Invited Symposium: What Can Genetic Models Tell Us About Attention-Deficit Hyperactivity Disorder (ADHD)?


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Clinical Psychopharmacology of AD/HD: Implications for Animal Models

Contact Person: Mary Solanto-Gardner, Ph.D. (solanto@pipeline.com)

Despite their widespread use in the treatment of Attention Deficity/Hyperactivity Disorder (American Psychiatric Association, 1994), the mechanisms of action of the psychostimulants, methylphenidate (MPH) and dextro-amphetamine (D-AMP) remain poorly understood. Animal models offer the possibility of investigating neurobiological processes which cannot be readily studied in humans. Development of these models, however, must be guided and constrained by a working knowledge of the clinical psychopharmacology of AD/HD.

Numerous studies, based on parent and teacher ratings, direct clinical observations, and laboratory tests, have shown that the psychostimulant drugs bring about significant reductions in AD/HD symptoms of inattentiveness and hyperactivity- impulsivity. These studies have also shown that stimulants bring about improvement in problems commonly associated with AD/HD, including poor performance on academic tasks (Solanto, 1999), aggressive behavior (Gadow, Nolan, Sverd, Sprafkin & Paolicelli, 1990), parent-child interaction problems (Barkley, 1989), and social unpopularity (Whalen et al., 1989). A recent review (Spencer et al., 1996) concluded that 70% of outpatients experience clinically significant improvement when treated with a given stimulant. An earlier report (Elia, Borcherding, Rapoport & Keysor, 1991) had shown furthermore, that when dosage was closely monitored and titrated, nearly all children (98% in a sample of 48 with AD/HD) responded to either MPH or D-AMP when both stimulants were tried.

The pharmacokinetics and pharmacodynamics of psychostimulants in clinical use have been well studied. The effective dose range in children is 0.3-1.0 mg/kg for MPH and 0.2-0.5 mg/kg for D-AMP. Therapeutic action is rapid and short-lived, with onset within 30 minutes, peak effects at about 2 hours, and maximal duration of 5 hours. Despite consistency of group response and generally linear improvement with increasing dose in the therapeutic range (Solanto, 1999), the response of individual children to MPH or D-AMP varies widely both within and across behavioral domains (Rapport, Denney, DuPaul & Gardner, 1994), and neither body weight (Rapport & Denney, 1997) nor blood level (Patrick, Mueller & Gualtieri, 1987) has utility in predicting the most effective dose. Furthermore, as many as 25% of all children with AD/HD may respond preferentially to one psychostimulant over the other (Elia et al., 1991).

Although children with AD/HD are typically treated for periods of several years, sometimes extending into adolescence, there is no systematic evidence to date of the development of tolerance or of sensitization ("reverse-tolerance"); effects of the drugs given acutely and given after chronic treatment appear to be similar, which suggests that clinical effects are not mediated by long-term changes in receptor sensitivity. Concomitantly, there is no long-term remedial effect of the drugs on behavior - i.e. symptoms return when the drug is discontinued. The calming effect of the stimulants was once thought to be "paradoxical," or opposite to the activating effect expected in normal individuals. A pivotal study in 1978, however, (Rapoport, Buchsbaum, Weingartner, Zahn & Ludlow, 1978) demonstrated that D-AMP had qualitatively similar effects in normal and AD/HD children and in normal adults in that all three groups showed decreases in activity and impulsivity, and increases in attentiveness following drug administration.

Neuropsychological, neurophysiological, and neuroimaging studies in individuals with AD/HD have attempted to ascertain the fundamental cognitive and behavioral processes which are altered by psychostimulant treatment, and the corresponding neurobiological mechanisms of stimulant drug action. Numerous studies have demonstrated that methylphenidate improves performance on laboratory tests of reaction time (Sykes, Douglas & Morgenstern, 1972), sustained attention (Losier, McGrath & Klein, 1996), and focused attention (de Sonneville, Njiokiktjien & Bos, 1994), and produces corresponding enhancement of the P300 component of the event-related EEG potential (Klorman, 1991), an index of allocation of attentional capacity. Studies of information-processing suggest that the beneficial effect of stimulants is specific to the response-organization rather than stimulus-evaluation stages of processing (van der Meere, 1996). Although some studies have shown improved performance on measures of paired-associate learning (Swanson, Kinsbourne, Roberts & Zucker, 1978) and more complex learning tasks (Vyse & Rapport, 1989), more robust effects of stimulants in children are shown on measures of retention (Evans, Gualtieri & Amara, 1986) rather than acquisition. Methylphenidate's positive effects on measures of working memory (Tannock, Ickowiz & Schachar, 1995) and motor inhibitory control (Tannock, Schachar, Carr, Chajczyk & Logan, 1989 ) indicate improvement in executive functions which may be key to methylphenidate's therapeutic effectiveness. Significant stimulant-mediated reduction in 24-hour motor activity and restlessness (Porrino, Rapoport, Behar, Ismond & Bunney, 1983), however, suggests that reduction in hyperactivity is a primary effect of the stimulants rather than simply a by-product of enhanced concentration or inhibitory control.

