Elsevier

Neuropharmacology

Volume 57, Issues 7–8, December 2009, Pages 665-672
Neuropharmacology

Effect of acute and repeated treatment with desipramine or methylphenidate on serial reversal learning in rats

https://doi.org/10.1016/j.neuropharm.2009.08.007Get rights and content

Abstract

Administration of stimulant and non-stimulant drugs that inhibit monoamine reuptake is known to improve cognitive and behavioral symptoms of attention deficit hyperactivity disorder (ADHD). Although this may reflect acute actions of these drugs, clinical observations suggest that prolonged treatment with these agents may result in a better therapeutic outcome. In the current study, we compared the effects of acute and repeated treatment with the stimulant drug, methylphenidate (MPH), and the non-stimulant norepinephrine reuptake inhibitor desipramine (DMI) in rats performing a reversal learning task meant to study behavioral flexibility in rats. Furthermore, we tested the effect of an acute challenge administration with these agents or vehicle on reversal performance of rats repeatedly treated with the drug or vehicle. Our results suggest the acute and repeated treatment with DMI improves reversal learning performance in a qualitatively and quantitatively similar manner. Further repeated treatment with DMI seems to produce a reversal learning improvement that persists at least 24 h after drug administration. Repeated MPH treatment only improved performance in the first within session reversal administered, suggesting that its beneficial effects may depend upon the complexity of the reversal condition tested. The differential outcome produced by stimulant and non-stimulant medications in this study may be explained in light of their distinct actions on brain catecholaminergic systems.

Introduction

Difficulty with certain facets of executive functioning is a common feature of attention deficit hyperactivity disorder (ADHD). For example, children and adults with ADHD exhibit performance deficits on tasks that require inhibitory control of behavior, including the stop-signal reaction time task, discrimination reversal learning and Go-NoGo tasks (Frank et al., 2007, Itami and Uno, 2002, Schachar et al., 2000, Schachar et al., 1995); other component processes of executive function are also impaired, including working memory (Kempton et al., 1999, Mehta et al., 2000a) and attentional set-shifting (Mehta et al., 2004). Collectively, performance in these tasks depends upon the integrity of brain regions whose functionality appears to be disrupted in ADHD patients, including the striatum and orbital and dorso-lateral divisions of the prefrontal cortex (Hesslinger et al., 2002, Makris et al., 2007, Valera et al., 2007).

Treatment with stimulant or non-stimulant ADHD medications can ameliorate cognitive dysfunction and behavioral symptoms of ADHD (Aron et al., 2003, Chamberlain et al., 2007, Faraone et al., 2005a, Faraone et al., 2005b, Frank et al., 2007, Kempton et al., 1999, Mehta et al., 2000a, Mehta et al., 2000b, Scheres et al., 2003, Spencer et al., 2001, Tannock et al., 1989). Together, agents such as methylphenidate, amphetamine and atomoxetine, likely exert their effects by increasing the extracellular levels of the neurotransmitters dopamine and norepinephrine in prefronto-cortical regions. These neurotransmitter responses reflect the acute pharmacodynamic responses elicited by the drugs, either through an increase neurotransmitter output (amphetamine) or blockade of catecholamine reuptake (methylphenidate and atomoxetine).

Multiple clinical reports suggest that repeated dosing with these agents is required before a significant improvement in ADHD behavioral symptoms can be measured (Spencer et al., 2005, Spencer et al., 1998), suggesting that chronic treatment with these drugs may be necessary to relieve behavioral symptoms. However, because physicians often titrate drug doses up over the first weeks of treatment, it is unclear whether the delayed onset of clinical efficacy arises from long-term adaptations secondary to repeated dosing or simply from the fact that an optimal drug dosage is reached only in a later stage of treatment.

