons encode stimuli conditioned to a negative event, as might occur during conditioned withdrawal, and stimuli predicting the avoidance of negative events, as might occur as an addict seeks out drugs to prevent withdrawal. In this review we first discuss how the subsecond dopamine release events might process conditioned withdrawal and drug seeking driven by negative reinforcement processes within the context of our dopamine data obtained during conditioned avoidance procedures. We next describe how the endocannabinoid system modulates phasic dopamine release events and how it might be harnessed to treat negative affective states in addiction. Specifically, we have demonstrated that endocannabinoids in the ventral tegmentum sculpt cue-induced accumbal surges in dopamine release and, therefore, may also be mobilized during drug withdrawal.

Cannabinoid modulation of drug reward and the implications of marijuana legalization

“…However, CB 1 receptor antagonists, while effective, are associated with significant negative side effects in humans, such as depression and suicidal tendencies (Hill and Gorzalka, 2009). Alternatively, because eCB mobilization occurs only in response to heightened activity, disrupting endogenous activity (e.g., by blocking enzymatic degradation) may more selectively target those synapses that are active during a specific event, such as re-exposure to drug cues (Oleson et al, 2014; Loewinger et al, 2013; Katona and Freund, 2008). This final point highlights that, while cannabinoids have had a pervasive influence on human culture for millennia, the recent discovery of the eCB system has permitted an unprecedented understanding (yet far from incomplete) of how these drugs affect the brain and behavior.…”

Interplay between synaptic endocannabinoid signaling and metaplasticity in neuronal circuit function and dysfunction

“…Not only can synaptic neuromodulators shape the instantaneous synaptic strength during behaviors based on the animal's current needs, but they can also control long-term forms of synaptic plasticity to trigger behavioral changes. This control may occur in response to changes in the animal's needs and upon learning or exposure to environmental cues (Hasselmo, 1995;Arnsten et al, 2012;Lee & Dan, 2012;Oleson et al, 2013). In pathological states, altered synaptic neuromodulation may lead to the aberrant assignment of salience to environmental events and internal representations during information processing, which may lead to cognitive and behavioral dysfunction.…”

Endocannabinoid and dopaminergic system: the pas de deux underlying human motivation and behaviors

“…The negative symptoms resulted from low DA release due to withdrawal can be a strong factor for someone to seek and use the substance. In this case, enhancing DA release from the VTA by increasing 2-AG, for example, can be pursued (Oleson et al 2014 ). It was also shown in the latter study, that, due to the high similarity between opioid and eCB system, cannabinoids can become a potential therapeutic substitute, which acts as an agonist, to replace opioid during its withdrawal.…”