A primary objective of this study was to investigate how amphetamine altered the mechanisms that control responding in a rat model of impulsive action. Our analysis of time-dependent changes in the probability of responding revealed that subjects make distinct patterns of errors when they can and cannot time the RI interval. By examining the effect of amphetamine on different conditions of the same task, we demonstrate that the drug increases or decreases impulsive actions when subjects must withhold responding for a fixed or variable delay, respectively. These results are particularly striking because, at its simplest, the requirements for each variation of the RI task are identical: Do not press the lever until the signal light illuminates. Therefore, the animal's expectation for delay length directly influenced the drug's effect, which may explain the apparently contradictory effects of amphetamine on impulsive action in previous studies.
Expectation of Delay Duration Alters the Probability of Impulsive Responding Across Time
Impulsive action is commonly measured in rodent models as the number or proportion of premature responses per session. This metric provides a global estimate of a subject's inability to withhold a response. We examined this measure in greater depth by analyzing the probability of impulsive responding across time. This analysis revealed that the likelihood of making an impulsive response at a particular time point varied, depending on the subjects' expectation of the premature phase. Specifically, training in the Fixed 4-s
condition resulted in far more responses in the final second of the premature phase, reminiscent of the scalloped pattern of responding under fixed interval schedules (Fester and Skinner, 1957
). A likely explanation for this profile is that subjects are timing the interval length and premature errors are anticipatory responses. This fits with evidence of increased impulsivity in the 5-CSRTT when the ITI is lengthened from 5 to 7+ seconds (see for example, Harrison et al, 1997
; Fletcher et al, 2007
). Indeed, lengthening the premature delay in this task is used to screen for individual differences in trait impulsivity (Dalley et al, 2007
; Belin et al, 2008
Unlike the Fixed 4-s
condition, subjects in the Fixed 60-s
condition showed a consistent likelihood of responding throughout the premature phase. That is, even though the length of the delay interval was predictable, subjects did not exhibit anticipatory responding toward the end of the interval. It is unlikely that the difference in these two patterns reflects an ability to time short (4
s) but not long (60
s) intervals as rats responding under DRL schedules can accurately assess delays of the longer duration (Seiden et al, 1979
; Lobarinas and Falk, 1999
; Bizot 1998
; Fowler et al, 2009
). The DRL task differs from the fixed delay version of the RI task in that the delay period in the latter is signaled. Perhaps this presence of a clear signal reduces the need to time an interval, which would be particularly taxing at the long delay. In other words, rats may rely on different cognitive mechanisms to inhibit responding for long and short delays: timing the former and relying on the visual stimulus in the latter condition.
In contrast to the Fixed 4-s and 60-s conditions, subjects in the Variable condition showed a greater likelihood of responding at the beginning of the premature phase. This highlights the usefulness of breaking down the probability of responding across time in that a cursory examination of responses at each delay shows more premature responding on trials with longer delay intervals; this may have led to the erroneous conclusion that animals are more likely to respond at the end of the premature phase. Responses that occurred early in the delay interval may have been elicited by the lever insertion, although it is not clear why this would occur in the Variable, but not in the Fixed 60-s, condition. Another possibility is that the increased responding in the initial time bins is a rapid adaptation to one or more short delays presented in the random sequence. That is, the alternation of delay intervals occasionally produced several trials in a row with the 1-s or 4-s delay, which could cause subjects to anticipate another short delay and respond accordingly.
Amphetamine-Induced Changes in Impulsive Action May Interact with Underlying Cognitive Processes
One of the most important findings in our study is that amphetamine has opposite effects on impulsive action when the delay interval is predictable or unpredictable. Amphetamine increased premature responding in fixed conditions of the RI task, regardless of whether the delay interval was short (4
s) or long (60
s). In contrast, if subjects were unable to predict the duration of the delay interval (Variable
condition), then amphetamine decreased premature responses. Thus, the effect of amphetamine on impulsive action (at least in the RI rat model) depends on whether animals can time the delay interval. This suggests that amphetamine is altering some cognitive process (eg, timing, attention, or conditioned avoidance), which has differential effects on premature responding in the three conditions.
