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