Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis

Abstract

How do ‘stimulants’ reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2–0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.

Introduction

The medications commonly used for attention-deficit hyperactivity disorder are methylphenidate, dextroamphetamine, and pemoline, which, along with cocaine, stimulate psychomotor activity. All these drugs act on neurons to promote the release of dopamine or to block the transport of dopamine by blocking the dopamine transporter. Although it has long been thought that the nitrogen atom was needed for amine-containing drugs to bind to the biological target (e.g. [33]), Madras and colleagues have recently shown that the nitrogen atom may be replaced by either an oxygen atom [23], [24] or a carbon atom, and the cocaine-like drugs will still selectively block the dopamine transporter target in vitro.

High doses of l-DOPA stimulate locomotion in normal rodents as well as in Parkinson patients by increasing brain dopamine [13]. This effect is observed despite the loss of 96% to more than 99% of the dopamine content and the dopamine terminals in the Parkinson putamen in the end stages of the disease. Low doses of l-DOPA, however, as well as other dopamine-like agonists, reduce locomotor activity in animals [2], [38], [42]. This biphasic action also occurs with dextroamphetamine or methylphenidate in animals which are either spontaneously active [12], [25], [41] or made hyperactive by a neonatal lesion [21].

The stimulant medications also elicit a biphasic action in humans, with low doses reducing locomotor activity and distractibility, and high doses (or overdosage) causing sleeplessness and other symptoms of excessive central nervous system stimulation. The clinical dose range for dextroamphetamine is between 0.2 and 0.6 mg/kg (given twice a day), similar to that for slowing animal locomotion. The dose range for methylphenidate is 0.3–0.6 mg/kg (given twice a day), while that for pemoline is 38–150 mg per day. Pemoline is titrated up from 19 mg/day to a maximum of 2 mg/kg/day in adults, although for children the daily doses frequently approach or exceed 3 mg/kg/day.

The dopamine transporter and the presynaptic receptors for dopamine (autoreceptors) regulate extracellular levels of dopamine in the synapse. The release of dopamine occurs during nerve impulses, as well as in a steady non-pulsatile manner during rest intervals between nerve impulses. The rise in extracellular dopamine is counteracted by: (1) rapid diffusion of dopamine from the synapse; (2) re-uptake of dopamine by the dopamine transporter; and (3) inhibition of further dopamine release by extracellular action of dopamine on the dopamine autoreceptors of the neuron. Drugs that bind to the dopamine transporter generally increase the extracellular level of dopamine by blocking the transport of dopamine into the neuron, or promoting the release of dopamine [10]. For example, blockade of the dopamine transporter by methylphenidate, or enhanced release of dopamine by dextroamphetamine elevates the extracellular level of dopamine to trigger a cascade of dopamine-receptor-mediated events. These events depend on the dose of methylphenidate or dextroamphetamine and the rate of entry of such drugs into the brain. These two factors regulate the time-course of the rise in extracellular dopamine, and thereby determine the magnitude of the therapeutic benefit or the stimulant effects and the degree of abuse liability [22], [30], [39].

The normal resting or basal level of extracellular dopamine is approximately 4 nM [8], [17], [27], and transiently rises at least 60-fold to about 250 nM during a normal nerve impulse. It has been calculated, but not measured, that the dopamine concentration in the synaptic space is 1.6 mM immediately upon release from the dopamine-containing vesicles, suddenly dropping thereafter to the measured level of 250 nM; [8]. The transiently elevated level of extracellular dopamine falls back to 4 nM, primarily by diffusion [8] but assisted by the dopamine transporter. Dextroamphetamine, methylphenidate and cocaine each increase the level of extracellular dopamine in the dopamine-rich regions of the brain, as measured directly by means of intracerebral dialysis [4], [6], [14], [15], [29], [31], [47]. Methylphenidate and cocaine raise the extracellular level of dopamine primarily by blocking the dopamine transporter, thereby preventing the re-entry of dopamine into the neuron [1]. Although dextroamphetamine (∼150 nM) also inhibits the dopamine transporter, this drug directly releases dopamine; methylphenidate and cocaine do not have this direct releasing action [5], [46]. The increased output of dopamine by stimulants has also been measured indirectly in human volunteers by brain imaging, using the method of ligand displacement from dopamine D2 receptors by endogenous dopamine [34].

