Next we sought to establish if disrupting the VTA endocannabinoid system alone is sufficient to decrease dopamine neurotransmission by infusing rimonabant directly into the VTA during reward seeking maintained in the ICSS task. As was found following systemic treatment, intrategmental rimonabant (200 ng i.c., unilateral)

significantly increased the latency to respond for brain stimulation reward (Figure 2E; MWU test, U = 0, p < 0.01; n = 8; mean values: b = 0.94, v = 1.10, rimo = 1.96 s) and decreased cue-evoked dopamine concentrations (Figure 2F; F(2,14) = 7.01, p < 0.01; 200 ng versus vehicle, p = 0.03; also see Figure S4A for mean dopamine concentration traces). The representative dopamine concentration traces (Figure 2G) show the effect of intrategmental rimonabant

on cue-evoked dopamine events in individual trials. Rimonabant-induced decreases in cue-evoked dopamine this website concentration during reward seeking maintained in the ICSS task can also be observed in audio-visual format (Movie S1). These data demonstrate that the VTA endocannabinoid system modulates dopamine signaling during the pursuit of brain stimulation reward. To assess whether disrupting endocannabinoid signaling also decreases dopamine transmission during the pursuit of natural reward, we treated animals with rimonabant while responding was maintained in an appetitive food-seeking task (Supplemental Experimental Procedures). Similar to the ICSS task, each lever response check details click here resulted in the delivery of food reinforcement and retraction of the lever for 10 s. After each 10 s timeout, a compound cue indicating reward availability was presented simultaneously with lever extension. Rimonabant decreased food seeking, as both a low (0.125 mg/kg i.v.; MWU test, U = 4, p = 0.03; n = 6) and high (0.3 mg/kg i.v.; MWU test, U = 0, p < 0.01; n = 8; mean

values: b = 1.45, v = 1.82, rimo = 17.7 s) dose increased response latency in comparison to vehicle treatment (Figure 3A). Rimonabant was administered prior to 60 responses, before animals reached satiety levels (avg. of 200 reinforced responses). As in the ICSS task, an increase in response latency was accompanied by a decrease in the concentration of cue-evoked dopamine release (Figure 3C; F(2,14) = 5.87, p < 0.01; 0.3 mg/kg versus vehicle, p = 0.04; also see Figure S2A for mean dopamine concentration traces). Rimonabant-induced decreases in cue-evoked dopamine concentration during individual (Figure 3D) and repeated (Figure 3E) trials are illustrated in pseudocolor. Likewise, intrategmental rimonabant-induced increases in response latency (Figure 3F; MWU test, u = 0, p < 0.01; n = 5; mean values: b = 1.18, v = 1.3, rimo = 2.75 s) were accompanied by a decrease in cue-evoked dopamine concentration (Figure 3G; F(2,14) = 9.86, p < 0.01; 200 ng versus vehicle, p = 0.014; also see Figure S4B for mean dopamine concentration traces).