The simplest explanation for an amphetamine-induced increase in premature responding in the fixed conditions of the RI task is that the drug altered timing abilities. This fits with evidence that amphetamine disrupts the ability to discriminate cues of different durations (Meck, 1996
; Bizot, 1997
) and produces a leftward shift of peak intervals in DRL tasks (Taylor et al, 2007
; Eckerman et al, 1987
). The latter finding suggests that amphetamine accelerates the perception of time. If this were true, increased premature responding could simply be an exacerbation of the normal, anticipatory responses we observed in the Fixed 4-s
condition. In agreement with this idea, amphetamine increases premature responses in other tasks with consistent delays, such as the 5-CSRTT (Cole and Robbins, 1987
; Harrison et al, 1997
; van Gaalen et al, 2006
) and DRL tasks (Seiden et al, 1979
; Lobarinas and Falk, 1999
; Bizot 1998
; Fowler et al, 2009
), but not in the stop task which uses a variable delay to the signal for RI (Feola et al, 2000
; Eagle and Robbins, 2003
). Disruptions in timing abilities would not affect performance in the Variable
condition, so it is not surprising that we failed to observe an amphetamine-induced increase in impulsive action in this version of the task.
Although amphetamine increased impulsive action in both Fixed
conditions of the RI task, the drug had different effects on the distribution of errors at longer and shorter delay intervals. More specifically, unlike the Fixed 4-s
condition, amphetamine did not produce time-sensitive errors in the probability of responding at the longer (60-s) delay interval, although a strong trend toward time-dependent errors late in the delay was present. These data argue against the idea that amphetamine is promoting impulsive actions through an accelerated perception of time, at least when the interval to be timed is relatively long. As noted previously, however, rats may successfully inhibit responding at these long delays by attending to the sensory cue that signals the end of the interval, rather than timing the interval itself. Performance improves (ie, impulsivity decreases) in a 15-s DRL task when a cue is presented at the end of the delay (Carey and Kritkausky, 1972
), suggesting that attending to an external sensory cue improves performance at intermediate delays. More importantly, amphetamine does not
produce a leftward shift in IRTs when a signal is present (Wiley et al, 2000
), although it does increase the response rate and decrease the number of reinforcers obtained, a pattern of deficits that points to elevated impulsivity but no alteration in timing abilities. The findings also fit with our idea that the effect of a drug on impulsive action (or any other response) depends on the cognitive process that is controlling behavior. If animals are timing delay intervals, then amphetamine speeds up this mechanism; if they are relying on external sensory cues, then amphetamine may impact performance through another process.
When relying on external signals, particularly in the Fixed 60-s
condition, rats may successfully inhibit responding by actively avoiding the lever. In DRL tasks (24 or 72
s), rats position themselves away from the operant manipulandum until a few seconds before responding (Fowler et al, 2009
), reminiscent of a pre-commitment strategy in pigeons (Rachlin and Green, 1972
) that reduces impulsivity. Just as a dieter avoids temptation by throwing out the junk food in their house, rodents may avoid approaching the lever to prevent premature responding. If rats are actively avoiding the lever in the Fixed 60-s
condition, then the locomotor-activating effects of amphetamine (Kalivas and Stewart, 1991
) may disrupt this strategy: promoting movement toward the lever, thereby increasing premature responding. Lever avoidance would be a disadvantageous strategy in the Variable
condition, as it would slow the latency to respond at short intervals, potentially delaying reward presentation. In fact, the latency to respond was reduced at short (1 and 4
s) intervals in the Variable
condition, which suggests that subjects were not actively avoiding the lever. Conditioned avoidance, therefore, may reduce the likelihood of making an error at long, but not at short, delays. This highlights, once again, that rats may employ different cognitive strategies to inhibit responding, and helps to explain the differential effects of amphetamine on action impulsivity when delays to respond are predictable or unpredictable.
