Elsevier

Biological Psychiatry

Volume 57, Issue 11, 1 June 2005, Pages 1391-1396
Biological Psychiatry

Advancing the neuroscience of ADHD
Stimulant Actions in Rodents: Implications for Attention-Deficit/Hyperactivity Disorder Treatment and Potential Substance Abuse

https://doi.org/10.1016/j.biopsych.2004.12.036Get rights and content

Most evidence supports the continued use of stimulants as the best available pharmacotherapy for the treatment of children with attention-deficit/hyperactivity disorder (ADHD), but little is known about possible enduring behavioral and neuroadaptational consequences of long-term stimulant exposure. Although a variety of preclinical studies, particularly those using methylphenidate (MP), have attempted to address these issues, most of these studies have used procedures that might not adequately simulate clinical treatment conditions, and results have not been entirely consistent. In particular, the rationale for selection of MP doses that simulate clinical exposure has not been well defined. We suggest that the use of more appropriate treatment conditions, including doses that result in plasma drug levels comparable to therapeutic levels, will provide a more accurate model for adequately assessing the therapeutic mechanisms and potential long-term consequences of stimulant psychotherapy in the treatment of ADHD.

Section snippets

Enduring Effects of Repeated Exposure

There is, however, considerable evidence that, under some experimental conditions, repeated exposure to amphetamine-like stimulants can have enduring effects in experimental animals (Robinson and Becker 1986; Segal and Kuczenski 1994; Vanderschuren and Kalivas 2000) as well as in humans (Sax and Strakowski 1998; Strakowski and Sax 1998; Strakowski et al 2001). Of particular interest is the progressive enhancement of some stimulant-induced behaviors with repeated administration, a process

Administration Routes and Dosing

For example, the clinical treatment of ADHD in adolescence involves oral administration of the drug. In contrast, most preclinical studies use the subcutaneous or intraperitoneal (IP) routes of administration. This difference in route is critically important with regard to assessing the effective dose used, because the oral route results in lower peak drug concentrations and a slower rate of drug accumulation, two components of the pharmacokinetic profile that can affect both the quantitative

Achieving Therapeutic Drug Levels

Theoretically, the objective of dose selection is to achieve brain levels of the drug in experimental animals comparable to therapeutic levels in humans, thus exposing the relevant brain molecular sites to similar drug concentrations. This rationale derives from the observation that the likely sites of action for these drugs (i.e., the norepinephrine and dopamine transporters) exhibit, at least in vitro, similar pharmacologic properties across humans and experimental animals (see, for example,

Neurotransmitter Response

In parallel neurochemical studies, we found that the regional extracellular neurotransmitter response to oral MP in this dose range was also unique and might have relevance both to the mechanisms underlying stimulant efficacy as well as potential abuse liability of stimulant pharmacotherapy. Consistent with the presumed mechanisms of action of this drug as an inhibitor of dopamine and norepinephrine uptake, oral MP in this range promoted a dose-dependent increase in both of these transmitters

Conclusion

In summary, doses of MP that have been used in most preclinical studies with rodents result in plasma (and brain) concentrations of the drug that far exceed typical clinically relevant doses in the treatment of ADHD. Thus, the translational utility of much of the currently available data in terms of long-term consequences of stimulant pharmacotherapy is, at best, ambiguous. Doses of MP that result in plasma concentrations that more closely approximate the therapeutic range promote unique

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