Psychopharmacology (2012) 219:313–326 lating presynaptic D2 autoreceptors, has been found to reduce impulsive action in the 5-CSRTT (Fernando et al. 2011; Koskinen and Sirvio 2001; Lecourtier and Kelly 2005; Passetti et al. 2003; Van Gaalen et al. 2006a; Winstanley et al. 2010). DA-mediated increases in the salience of the reward-related cues in the task and/or increased response vigor by amphetamine may explain its effects in the 5-CSRTT (Berridge and Robinson 1998; Cardinal et al. 2002). This results in a higher rate of performance reflected by a lower amount of errors of omission and faster response latency, albeit at the expense of task accuracy and reduced impulse control. This is consistent with the well-established effect of psychostimu- lant drugs on behavior, i.e., a general enhancement of the rate of behavioral performance causing short and simple behaviors to dominate the behavioral repertoire and cutting short of complex chains of behavior (Lyon and Robbins 1975). At the highest dose of amphetamine (1 mg/kg), this results in a more general disruption of task performance in the 5-CSRTT. Interestingly, the increase in errors of omission at this highest dose likely relies on rather than DA neurotransmission because this effect was mim- icked by atomoxetine but not GBR12909. This indicates that at higher doses, the effects of amphetamine on 5- CSRTT performance are mediated by increases in both DA and neurotransmission. Neurobiological and pharmacological data provide evi- dence for the hypothesis that plays a key role in both the etiology and treatment of ADHD (Arnsten, 2009; Biederman and Spencer 1999). Moreover, clinical observa- tions have shown that a subgroup of patients who do not respond to psychostimulants, such as amphetamine and methylphenidate, do respond to atomoxetine (Newcorn et al. 2008). Selective inhibition of reuptake by atom- oxetine reduced premature responding in the 5-CSRTT under long ITI conditions. neurotransmission has been implicated in the regulation of behavior under novel or demanding circumstances (Aston-Jones and Cohen 2005; Cole and Robbins 1992; Dalley et al. 2001; McGaughy et al. 2002; Sirviö et al. 1993). In the 5-CSRTT, PFC levels rise when task contingencies are changed (Dalley et al. 2001), and cortically NA-depleted rats are slower to adapt to changing task requirements (Milstein et al. 2007). Our observation that atomoxetine was predominantly effective under (relatively) novel and challenging, long ITI conditions corresponds with these findings. Interestingly, previous studies that reported reduced impulsivity in the 5- CSRTT under baseline conditions after atomoxetine treatment used a shorter stimulus duration (0.5 s versus 1 s in the present study; Blondeau and Dellu-Hagedorn 2007; Robinson et al. 2008; Sun et al. 2011). Under these more demanding test conditions, levels of premature responses are higher, and performance may depend on signaling to a greater 321 extent. An alternative, not necessarily inconsistent explana- tion, is that the absence of an effect of atomoxetine on impulsivity under baseline conditions in our study was due to a floor effect so that the increase in premature responses under long ITI conditions provided a larger window to observe a decrease in impulsivity. Interestingly, atomoxetine indeed seems to reduce impulsive action in the 5-CSRTT primarily in rats characterized by high levels of premature responses (Blondeau and Dellu-Hagedorn 2007; Fernando et al. 2011) or high levels of premature responding due to prolonged ITI durations (Navarra et al. 2008; Paterson et al. 2011). In these studies, no effect of selective blockade of by atomoxetine on impulsive action was observed in low impulsive rats (Fernando et al. 2011), efficient rats (Blondeau and Dellu-Hagedorn 2007) or at short intertrial interval durations (4- and 5-s ITI: Paterson et al. 2011; Navarra et al. 2008) consistently reflected by low baseline levels of premature responding. Atomoxetine also increased errors of omission and lengthened response latencies, under both baseline and long ITI conditions, suggesting that this drug somewhat slowed down the performance in the 5-CSRTT. These effects of atomoxetine are consistent with previous findings with noradrenaline reuptake inhibitors, especially at higher doses (Blondeau and Dellu-Hagedorn 2007; Fernando et al. 2011; Navarra et al. 2008; Paine et al. 2007; Sun et al. 2011; Van Gaalen et al. 2006a). Motivational deficits do not likely underlie these increased omissions and response latencies because reuptake inhibitors have been shown to increase reinforcement rates in differential reinforcement of low responding schedules (O'Donnell et al. 2005). Interestingly, under the challenging long ITI conditions, accuracy was improved by systemic atomoxetine (see also Navarra et al. 2008) supporting the role of neurotrans- mission in behavioral vigilance (Arnsten 2004; Aston-Jones and Cohen 2005). Together, these data suggest that neurotransmission is particularly involved in the modula- tion of behavior in the 5-CSRTT under circumstances when task performance is suboptimal, either as a result of demanding task requirements or as a result of inherent individual differences in behavior. Increasing neuro- transmission then leads to a more conservative pattern of responding whereby task accuracy and impulse control increase but speed of performance declines somewhat. The serotonin reuptake inhibitor citalopram resulted in a decrease in premature responding in the 5-CSRTT at an intermediate dose of 1 mg/kg. A similar improvement in impulse control was observed under long ITI conditions. In contrast to amphetamine, GBR12909 and atomoxetine, the effect of citalopram on premature responding was quite selective as accuracy and errors of omission were not affected. Our finding is in line with the observation that enhanced 5-HT transmission in 5-HT transporter knockout