The RI task does not place strong attentional demands on the subject: Rats have up to 10
s to respond during the correct phase and the correct and premature phases have distinct signals that can be detected from any place in the chamber. Nonetheless, enhancing attention could improve performance, particularly in the Variable
condition because subjects must constantly monitor the environment as they wait for the signal to respond. Amphetamine improves attention (Bizarro et al, 2004
; Grilly, 2000
) and decreases distractibility (Agmo et al, 1997a
), which may explain why it improves performance (ie, decreases impulsive action) in the Variable
condition, but not in the two Fixed
conditions. On the other hand, it may be that amphetamine improves attention in all three conditions, but the effects on impulsive action are masked in the Fixed
conditions by drug-induced disruptions in other processes, such as timing or conditioned avoidance.
We have identified three cognitive processes (timing, conditioned avoidance, and attention) that may explain the differential effects of amphetamine in fixed and variable delay versions of the RI task. This list, however, is not exhaustive: other cognitive processes may contribute to successful performance in the RI task. For example, amphetamine has well-established effects on motivation, increasing responding for sucrose on break-point schedules of reinforcement (Mayorga et al, 2000
; Poncelet et al, 1983
). In the RI task, differences in the length of time between reward delivery (ie, under different delay conditions) could impact the motivation to respond. In addition, external signals, such as the houselight, that explicitly signaled the premature phase may interact with the pharmacological effects of amphetamine (Wiley et al, 2000
). The latter possibility is particularly intriguing in that amphetamine produced opposing effects on impulsive choice when a houselight was present or absent during the delay to reward delivery (Cardinal et al, 2000
). External cues, therefore, may alter the behavioral effects of pharmacological manipulations. Previously, we emphasized that each behavioral paradigm relies on a unique combination of cognitive processes, and that these should be carefully considered in designing rodent tests of impulsive action (Hayton and Olmstead, 2009
Neurobiology of Impulsive Actions
Amphetamine's distinct effects on the Fixed
conditions of the RI task may reflect the drug's effects on various neurotransmitter systems. Amphetamine is not a selective drug: it acts preferentially on the dopamine transporter, but also has an action on serotonin and noradrenaline transporter systems (Sulzer et al, 2005
). Increasing noradrenergic tone, through selective reuptake inhibitors, decreases impulsive action in the 5-CSRTT (Navarra et al, 2008
; Robinson et al, 2008
) and the stop task (Robinson et al, 2008
), and improves the ability to correctly time intervals (Balci et al, 2008
). Increases in serotonergic tone also decrease impulsive action on DRL schedules (Richards et al, 1993
; Sokolowski and Seiden, 1999
), whereas serotonin depletion increases this measure in the 5-CSRTT (Harrison et al, 1997
) and on DRL schedules (Jolly et al, 1999
). Serotonergic mechanisms interact with the effect of amphetamine in the 5-CSRTT in that blockade of the 5-HT2A receptor prevents amphetamine-induced increases in premature responding (Fletcher et al, 2011
), although this drug also reduces impulsive actions when administered alone (Fletcher et al, 2007
; Higgins et al, 2003
). Amphetamine, therefore, may affect performance in the RI task by interacting with the multiple neurotransmitter systems that directly or indirectly (ie, via timing, avoidance, or attention) alter impulsive action.
Impulsive actions are a feature of several psychiatric disorders, including ADHD (Kollins, 2008
). In this investigation, we examined amphetamine's effect on impulsive action, but our analysis was on the entire population, instead of subjects with elevated impulsivity. Interestingly, individual differences in trait impulsivity are strongly correlated with changes in dopamine receptor binding in the striatum (Dalley et al, 2007
), which suggests a possible mechanism for amphetamine's effects in the clinical population.
This investigation aimed to reconcile how stimulants, such as amphetamine, can have distinct effects on impulsivity, depending on the design of the behavioral paradigm. Our findings further emphasize that the effects of a drug on any behavioral measure must be interpreted in the context of the cognitive processes that are controlling responding.