Investigating the modulation of methylphenidate’s effects on impulsivity by fluoxetine

The co-prescribing of methylphenidate (MPH) and a selective serotonin reuptake inhibitor for patients presenting co-morbidly with both attention deficit/hyperactivity disorder and depression or anxiety is in some cases recommended. Little research has been conducted on the specific cognitive and behavioural outcomes of this. Studies with rats have shown that SSRI’s potentiate MPH-induced dopamine release in the pre-frontal cortex, hippocampus and nucleus accumbens, as well as enhancing MPH-induced hyper-locomotion (Borycz, Zapata, Quiroz, Volkow, & Ferré, 2008; Weikop, Yoshitake, & Kehr, 2007b). Impulsivity is a behavioural construct with dissociable sub-types, of which one, ‘action restraint’, has been consistently shown to be associated with increased dopamine activity in the mesolimbic system, including the nucleus accumbens. It was hypothesised that rats would make more ‘no-go’ errors in a Go/No-Go task, indicative of an increase in ‘action restraint’ type impulsivity, when co-administered fluoxetine (FLX) and MPH compared to either drug administered alone. Although this was not shown in the current study, tentative evidence was found to suggest that the combination of these drugs may negatively impact on attention, based on a decrease in ‘go’ accuracy. A second subtype of impulsivity, “action cancellation”, was tested using a new variant of the Stop-Signal Reaction Time (SSRT) task that we have developed for rats. Studies show that this subtype of impulsivity seems to be unaffected by changes in dopamine activity, but is improved by increases in norepinephrine. In the Weikop study mentioned above, the SSRI citalopram enhanced not only MPH-induced dopamine release, but also norepinephrine release in the nucleus accumbens. Thus it was hypothesised that FLX may potentiate MPH’s impulsivity-reducing effects as measured by stopping latency in the SSRT. We were not able to show this in the current study, however the demonstration that lower doses of MPH reduced stopping latency, consistent with previous versions of the SSRT, validated the new version developed for the current study. A final experiment revealed a rapid, short-term increase in locomotor activity when rats were co-administered FLX and MPH, an effect not present when either drug was administered singly. This synergistic effect replicates previous findings, and indicates a potentiation of dopamine release in the nucleus accumbens, as was found in previous studies. Although FLX was not found to moderate MPH’s effects on impulsivity in the current study, synergistic effects of the two drugs were effects were found on motor activity and potentially on attention also. This is an indication of the value of further research into specific behavioural and cognitive process that may be affected by co-administration of MPH and an SSRI.