, 2004). Rather than being released through a vesicular mechanism, endocannabinoids are distinct from other neurotransmitters in that they are formed and released “on demand” during specific neural events (Freund et al., 2003). It is likely, therefore, that endocannabinoids regulate dopamine signaling

during reward seeking exclusively in situations in which dopamine neurons fire at high frequencies—like when animals are presented with environmental cues predicting reward (Schultz et al., 1997). To investigate whether endocannabinoids modulate the neural mechanisms of reward seeking, we measured changes in the concentration of cue-evoked dopamine transients in the NAc shell while pharmacologically altering endocannabinoid signaling during Abiraterone research buy operant behavior. A pharmacological approach was chosen because we previously

demonstrated that blocking CB1 receptors using rimonabant (a CB1 receptor antagonist) reduced drug-induced transient CH5424802 dopamine release into the NAc (Cheer et al., 2007b). Operant behavior was maintained by either brain stimulation reward or food reinforcement while an environmental cue signaled the availability of reward. We found that disrupting endocannabinoid signaling uniformly decreased the concentration of cue-evoked dopamine transients and reward seeking. These findings prompted us to investigate whether increasing endocannabinoid levels would facilitate reward seeking, and if so, which endocannabinoid is responsible. Using recently developed pharmacological tools designed to manipulate specific components of the endocannabinoid system, we found that augmenting 2AG, but not anandamide, levels by disrupting metabolic enzyme activity increased dopamine signaling during reward seeking—suggesting that 2AG sculpts ethologically relevant patterns of dopamine release during reward-directed behavior.

Dopamine was measured in the NAc shell using fast-scan cyclic voltammetry else (FSCV) while responding was maintained in a previously described intra-cranial self-stimulation (ICSS) task (Cheer et al., 2007a). As in our previous report (Cheer et al., 2007a), a compound cue predicted reward availability. This occurred across multiple sensory modalities; specifically, a house light turned off, an ongoing tone ceased, and then 1 s later a white stimulus light mounted above the lever was presented simultaneously with lever extension. A 10 s timeout followed each lever response. Under these conditions, electrically-evoked dopamine release occurred following a lever response and was temporally dissociable from cue-evoked dopamine release events, allowing for changes in the concentration of cue-evoked dopamine to be measured across trials. In agreement with previous studies (Day et al., 2007 and Owesson-White et al.