988 Table 4 Regions of interest during reward feedback Psychopharmacology (2012) 219:981–990 Area Max T Cluster size MNI coordinates 1 2 3 4 5 6 7 8 9 10 L inferior temporal cortex R inferior temporal cortex Middle orbitofrontal cortex Medial superior frontal cortex L inferior parietal cortex Posterior cingulate Anterior cingulate R angular gyrus R inferior parietal cortex R superior frontal cortex 8.5 8.3 6.1 8.7 15.4 6.4 6.1 8.3 8.7 5.9 Max T maximum T value, R right, L left subjects were slower after THC administration during both neutral and reward trials, indicating that THC has a more generalized motor or attentional effect in addition to the reward-specific effects observed in the present study. Indeed, another study assessing the effects of acute THC administra- tion reported that THC can increase reaction times on a number of tasks assessing either memory, attention, or simple reaction times (Curran et al. 2002). Analyses of individual ROIs yielded some effects of THC (described in the “Results” section), but none survived the corrected threshold for multiple comparisons. They do suggest that brain activity during feedback was attenuated most in the posterior cingulate, the superior frontal cortex, and orbitofrontal cortex. These have all been associated with reward processing (Hayden et al. 2008; McCoy and Platt 2005; Tabuchi et al. 2005; Dom et al. 2005; Egerton et al. 2005; Wallis and Kennerley 2010) or effects of THC administration (Fusar-Poli et al. 2009; Stokes et al. 2010). Nevertheless, the most robust finding was a network-wide effect of THC. The eCB system has been implicated in various aspects of addiction, such as drug-seeking and relapse (De Vries and Schoffelmeer 2005). Animal studies showed that activating the eCB system with an agonist provoked relapse to use of other drugs, suggesting a generic but complex role for eCB in reward (Wiskerke et al. 2008). Blocking the eCB system with the antagonist rimonabant led to the opposite effect, reducing drug-seeking and relapse (De Vries et al. 2001). One could argue that if THC activates the eCB system and thereby induces mild elevation of activity of the reward system (Bossong et al. 2009; Stokes et al. 2010), the impact of other rewarding stimuli may be dampened as a result, thus explaining the attenuation of brain activity due to a monetary reward. An indication for such a mechanism can be derived from the effect of chronic cannabis use on motivation in general. Although there is no clear evidence for loss of motivation, the negative effects of chronic 43 51 31 30 350 202 30 132 39 27 x −56 60 −4 16 −32 −4 0 40 56 16 y −64 −60 60 68 −68 −48 8 −68 −40 20 z −20 −20 −4 16 36 28 32 40 48 52 cannabis use on school performance and later life outcomes may be seen as an indication (Fergusson and Boden 2008), but this interpretation warrants further investigation. In our study, anticipation of a reward activated the striatum, insula, anterior cingulate, and frontal brain regions, and feedback of reward activated the posterior and anterior cingulate, inferior parietal cortex, orbitofrontal, and superior frontal cortex. This pattern of brain activity is in line with previous reward imaging studies, which have reported striatal activity during anticipation and frontal activity during feedback of reward (Bjork and Hommer 2007; Knutson et al. 2001a; Knutson and Cooper 2005; O'Doherty 2004). The nucleus accumbens did not show significantly elevated activity during reward anticipation in our study. Additional ROI analyses with the nucleus accumbens as an anatomically defined ROI also did not show a significant effect of THC (data not shown). Factors that may have reduced effects of reward in the striatum and nucleus accumbens include the fact that subjects were paid 250 euros for participation in the study. An extra reward of 24 euros that was won during the reward task may have been too small in comparison. Specifically for the nucleus accumbens, it can be noted that fMRI measurements in this region tend to be less reliable, as it is located close to the nasal cavity, which reduces the BOLD signal to noise ratio. The significant anticipatory effect of reward in striatum was slightly reduced after THC, but this effect was too small to become significant. This is contrary to what we expected, as the striatum shows high densities of CB1 receptors, and THC is known to elicit rewarding and dopamine-elevating effects on the striatum (Bossong et al. 2009; Gardner 2005). However, recent studies in humans indicated that the role of THC in increasing dopamine levels in the striatum may be limited (Stokes et al. 2009; Barkus et al. 2011). Effects of THC in the striatum may also have been influenced by the fact that our subjects were