Indirect evidence in favor of the latter view is found in some studies of drug effects on executive function deficits in ADHD. For example, acute administration of ADHD medications improves inhibitory control and executive functioning in healthy humans (Chamberlain et al., 2006, Clatworthy et al., 2009, Mehta et al., 2000b) and otherwise normal animal models (Berridge et al., 2006, Eagle et al., 2007, Navarra et al., 2008, Robinson et al., 2007, Seu et al., 2009), indicating that their cognitive-enhancing actions may result from acute dosing, assuming a clinically meaningful dose is used. Very few studies have addressed the issue of whether this is also the case in ADHD patients. In fact, the effect of ADHD medications on cognitive functions in patients has mostly been assessed in individuals who have a long-term history of treatment; in two separate studies, Rhodes et al. found no improvement in executive functions following a single administration of the stimulant methylphenidate in drug-naïve ADHD patients (Rhodes et al., 2004, Rhodes et al., 2006), while a different group showed an improvement in executive functions and response inhibition after the acute administration of the same drug in a sample consisting mostly of never-medicated ADHD children (Tannock et al., 1995a, Tannock et al., 1995b).

Together these observations seem to indicate that the cognitive-enhancing effect of ADHD medications arises from their acute actions; however, it remains possible that the long-term history of treatment alters the acute effect of these agents resulting in a better and/or longer-lasting outcome. We sought to further explore this topic by comparing the effect of acute and repeated treatment with catecholamine reuptake inhibitors in rats performing an operant reversal learning task designed to study behavioral flexibility and/or response inhibition. In a common reversal learning task, after response–outcome associations are learned by subjects, they are unexpectedly changed by the experimenter, and subjects must modify their behavior in order to find the new predictors of reward. Performance in reversal learning tasks depends upon the integrity of prefronto-cortical regions (Dias et al., 1996) and is impaired in ADHD children (Itami and Uno, 2002). We have recently shown that acute administration of the stimulant methylphenidate (MPH) or the non-stimulant desipramine (DMI) improves reversal learning performance in drug-naïve rats (Seu et al., 2009), and in the current study, we sought to further examine whether the acute administration of these agents in rats with a long-term history of treatment with the same drugs would produce a quantitatively or qualitatively different effect. A previous study has shown that both acute and chronic treatment with DMI improves reversal learning and attentional set-shifting in rats (Lapiz et al., 2007); however, because this study used two different doses of the drug for the acute and for the chronic treatment manipulations and the drug was administered chronically using osmotic pumps, it is not possible to clearly disambiguate acute from chronic actions. In contrast, in the current study, the same dose and route of administration were used for the acute and the repeated treatment. Additionally, our experimental design allowed us to establish whether the beneficial effect of repeated dosing with these drugs on reversal performance may extend beyond the range of pharmacodynamic actions of these drugs, by comparing performance of rats repeatedly treated with MPH or DMI at 30 min or 24 h after the last administration of the drug. We hypothesized that the acute administration of DMI and MPH in rats with a previous history of treatment with the same drugs will result in an improvement of reversal learning performance qualitatively similar but quantitatively larger than that obtained with an acute administration of the same drugs, while we did not have any a priori hypothesis relatively to a potential longer-lasting effect of repeated treatment.

Section snippets

Subjects

Sixty-eight adult male Long-Evans rats (Harlan, Indianapolis IN) were used in these experiments. The subjects were ∼60 days of age at the initiation of training and ranged in weight from 250 to 350 g during the experimental period. All rats were initially food-restricted to 80–85% of their free-feeding weights and subsequently fed ∼15 g rat chow per day in their home cage within 1–3 h after testing. Water was continuously available, except while in the operant testing chambers. Rats were housed

Effect of the repeated treatment with DMI or MPH on the retention and reversal of a 2-position discrimination task

Two rats in the DMI group, one in the MPH group and one in the saline group consistently failed to initiate trials when returned to behavioral testing after the initial 6 days of treatment and were excluded from the study, resulting in a total sample of 64 rats.

Performance of the retention of the discrimination acquired prior to the initiation of drug administration was not affected by group; as shown in Fig. 2A, after 7 days of drug administration, there was no effect of group for total trials

Discussion

We have previously shown that acute administration of catecholamine reuptake inhibitors, including the stimulant drug MPH and the non-stimulant norepinephrine reuptake inhibitors DMI and atomoxetine, improve reversal learning performance in rats (Seu et al., 2009). Accordingly, other groups have reported a beneficial effect of these drugs on rat performance in tasks that measure different aspects of inhibitory control (Eagle et al., 2007, Navarra et al., 2008, Robinson et al., 2007). Moreover,

Acknowledgements

Funding: These experiments were funded, in part, by PHS grants P50-MH77248 and P20-DA22539 to JDJ, as well as a grant from the Tenenbaum Creativity Initiative at UCLA.

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