Such studies indicate that dextroamphetamine [19] appreciably elevates synaptic dopamine such as to inhibit the binding of various imaging ligands to dopamine D2 receptors by 6–48%, while methylphenidate [3] and cocaine [32] result in an inhibition of ∼10%. These values indicate a considerable increase in the basal resting levels of dopamine in the extracellular synaptic space. However, the imaging method limits the collection of data to 30–60-s intervals, far slower than the rapid msec time-course of nerve-impulse-associated release of dopamine. The brain image, therefore, reflects the time-averaged result of the competition between endogenous dopamine (resting and pulsatile) and the [¹¹C] ligand. Low doses of stimulant drugs increase the resting level of extracellular dopamine far more than they increase the nerve-impulse-associated pulsatile output of dopamine. This conclusion comes from amperometry methods both in vitro and in vivo, using carbon fiber microelectrodes which are 6–10 μ wide. For example, the low dose of 0.5 mg/kg dextroamphetamine elevates the basal or resting level of dopamine by sixfold in the living rat brain [18], but increases the pulsatile or stimulated release of dopamine by only twofold or less [11], [26], [43]. While increasing the spontaneous output of dopamine, low concentrations of dextroamphetamine can even decrease the electrically stimulated output of dopamine in brain slices [16]. In fact, 0.5 mg/kg dextroamphetamine given to 23 hyperactive children lowered the spinal fluid level of homovanillic acid, the major metabolite of dopamine, by 34% in direct relation to the clinical improvement of their hyperactive syndrome [36]. By raising the baseline level of extracellular dopamine, therefore, the net effect of the low dose of the stimulant drug is to lower the relative rise in the pulsatile release of dopamine, expressed as a percent rise from the baseline. At low doses of stimulants, therefore, the elevated resting extracellular dopamine lowers the relative rise (compared to baseline) in the pulsatile release of dopamine by acting on presynaptic dopamine D2 receptors (on the nerve terminal) which in turn inhibits the stimulated release of additional dopamine [7], [37], [43]. Hence, the cellular pharmacology of the stimulant drugs at low doses may be thought of as follows. The normal resting level of extracellular dopamine (of the order of 4 nM) transiently rises 60-fold (to ∼250 nM) during a normal nerve impulse. This transiently elevated level of extracellular dopamine falls back to 4 nM in a matter of a few millisecs, primarily by diffusion but assisted by the dopamine transporter.

In the presence of methylphenidate or dextroamphetamine, the dopamine transporter is blocked and the resting extracellular level of dopamine would rise by about sixfold. In turn, the elevated resting level of dopamine acts on the presynaptic dopamine D2 receptors to reduce the relative rise in the impulse-triggered release of additional dopamine to only twofold. At higher doses of dextroamphetamine, above 1 or 2 mg/kg, the magnitude of the increase markedly raises the resting level of extracellular dopamine by 14- to 35-fold [18], [35], [36], while raising the pulsatile output of dopamine by sevenfold [11], [43]. These higher doses are associated with generalized stimulation of the nervous system, arising from the very high level of extracellular dopamine at rest and the increased release of dopamine during the nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming the presynaptic inhibition of further dopamine release.

As just outlined, the enhanced output of dopamine by low doses of stimulant drugs reduces the impulse-associated rise of dopamine, relative to the baseline. That is, the relative rise of dopamine during the impulse is lowered because of this elevated baseline. The smaller pulsatile surge of dopamine would result in less activation of the post-synaptic dopamine D1 and D2 receptors, thereby resulting in reduced psychomotor activity. These psychomotor-controlling dopamine receptors are hypothesized to vary their response in proportion to the relative rise in pulsatile dopamine, but there is no direct experimental work to validate this particular point. For example, the elevated extracellular dopamine would occupy more D1 and D2 receptors during rest, reducing or desensitizing these receptors from the dopamine which arrives during the nerve impulses. While this hypothesis may account for the hypolocomotor action of low doses of stimulants, high doses of stimulants cause marked elevations in the resting and pulsatile levels of extracellular dopamine, providing high enough extracellular levels of dopamine to oversaturate and overstimulate postsynaptic dopamine receptors, overwhelming the presynaptic inhibitory action of dopamine. These high levels are associated with hyperdopaminergic somatic, behavioral and psychological signs and symptoms which necessitate lowering the clinical dose.

Do the clinical concentrations of methylphenidate and dextroamphetamine in plasma correspond to the concentrations which occupy the main clinical target for these medications, the dopamine transporter? Although there is a wide range of published values for the concentration of methylphenidate which occupies 50% of the dopamine transporter sites in native tissues in vitro, reasonably consistent values are emerging from work with the cloned dopamine transporter [9], [20]. At present there is only one study [20] which examined all three stimulants (methylphenidate, dextroamphetamine and cocaine) on the cloned dopamine transporter. From a clinical point of view, it is important to note that the plasma concentration of methylphenidate in children at the peak action between 1 and 3 h [40] closely matches the concentration which occupies the dopamine transporter [20], namely, between 20 and 30 nM. This is compatible with the view that the dopamine transporter is the main target for the clinical action of methylphenidate. The situation with dextroamphetamine is generally similar, because the clinical concentration of dextroamphetamine in plasma (∼150 nM; [28]) is sufficient to occupy a significant proportion of the dopamine transporter (d-amphetamine has an inhibition constant of 100 nM for the dopamine transporter; [20]). Further support that the dopamine transporter is the main target for the stimulant drugs comes from genetic knockout experiments. Mice which are genetically bred without the dopamine transporter do not display increases in dopamine in response to cocaine [10]. Although such animals would presumably not exhibit any locomotor slowing upon administration of low doses of stimulant drugs, this has apparently not yet been directly examined. In humans, moreover, the onset of clinical symptoms with intravenous methylphenidate or cocaine parallels the onset of occupancy of the dopamine transporter by tracer amounts of [¹¹C] cocaine or [¹¹C] methylphenidate [44], [45]; such occupancy studies have not yet been done using oral methylphenidate. Although these findings generally support the view that stimulant drugs primarily act on the dopamine transporter, such tracer radioligands may also bind to other sites in the brain.