Psychopharmacology (2009) 205:489–502 To control for the decrease in preference for the large reward that occurred with 6.0 mg/kg morphine at the 0-s delay, further analyses were performed. To this end, all data from the morphine/naloxone combination study were also calculated as percentage change in preference from the 0-s delay (Fig. 3d). Analyses on these data revealed that morphine significantly shifted the preference for the large reward depending on the delay [dose: F(3,45) =1.79, ε= 0.71, p =0.18; dose × delay: F(12,180) = 2.40, ε= 0.81, p= 0.012]. These effects of morphine on the preference for the large reward depending on the delay were reversed by 1.0 mg/kg naloxone. Discussion The main findings of the present study are that acute challenges with morphine modulate impulsive behavior, as expressed in impaired inhibitory response control and—to a somewhat lesser extent—impulsive decisions. The number of premature responses in the 5-CSRTT was dose- dependently increased following morphine, and in addition, morphine also biased the preference from larger more beneficial delayed rewards towards small and immediate rewards. The observation that the effects of morphine were abolished by naloxone strongly suggests μ-opioid receptor involvement in different forms of impulsive behavior. In contrast, morphine did not change response inhibition as measured in the stop-signal task, although in a correlation analysis, baseline-dependent effects of morphine on re- sponse inhibition were detected and morphine seemed to improve response inhibition in rats with “slow” stopping abilities. In the absence of an effect of naloxone on the different forms of impulsive behavior, our data do not provide clear evidence for a role of tonically activated μ-opioid receptors by endogenous opioids in measures of impulsivity. In as much as these observations can be extrapolated to clinical data, they do not support the recently reported beneficial effects of a single dose of naltrexone in healthy volunteers on a measure of inhibitory response control (Mitchell et al. 2007). However, in that study, the effects of naltrexone (50 mg) on inhibitory response control were derived from a calculated measure in a delay discounting task and not from results obtained in a separate task measuring inhibitory response control, which may have accounted for this discrepancy in findings. The observation that morphine robustly increased premature responding in the 5-CSRTT extends previous reported acute effects of psychostimulants such as amphetamine, cocaine, and nicotine on impulsive action (Cole and Robbins 1987, 1989; Evenden 1998; Harrison et al. 1997; Paine and Olmstead 2004; Pattij et al. 2007b; Van Gaalen et al. 2006a). Strikingly, the high dose of 497 morphine (6.0 mg/kg) was found to improve a different measure of inhibitory response control in this paradigm by reducing the number of perseverative responses following correct choice and before food reward collection (see for review, Robbins 2002). This finding may suggest benefi- cial effects of morphine on aspects of compulsive behavior. However, this dose of morphine also strongly increased the number of omissions and lengthened response latencies, and therefore, these effects on persev- erative responding are likely due to non-specific drug effects on motor behavior. In contrast to the effects of morphine on measures of inhibitory control, other param- eters in the 5-CSRTT reflecting attentional performance, such as accurate choice, were not affected by morphine. These latter findings are supported by recent observations showing that morphine in a similar dose range did not influence measures of sustained attention in a modified 5- CSRTT with a stimulus duration of 5 s and a test session consisting of 250 trials (Boyette-Davis et al. 2008). To date, clinical evidence demonstrating inhibitory response control deficits in opiate abusers is only scarcely available. While the majority of these studies do not find clear behavioral evidence of inhibitory response control disturbances in opiate addicts (Passetti et al. 2008; Verdejo-Garcia and Perez-Garcia 2007; Verdejo-Garcia et al. 2007), some changes in brain activation patterns following a Go/NoGo task have been detected in opiate users (Forman et al. 2004). Furthermore, a recent study found evidence for reflection impulsivity in opiate users (Clark et al. 2006), i.e., the tendency to act before all necessary information is evaluated. Although reflection impulsivity may conceptually be regarded as a separate form of impulsive behavior (see for discussion, Evenden 1999), it might contain aspects of both deficient inhibitory response control and impulsive decision making. Consistent with the aforementioned paucity of evidence demonstrating inhibitory control deficits in opiate users, morphine had no clear effects on response inhibition as measured in the stop-signal task. Thus, our stop-signal task data suggest minor μ-opioid receptor involvement in the ability to inhibit ongoing behavior and contrast the findings in the 5-CSRTT. The latter task measures the ability to withhold inappropriate (premature) responses, and clearly, the opioid system modulates these inhibitory response control processes. These observations add to the growing literature demonstrating that the 5-CSRTT and stop- signal task measure different cognitive processes that can be dissociated neuroanatomically and pharmacolog- ically (Eagle et al. 2008; Winstanley et al. 2006). Further in-depth analyses on the stop-signal data revealed that the effect size of morphine on estimated SSRT, the primary parameter reflecting response inhibition, correlated nega- tively with SSRTs under vehicle condition. Thus, in