Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration
Introduction
Nearly 60 years ago, Charles Bradley [15]made the first observation that benzedrine (a racemic mixture of d- and l-amphetamine) had a distinct calming effect on the behavior of hyperactive children. Since that time, a plethora of studies have attested to the effectiveness of the psychostimulants in alleviating the cardinal symptoms of attention-deficit hyperactivity disorder (ADHD) and these drugs are now widely used to treat it. Relatively little substantive progress, however, has been made in delineating the therapeutic mechanisms of action of these drugs, although several well-developed hypotheses have been proffered 152, 177, 227, 231, 288.
Contrasting with a relative dearth of specific knowledge concerning the clinical mechanisms of action of stimulants are significant advances in the past 10 years in the pre-clinical neuropsychopharmacology of these drugs. New techniques such as microdialysis, which permits measurement of neurotransmitter levels in awake, behaving animals, as well as the development of many new drugs with effects on specific receptor subtypes, offer the potential of identifying the neurotransmitter systems and specific receptors which mediate the observed effects of stimulants in animals in multiple domains of behavior. At the same time, more sophisticated genetic, neuroimaging, neuropsychological and behavioral studies in clinical populations have provided important clues as to underlying aberrant neurobiological processes which may be altered by clinically effective drugs. The purpose of this paper is to review recent developments in each of these areas, premised on the belief that the integration of these results will lead to generation of more precise, testable hypotheses concerning clinical mechanisms of stimulant drug action in patients with ADHD.
The first section will summarize research concerning drug effects in ADHD and will serve to constrain and guide our attention to drug studies in animals which are relevant to the phenomena seen clinically. This section will be followed by segments devoted to: the basic neuropharmacology of amphetamine and methylphenidate (MPH); the psychopharmacology of stimulant effects with respect to locomotor activity, reward processes, rate-dependency, and cognitive processes, including learning, attention, and memory; genetic studies; neuroimaging studies; animal models of ADHD; and comparison between stimulant and non-stimulant drug effects in ADHD. Within each subsection, effects in animal and human subjects will be presented. The final section will be devoted to an integration of these results, with discussion of hypotheses concerning specific sites and mechanisms of action and implications for future pre-clinical and clinical research.
Of the three psychostimulants used to treat ADHD—d-amphetamine (d-AMP) , MPH, and pemoline—the first two are by far the most widely prescribed and have been the focus of the most pre-clinical and clinical research. Therefore, this review will be limited to studies of d-AMP and MPH.
Section snippets
Clinical pharmacology of stimulants
ADHD is characterized by three major symptom clusters—inattentiveness, impulsivity and hyperactivity—which are differentially present in the three subtypes of the disorder recognized in the DSM-IV [1]. Numerous well-controlled studies have shown that the most widely used stimulants, d-AMP (Dexedrine), and MPH (Ritalin), are highly effective in alleviating all three clusters of symptoms assessed on the basis of parent and teacher behavior rating scales, direct observations in natural settings,
Neuropharmacology of stimulants
In order to understand the nature of the effects of d-AMP on catecholaminergic function, it is necessary to have some understanding of the anatomic distribution and functional characteristics of the dopaminergic and noradrenergic neurotransmitter systems.
Stimulant effects on locomotor activity
Careful studies using truncal actometers have shown that children with ADHD are more active than normal children during nearly all daytime activities as well as during sleep [182], and that d-AMP (15 mg/day or as tolerated, at 8:00) significantly decreased activity level throughout the day [181].
