Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration

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Abstract

The psychostimulants, d-amphetamine (d-AMP) and methylphenidate (MPH), are widely used to treat attention-deficit hyperactivity disorder (ADHD) in both children and adults. The purpose of this paper is to integrate results of basic and clinical research with stimulants in order to enhance understanding of the neuropharmacological mechanisms of therapeutic action of these drugs. Neurochemical, neurophysiological and neuroimaging studies in animals reveal that the facilitative effects of stimulants on locomotor activity, reinforcement processes, and rate-dependency are mediated by dopaminergic effects at the nucleus accumbens, whereas effects on delayed responding and working memory are mediated by noradrenergic afferents from the locus coeruleus (LC) to prefrontal cortex (PFC). Enhancing effects of the stimulants on attention and stimulus control of behavior are mediated by both dopaminergic and noradrenergic systems. In humans, stimulants appear to exert rate-dependent effects on activity levels, and primarily enhance the motor output, rather than stimulus evaluation stages of information-processing. Similarity of response of individuals with and without ADHD suggests that the stimulants do not target a specific neurobiological deficit in ADHD, but rather exert compensatory effects. Integration of evidence from pre-clinical and clinical research suggests that these effects may involve stimulation of pre-synaptic inhibitory autoreceptors, resulting in reduced activity in dopaminergic and noradrenergic pathways. The implications of these and other hypotheses for further pre-clinical and clinical research are discussed.

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)=(ab)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.

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