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Home , Amphetamine, Dextroamphetamine, Dopamine transporter, Methylphenidate, Reuptake

Molecular Psychiatry (1998) 3, 386–396  1998 Stockton Press All rights reserved 1359–4184/98 $12.00

MECHANISMS OF ACTION Anti-hyperactivity : and P Seeman1 and BK Madras2

1Departments of and Psychiatry, Medical Science Building, Room 4344, University of Toronto, 8 Taddle Creek Road, Toronto, M5S 1A8; 2Division of Neurochemistry, Department of Psychiatry, Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, PO Box 9102, Southborough, MA 01772-9102, USA

How do ‘’ reduce hyperactivity in children and adults? How can which raise extracellular result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson’s ? These apparent para- doxes are the focus of this brief review on the of used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for deficit hyperactivity disorder. Keywords: hyperactivity; attention deficit; methylphenidate; amphetamine; dopamine

The use of stimulant medicatons for attention deficit bond with the ,5,7 the hyperactivity disorder has almost tripled since 1990. atom does not, thus raising considerably interesting The increased usage presumably stems from the wider theoretical problems as to how such carbon-based mol- recognition and the more criterion-based diagnosis of ecules bind to the dopamine transporter.) this disorder, occurring in 2–6% of children in North Because methylphenidate has two asymmetric car- America, as well as from the expanding knowledge that bon atoms (asterisks in Figure 1), this drug has four dif- such stimulant medications continue to be effective ferent forms, (+)- and (−)-erythromethylphenidate, and over many months or years, well into adulthood, and (+)- and (−)-threomethylphenidate.8 The methylphen- do not produce long-term adverse effects.1–4 idate used clinically is a 50:50 mixture of (+)- and (−)- threomethylphenidate, and is ten-fold to one hundred- fold more potent on various tissues compared to the Chemistry (±)-erythro- form.8 The medications commonly used for attention deficit hyperactivity disorder are methylphenidate, dextroam- phetamine, and , which, along with , Behavioral pharmacology stimulate psychomotor activity. The chemical struc- High doses of l-DOPA* (which is converted to dopa- tures of these compounds are shown in Figure 1, with mine in the brain) stimulate locomotion in normal rod- dopamine included for comparison. All these drugs act ents as well as in Parkinson patients by increasing on to promote the release of dopamine or to brain dopamine.9 This effect is observed despite the block the transport of dopamine by blocking the dopa- loss of 96% to more than 99% of the dopamine content mine transporter. and the dopamine terminals in the Parkinson It has long been thought that the atom is in the end stages of the disease.10,11 Low doses of l- needed for -containing drugs to bind to the bio- DOPA, however, as well as other dopamine-like agon- 5 logical target, but Madras and colleagues have recently ists, reduce locomotor activity in animals.12–14 This shown that the nitrogen atom may be replaced by biphasic action also occurs with 6,7 either an oxygen atom or a carbon atom (BK Madras or methylphenidate in animals which are either spon- et al, to be published), and the cocaine-like drugs will taneously active15–17 or made hyperactive by a neonatal still selectively block the dopamine transporter target lesion.18 An example of such biphasic action of dex- . (Although the nitrogen and oxygen atoms each troamphetamine (d-amphetamine) is shown in have lone pair electrons which can form a Figure 2.

Correspondence; Dr P Seeman, Depts of Pharmacology and Psy- chiatry, Medical Science Building, Room 4344, University of Toronto, 8 Taddle Creek Road, Toronto, Canada M5S 1A8 Received 26 February 1998; revised 29 March 1998; accepted 31 March 1998 * Levo-dihydroxyphenylalanine. Anti-hyperactivity medication P Seeman and BK Madras 387

Figure 2 Biphastic action of dextroamphetamine (d- amphetamine) on mice, eliciting hypolocomotion at low doses (i.p.), but stimulating motor activity at high doses. The spontaneous motor activity was measured using Stoelting sensor activity meters. The different strains of mice, BALB/cJ, C3H/HeJ, and A/J, had been obtained from Jackson Labora- tories ( Harbor, ME, USA). The asterisks indicate loco- motor activity statistically significantly different from control (P Ͻ 0.02). Adapted from Ref. 15.

