During the baseline condition, mice exhibited different response profiles in the Go/No-go task. The MADR lines did not differ in measures of behavioral inhibition. However, MALDR mice had more hits than MAHDR mice, suggesting that they were more responsive to the Go cue. Because a light was used as the Go cue for all mice, it is possible that this cue was more salient for MALDR mice. Additional research would be needed to address this possibility. Drug naïve MAHSENS mice exhibited lower levels of operant activity across all measures than did drug naïve MALSENS mice. This line difference in operant activity is not likely to be due to a difference in sucrose preference or motivation because these lines do not differ in preference for another sweet substance, saccharin (Scibelli et al. 2011
). However, it may be that the lower rates of operant responding reflected differences in general activity, as MAHSENS mice have been shown to have lower basal locomotor activity than MALSENS mice (Scibelli et al. 2011
We did not directly compare the MADR mice to the MASENS mice for several reasons. This was primarily because differences in selection criteria prevent meaningful comparisons. Additionally, differences in the age and weight for these two sets of lines could have influenced some of our findings. Walter & Giovanni (2003)
showed that age can influence some measures of impulsivity in mice. In our study increased age was correlated with more false alarms in MASENS mice (r = .26, p = .046). Also, increased weight was correlated with more false alarms and more hits in MASENS mice (r = .38, p = .003, r = .38, p = .003). There were no significant relationships for MADR mice, which entered into the study at a younger age.
MA had marked effects on all lines of mice tested, and resulted in a dose-dependent decrease in false alarms, precue response rate, and hits. It seems likely that, certainly at the higher doses, the effects of MA on each of these measures were due to a general reduction in responding in the task. Importantly, our results at the higher doses are similar to a recent finding that amphetamine decreased responding in mice in the Go/No-go task while having no effects specific to measures of behavioral inhibition (Loos et al 2010
). Interestingly, these authors also found that the same doses of amphetamine increased
premature responding in the 5CSRTT without affecting responding on other measures in mice. This suggests that the effects of amphetamine on behavioral inhibition are task-specific. Nonetheless, it is possible that lower doses of MA would yield additionally interesting data in the Go/No-go task.
Although MA dose-dependently decreased responding in all mice, the exact nature of this effect varied. In MASENS mice, MA decreased responding regardless of the dependent measure examined. However, in MADR mice, MA dose-dependently decreased precue response rate and false alarms more than hits. This effect was particularly robust in female MAHDR mice. Since MADR mice do not differ by either sex or line in sensitivity to the locomotor activating effects of acute or repeated treatment with doses of MA up to those used here (Shabani et al., 2011
), it seems unlikely that locomotor differences are the cause of differences in measures of behavioral inhibition. Our finding for MADR mice is consistent with previous findings of other studies that found psychostimulants to increase behavioral inhibition in the Go/No-go task (de Wit et al. 2002
; Vaidya et al. 1998
). MA may be increasing behavioral inhibition via its actions on several different neurotransmitter systems, as it has been shown to increase levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) (Rothman et al 2001
). Both NE and 5-HT have been shown to alter behavioral inhibition in the Go/No-go task (Ma et al. 2003
; Harrison et al. 1999
, respectively). More interestingly, a study by Frank et al. (2007)
showed that individuals with ADHD had lower accuracy on a probabilistic selection task, and that subjects that were on medication (methylphenidate) increased their accuracy for the Go signal in the task, but not the No-go signal. The authors suggest that because individuals with ADHD have lower striatal DA (Sagvolden et al. 2005
), methylphenidate is having its effects on the Go process by increasing striatal DA. Indeed, another study by the same group found that low doses of haloperidol (which increases DA in the striatum at low doses; Garris et al. 2003
) increased number of hits in a go/no-go task (Frank & O'Reilly 2006
). This research is consistent with our finding that MA increased hits in MAHDR mice at the lowest dose, although it should be noted that this effect did not survive the Bonferonni post hoc correction for significance.
As stated above, the high and low MASENS lines did not markedly differ in their response to MA. Nonetheless, the MASENS mice did
differ by sex. MA significantly reduced hits in the males more than in the females. Previous research has shown female MASENS mice to have a higher preference for saccharin than males (Scibelli et al. 2011
). Thus, it is possible that this higher preference is protective against any effects MA may have on the appetitive value of sucrose, which may explain the results we see. It is difficult to compare these sex differences with other literature, in part due to the lack of studies examining sex effects. In the studies examining the effects of methylphenidate or d-amphetamine on go/no-go performance, two studies had no females (Vaidya et al. 1998
; Loos et al. 2010
), one study did not appear to include sex in their analysis (Fillmore et al. 2003
), and the final study found no effect of sex (de Wit et al. 2002
). In terms of other behavioral inhibition tasks, to our knowledge no gender differences have been reported in MA abusers (e.g. Monterosso et al, 2005
; Tabibnia et al, 2011
; Vergedo-Garcia et al, 2006
), but these studies did not explicitly include sex in their analysis. Therefore, it is difficult to see how such findings relate to human studies.
In conclusion, we did not find any differences in behavioral inhibition at baseline, but we did find that MA decreased false alarms and precue response rate to varying degrees depending on the mice tested. These changes were often accompanied by decreases in hits, suggesting a general decline in operant activity was responsible. However, decreases in hits did not accompany decreases in measures of behavioral inhibition under all doses for MADR mice, implying increased behavioral inhibition following these particular doses of MA. This effect was particularly strong in female MAHDR mice, suggesting that a combination of sex and selection for MA drinking can influence MA's effects on behavioral inhibition. Finally, this study highlights the importance of concurrent measures of activity to interpret alterations in measures of behavioral inhibition and the need, in future research, to delineate the components that contribute to the expression of behavioral inhibition.