As occurred in the ICSS-FTO task, reward availability was signaled to the animal by the presentation of a compound cue. This signaled reward Apoptosis inhibitor availability across multiple sensory modalities; specifically, a house light turned off, an ongoing tone ceased and a white stimulus light mounted above the lever was presented. All stimuli were presented simultaneously with lever extension. As predicted, anticipatory dopamine (Figure 4A) was only observed under FTO conditions.

Importantly also, the concentration of cue-evoked dopamine was significantly lower under VTO conditions (Figure 4C; MWU test, U = 27.5, p = 0.032; n = 11), which likely reflects a decrease in value imposed by the longer, unpredictable delays in reward availability occurring in the ICSS-VTO task (Bromberg-Martin and Hikosaka, 2011, Day et al., 2010 and Kobayashi and Schultz, 2008), while response latencies were significantly increased (Figure 4B; MWU test, U = 24, p < 0.01; n = 14) due to greater operandum disengagement. The data presented in Figure 2 demonstrate that rimonabant decreased cue-evoked dopamine signaling and reward seeking in the ICSS-FTO task. Under these conditions however, rather

than decreasing reward-directed behavior by interfering with the neural representation of an environmental cue, disrupting endocannabinoid neurotransmission might decrease reward-directed behavior selleck chemical by interfering with an interoceptive

timing signal because pharmacological manipulation of either the endocannabinoid or mesolimbic dopamine system can modulate neural representations tuclazepam of time during behavioral tasks (Crystal et al., 2003, Meck, 1983, Meck, 1996 and Taylor et al., 2007). To address this, we tested the effects of rimonabant using the ICSS-VTO procedure. Rimonabant significantly increased the latency to respond in the ICSS-VTO task (Figure 4D; MWU test, U = 0, p < 0.05; n = 4) as occurred in the ICSS-FTO task, thereby supporting our hypothesis that endocannabinoids regulate reward directed behavior by modulating the encoding of environmental cues predicting reward availability rather than interfering with interval timing. We next sought to assess the effects of augmenting endocannabinoid levels on the neural mechanisms of reward seeking. The ICSS-VTO task was selected to eliminate potential floor effects involving response latency (as latencies to respond in the ICSS-FTO task can be in the subsecond range for well-trained animals). To increase endocannabinoid concentrations, animals were treated with the putative endocannabinoid uptake inhibitor VDM11 using a cumulative dosing approach. Contrary to our hypotheses, VDM11 dose-dependently (300–560 μg/kg i.v.) increased response latency (Figure 5A; F(2,23) = 5.69, p < 0.01; 560 μg/kg versus vehicle, p = 0.