Cannabinoid Modulation of Dopamine Release During Motivation, Periodic Reinforcement, Exploratory Behavior, Habit Formation, and Attention.

Motivational and attentional processes energize action sequences to facilitate evolutionary competition and promote behavioral fitness. Decades of neuropharmacology, electrophysiology and electrochemistry research indicate that the mesocorticolimbic DA pathway modulates both motivation and attention. More recently, it was realized that mesocorticolimbic DA function is tightly regulated by the brain's endocannabinoid system and greatly influenced by exogenous cannabinoids-which have been harnessed by humanity for medicinal, ritualistic, and recreational uses for 12,000 years. Exogenous cannabinoids, like the primary psychoactive component of cannabis, delta-9-tetrahydrocannabinol, produce their effects by acting at binding sites for naturally occurring endocannabinoids. The brain's endocannabinoid system consists of two G-protein coupled receptors, endogenous lipid ligands for these receptor targets, and several synthetic and metabolic enzymes involved in their production and degradation. Emerging evidence indicates that the endocannabinoid 2-arachidonoylglycerol is necessary to observe concurrent increases in DA release and motivated behavior. And the historical pharmacology literature indicates a role for cannabinoid signaling in both motivational and attentional processes. While both types of behaviors have been scrutinized under manipulation by either DA or cannabinoid agents, there is considerably less insight into prospective interactions between these two important signaling systems. This review attempts to summate the relevance of cannabinoid modulation of DA release during operant tasks designed to investigate either motivational or attentional control of behavior. We first describe how cannabinoids influence DA release and goal-directed action under a variety of reinforcement contingencies. Then we consider the role that endocannabinoids might play in switching an animal's motivation from a goal-directed action to the search for an alternative outcome, in addition to the formation of long-term habits. Finally, dissociable features of attentional behavior using both the 5-choice serial reaction time task and the attentional set-shifting task are discussed along with their distinct influences by DA and cannabinoids. We end with discussing potential targets for further research regarding DA-cannabinoid interactions within key substrates involved in motivation and attention.

Endocannabinoid modulation of dopamine release during reward seeking, interval timing, and avoidance.

Endocannabinoids (eCBs) are neuromodulators that influence a wide range of neural systems and behaviors. In the current review, we describe our recent research showing how eCBs, particularly 2-arachidonoylglycerol (2-AG), concurrently shape mesolimbic dopamine (DA) release and associated behavior. We will restrict our discussion by emphasizing three distinct behaviors: reward seeking, interval timing, and active avoidance. During reward seeking we find that 2-AG is necessary to observe cue-evoked DA release events that are thought to represent the value of a rewarding outcome. We then describe data showing that 2-AG modulates unique patterns of DA release and behavior observed under conditions of periodic reinforcement. These data are discussed within the context of interval timing and adjunctive behavior. eCB modulation of DA release is also implicated in defensive behavior, including the avoidance of harm. As in reward seeking, our data suggest that the concentration of DA that is evoked by a warning signal can represent the value of an avoidance outcome. And, disrupting eCB signaling concomitantly reduces the concentration of the avoidance value signal and active avoidance. Disruptions in reward seeking, interval timing, and defensive behavior are commonly observed in a variety of movement disorders (e.g., Parkinson's and Huntington's disease) and disorders of motivation (e.g., addiction). We believe our data on eCB-DA interactions have implications for the development of novel pharmacotherapies to treat these disorders. Thus, we conclude by discussing how eCB pharmacology might be harnessed to treat disorders of movement and motivation.

Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212-2 and heroin in adult male rats.

Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance. Because the endogenous cannabinoid and opioid systems exhibit considerable cross-talk and cross-tolerance frequently develops following repeated exposure to either opioids or cannabinoids, there is interest in investigating whether a history of synthetic cannabinoid exposure influences the ability of heroin to increase DA release. To test the effects of chronic cannabinoid exposure on cannabinoid- and heroin-evoked DA release, male adult rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2; WIN) using an intravenous (IV) dose escalation regimen (0.2-0.8 mg/kg IV over 9 treatments). As predicted, WIN-treated rats showed a rightward shift in the dose-response relationship across all behavioral/physiological measures when compared to vehicle-treated controls. Then, using fast-scan cyclic voltammetry to measure changes in the frequency of transient DA events in the nucleus accumbens shell of awake and freely-moving rats, it was observed that the DA releasing effects of both WIN and heroin were significantly reduced in male rats with a pharmacological history of cannabinoid exposure. These results demonstrate that repeated exposure to the synthetic cannabinoid WIN can produce tolerance to its DA releasing effects and cross-tolerance to the DA releasing effects of heroin.

A transient dopamine signal encodes subjective value and causally influences demand in an economic context.

The mesolimbic dopamine system is strongly implicated in motivational processes. Currently accepted theories suggest that transient mesolimbic dopamine release events energize reward seeking and encode reward value. During the pursuit of reward, critical associations are formed between the reward and cues that predict its availability. Conditioned by these experiences, dopamine neurons begin to fire upon the earliest presentation of a cue, and again at the receipt of reward. The resulting dopamine concentration scales proportionally to the value of the reward. In this study, we used a behavioral economics approach to quantify how transient dopamine release events scale with price and causally alter price sensitivity. We presented sucrose to rats across a range of prices and modeled the resulting demand curves to estimate price sensitivity. Using fast-scan cyclic voltammetry, we determined that the concentration of accumbal dopamine time-locked to cue presentation decreased with price. These data confirm and extend the notion that dopamine release events originating in the ventral tegmental area encode subjective value. Using optogenetics to augment dopamine concentration, we found that enhancing dopamine release at cue made demand more sensitive to price and decreased dopamine concentration at reward delivery. From these observations, we infer that value is decreased because of a negative reward prediction error (i.e., the animal receives less than expected). Conversely, enhancing dopamine at reward made demand less sensitive to price. We attribute this finding to a positive reward prediction error, whereby the animal perceives they received a better value than anticipated.

Selective activation of dorsal raphe nucleus-projecting neurons in the ventral medial prefrontal cortex by controllable stress.

Exposure to uncontrollable stressors produces a variety of behavioral consequences (e.g. exaggerated fear, reduced social exploration) that do not occur if the stressor is controllable. In addition, an initial experience with a controllable stressor can block the behavioral and neural responses to a later uncontrollable stressor. The serotonergic (5-HT) dorsal raphe nucleus (DRN) has come to be viewed as a critical structure in mediating the behavioral effects of uncontrollable stress. Recent work suggests that the buffering effects of behavioral control on the DRN-dependent behavioral outcomes of uncontrollable stress require ventral medial prefrontal cortex (mPFCv) activation at the time of behavioral control. The present studies were conducted to directly determine whether or not controllable stress selectively activates DRN-projecting neurons within the mPFCv. To examine this possibility in the rat, we combined retrograde tracing (fluorogold iontophoresed into the DRN) with Fos immunohistochemistry, a marker for neural activation. Exposure to controllable, relative to uncontrollable, stress increased Fos expression in fluorogold-labeled neurons in the prelimbic region (PL) of the mPFCv. Furthermore, in a separate experiment, a prior experience with controllable stress led to potentiation of Fos expression in retrogradely labeled PL neurons in response to an uncontrollable stressor 1 week later. These results suggest that the PL selectively responds to behavioral control and utilizes such information to regulate the brainstem response to ongoing and subsequent stressors.