The effects of amphetamine on behavior in animals vary substantially with dosage. Studies have shown that DA agonists, including l-amphetamine [243], apomorphine 53, 244and l-dopa [53], at the very low
Animals
Stimulant drugs have been shown to have rewarding properties in self-stimulation and conditioned reinforcement paradigms. Animals have been shown to self-administer d-AMP [102], and amphetamine produces increased responding for brain self-stimulation in dose-dependent fashion in the range of 0.25–1.0 mg/kg, i.p. [107]. Furthermore, d-AMP enhances the reward value of other stimuli. Numerous studies have shown that d-AMP enhances responding to a previously conditioned reinforcer (CR). This effect
Animals
Rate-dependency refers to the observation that low baseline rates of response are increased by a drug whereas higher rates are found to increase to a lesser extent or to decrease as a result of drug treatment; response rate is thus an inverse function of baseline rate, as described in the model, log (D/C)=(a−b)log (C), where D is response rate on drug, C is baseline response rate, and a and b are constants [51]. Many studies in a wide range of species, reviewed by Dews and Wenger [51]have
Attention
Effects of d-AMP on ‘attention’ or stimulus control of behavior are assessed on tasks in which the animal must respond selectively to a cue (e.g. presentation of a light) which indicates which response alternative (e.g. left or right lever) will yield reinforcement. These tasks would appear to be analogous to choice reaction time tasks in humans, with the exception of the absence of an immediate reinforcer in the latter. Effects of d-AMP in rats in these studies are biphasic, with low doses
Genetic studies
Research in molecular genetics is beginning to yield data which supports the hypothesis that dopaminergic functioning is aberrant in ADHD. Several recently completed studies 42, 78, 276have reported an association between ADHD and the 480-base pair DAT1 allele for the DA transporter. There is no indication currently, however, as to whether or in what way this polymorphism may affect DA transporter function. Recent research 132, 249also suggests increases in prevalence of the 7-repeat allele for
Brain imaging studies
New techniques of brain imaging in animal and human studies provides a ‘window’ which can potentially reveal exactly which sites in the brain are targeted by psychostimulants and other drugs.
Animal models
Several well-developed models of ADHD have been generated in animals by neurotoxic lesions of dopaminergic nerve endings, and by selective breeding. Shaywitz 225, 226and others [144]produced rats with high locomotor activity and deficits in avoidance learning by administering intracisternal injections of 6-OH-DA (plus desipramine (DMI), to protect noradrenergic endings) to pups. Injections of d-AMP or MPH in doses which increased the activity level of normal rats reduced locomotor activity and
Effects in ADHD of non-stimulant drugs affecting specific neurotransmitter systems
Given that the psychostimulants have, as described, numerous effects on both the DA and NE neurotransmitter systems, comparison with drugs having somewhat more delimited effects may be helpful in parsing out therapeutic mechanisms of action [288]. In small samples, the DA agonists, piribedil and amantadine, were not found to be clinically effective [288], possibly because the dosages were too high. The DA antagonist, haloperidol [281]was moderately effective in reducing global ratings of
Discussion and implications
Integration of the basic neuropharmacology of the psychostimulants with the results of pre-clinical and clinical studies of their effects on behavior, cognition, electrophysiology, brain imaging, and neurochemistry suggests likely or possible modes of therapeutic action of these drugs in ADHD with respect to the following questions.
References (290)
- et al.
Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggest a role in vigilance
Prog Brain Res
(1991) - et al.
Behavioural consequences of the infusion of dopamine into the nucleus accumbens of the common marmoset (Callithrix Jacchus)
Neuropharmacology
(1987) - et al.
Current advances and trends in the treatment of depression
Trends Pharm Sci
(1994) - et al.
Short and long-term changes in dopamine and serotonin receptor binding sites in amphetamine-sensitized rats: a quantitative autoradiographic study
Brain Res
(1995) - et al.
Differential effects of excitotoxic lesions of the basolateral amygdala, ventral subiculum and medial prefrontal cortex on responding with conditioned reinforcement and locomotor activity potentiated by intra-accumbens infusions of d-amphetamine
Behav Brain Res
(1993) - et al.
Effects of lesions to ascending noradrenergic neurons on performance of a 5-choice serial reaction task in rats: implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal
Behav Brain Res
(1983) - et al.
Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
Cerebrospinal fluid monoamine metabolites in boys with attention-deficit hyperactivity disorder
Psychiatry Res
(1994) - et al.
Guanfacine treatment of comorbid attention deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience
J Am Acad Child Adolesc Psychiatry
(1995) - et al.
Differences in the effects of amphetamine and methylphenidate on brain dopamine turnover and serum prolactin concentration in reserpine-treated rats
Life Sci
(1979)