The results of neuroimaging studies of children with AD/HD are now converging in revealing abnormalities in the anterior frontal cortex and basal ganglia - areas primarily responsible for executive function and motor control, respectively. Early studies of regional cerebral blood flow revealed hypoperfusion in the right striatum (Lou, Henriksen & Bruhn, 1990), with increased perfusion following a dose of methylphenidate. More recent anatomical MRI studies have shown reduced volume in right anterior frontal cortex (Castellanos et al.1996b; Hynd, Semrud-Clikeman, Lorys, Novey & Eliopulos, 1990), as well as in caudate (Aylward et al., 1996; Castellanos et al.1996b; Hynd et al., 1990), and globus pallidus (Aylward et al., 1996; Castellanos et al.,1996b), particularly on the right (Castellanos et al.,1996b),in children with AD/HD. Of particular interest in the sample studied by Castellanos and colleagues were significant (negative) correlations between performance on inhibitory tasks and the volume of the three brain regions (predominantly on the right) which differentiated the normal control and AD/HD groups (Casey et al., 1997), providing support for the functional significance of the neuroanatomical findings. PET studies have, disappointingly, not revealed effects of acute (Matochik et al., 1993) or chronic (Matochik et al., 1994) MPH or D-AMP treatment in any brain region beyond what might be expected by chance.

The CNS mechanisms of therapeutic action of the psychostimulants has been the focus of considerable thought and debate (Castellanos, 1997 ; Pliszka, McCracken & Maas, 1996; Solanto, 1998; Swanson, Castellanos, Murias, La Hoste & Kennedy, 1998). Research in animals has established that at the cellular level both MPH and D-AMP potentiate the action of dopamine and norepinephrine in the synapse by facilitating their release, blocking re-uptake, and to a lesser extent, inhibiting the catabolic activity of monoamine oxidase (Groves, Ryan, Diana, Young & Fisher, 1989). Systematic clinical trials in children comparing selectively noradrenergic and dopaminergic agents have shown that the most effective drugs are those which, like the psychostimulants, have effects on both catecholamines (Zametkin & Rapoport, 1987).

Animal studies provide some insights with respect to the functional neurophysiology of norepinephrine and dopamine and their possible involvement in AD/HD. Research in monkeys by Arnsten (Arnsten, 1997) and Aston-Jones (Aston-Jones, Rajkowski, Kubiak, Alexinsky & Akaoka, 1994 ) indicates that noradrenergic pathways from the locus coeruleus to the pre-frontal cortex are important in mediating inhibitory control, working memory, and tolerance of delay. Dopamine, on the other hand, is found in nigrostriatal and mesocorticolimbic pathways which are important in regulation of motor activity (Roth & Elsworth, 1996). Dopaminergic neurons proceeding from the ventral tegmental area forward to the nucleus accumbens via the medial forebrain bundle mediate the rewarding effects of pleasurable stimuli and of psychostimulant drugs (Gardner, 1997). Stimulant effects on activity in animals are bi-phasic with lower doses of D-AMP (0.5-2.0 mg/kg) or MPH (4-5 mg/kg) increasing locomotor activity, and higher doses (5-10 mg/kg for D-AMP and 8-16 mg/kg for MPH) decreasing activity concomitant with pronounced increases in stereotypic behaviors.

Integration of basic and clinical research findings has suggested several hypotheses of mechanisms of stimulant drug action. Among these are that the reduction in activity level and increase in attentional focus seen in children are comparable to the reduction in activity and increase in stereotypy seen at high stimulant doses in animals. Several studies of divergent thinking and cognitive perseveration, however, have indicated that the therapeutic effects on attention and activity in children are not associated with increased cognitive constriction or stereotypic thinking (Douglas, Barr, Desilets & Sherman, 1995; Solanto & Wender, 1989; Tannock & Schachar, 1992). An alternative hypothesis is that the reduction in activity level in children is mediated by stimulation of inhibitory pre-synaptic autoreceptors, which reduce dopamine activity and thereby compensate for excess dopamine activity in AD/HD. Some support for this possibility has been provided in research in which very low MPH doses of 0.1 mg/kg - thought to be in the range (0.25 mg/kg D-AMP) shown to stimulate autoreceptors in animal research (Bunney, Aghajanian & Roth, 1973; Groves & Tepper, 1983) - also reduced activity in children with AD/HD (Solanto, 1986). Further support comes from recent research in which levels of the dopamine metabolite HVA in CSF were positively correlated with severity of hyperactivity in AD/HD children, and also significantly predicted a positive response to methylphenidate treatment (Castellanos et al., 1994; Castellanos et al.,1996a). The hypothesis that the therapeutic effects of psychostimulants involve dopaminergic pathways which mediate reward (Haenlein & Caul, 1987) received support in a study in which MPH increased the effort children expended in order to obtain reward on a progressive ration schedule (Wilkison, Kircher, McMahon & Sloane, 1995). The clinical observation that psychostimulants do not have euphorigenic effects in children, however, is evidence against the hypothesis that their therapeutic effects are mediated by stimulation of endogenous reward pathways.

Clearly, much research is necessary to elucidate the therapeutic mechanisms of stimulant drug action. Integration of pre-clinical and clinical research has the potential to considerably advance our understanding in this area . The foregoing suggests that in order to adequately mirror the clinical phenomena of drug response in AD/HD, animal models must be characterized by the following: (1) demonstrated effect of doses comparable to the therapeutic range in humans (2) immediate onset of action, and absence of tolerance or sensitization with repeated administration (3) absence of remedial effect of drug treatment after it is discontinued (4) effects on both dopaminergic and noradrenergic receptors/pathways (5) qualitatively similar behavioral effects of drug treatment in the animal model and in normal control animals.

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Solanto-Gardner, M.; (1998). Clinical Psychopharmacology of AD/HD: Implications for Animal Models. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/sadile/solanto-gardner0417/index.html
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