and distractibility, and high doses (or overdosage) causing sleeplessness and other symptoms of excessive central stimulation. The clinical dose2,19 range for dextroamphetamine is between 0.2 and 0.6 mg kg−1 (given twice a day), which happens to be similar to that for slowing animal locomotion, as shown in Figure 2. The dose range for methylphenidate is 0.3 mg kg−1 to 0.6 mg kg−1 2,3,20 (given twice a day), while that for pemoline is 38–150 mg per day. Pemo- line is titrated up from 19 mg day−1 to a maximum of 2mgkg−1 day−1 in adults, although for children the daily doses frequently approach or exceed Figure 1 Chemical structures of medications used clinically −1 −1 2,3 to reduce hyperactivity, and their similarity to dopamine and 3mgkg day . cocaine. Each asterisk indicates an asymmetric carbon atom which results in two chemical forms. Thus, amphetamine has Regulation of synaptic dopamine levels two forms, (+)- and (−)-, while methylphenidate has two asymmetric carbon atoms, resulting in four forms, wherein The dopamine transporter and the presynaptic recep- the mixed form (±)-threo-methylphenidate is used clinically. tors for dopamine () are two key regu- Although each stimulant contains a nitrogen atom which can lators of extracellular levels of dopamine in the synap- bond to the dopamine transporter target, Madras and col- space. The release of dopamine (into the leagues have shown that the nitrogen atom can be replaced extracellular synaptic space) from dopamine-contain- by an oxygen atom6,7 or a carbon atom (Madras et al,tobe ing neurons occurs in a pulsatile manner during nerve published) while still retaining the drug’s potency in vitro. impulses, and in a steady non-pulsatile manner during rest intervals between nerve impulses. This rise in extracellular dopamine is counteracted Clinical doses by three known mechanisms: (1) rapid diffusion of Similar to the situation outlined above for animals, the dopamine from the ; (2) of dopamine stimulant medications also elicit a biphasic action in by the dopamine transporter which is situated along humans, with low doses reducing locomotor activity the nerve ; and (3) inhibition of further Anti-hyperactivity medication P Seeman and BK Madras 388 dopamine release by extracellular action of dopamine endogenous dopamine (resting and pulsatile) and the on the dopamine autoreceptors of the . [11C]. Thus, the PET data listed in Table 1 rep- Drugs that bind to the dopamine transporter gener- resent the average net effect of elevated extracellular ally increase the extracellular level of dopamine by dopamine arising from an increase in the resting level blocking the transport of dopamine into the neuron, or of dopamine as well as in the pulsatile release of dopa- promoting the release of dopamine.21,22 For example, mine. blockade of the dopamine transporter by methylphen- Low doses of stimulant drugs increase the resting idate, or enhanced release of dopamine by dextroam- level of extracellular dopamine far more than they phetamine elevates the extracellular level of dopamine increase the nerve-impulse-associated pulsatile output to trigger a cascade of dopamine-receptor-mediated of dopamine. This conclusion comes from amperome- events. These events depend on the dose of methyl- try methods both in vitro and , using carbon fiber phenidate or dextroamphetamine and the rate of entry microelectrodes which are 6–10 ␮m wide. For of such drugs into the brain. These two important fac- example, the low dose of 0.5 mg kg−1 dextroamphetam- tors regulate the time-course of the rise in extracellular ine elevates the basal or resting level of dopamine by dopamine, and thereby determine the magnitude of the six-fold in the living rat brain,49,50 but increases the therapeutic benefit or the stimulant effects and the pulsatile or stimulated release or dopamine by only degree of abuse liability.23–26 two-fold or less51–53 (see Table 2). While increasing the spontaneous output of dopam- ine, low concentrations of dextroamphetamine can Stimulant drugs raise extracellular dopamine, but even decrease the electrically stimulated output of reduce pulsatile dopamine relative to the resting − dopamine in brain slices.54 In fact, 0.5 mg kg 1 dex- level troamphetamine given to 23 hyperactive children low- The normal resting or basal level of extracellular dopa- ered the spinal fluid level of homovanillic acid, the mine is approximately 4 nM,27–29 and transiently rises major metabolite of dopamine, by 34% in direct at least 60-fold to about 250 nM during a normal nerve relation to the clinical improvement of their hyperac- impulse. This transiently elevated level of extracellular tive syndrome.55 dopamine falls back to 4 nM, primarily by diffusion29 By raising the baseline level of extracellular dopa- but assisted by the dopamine transporter, as illustrated mine, therefore, the net effect of the low dose of the in Figure 3 (A and B). stimulant drug is to lower the relative rise in the pulsa- Dextroamphetamine22,30–33 and methylphenidate,31,34,35 tile release of dopamine, expressed as a percent rise as well as cocaine,32,33,36 all increase the level of extra- from the baseline. cellular dopamine in the dopamine-rich regions of the At low doses of stimulants, therefore, the elevated brain, as measured directly by means of intracerebral resting extracellular dopamine lowers the relative rise dialysis. (compared to baseline) in the pulsatile release of dopa- Methylphenidate and cocaine raise the extracellular mine by acting on presynaptic dopamine D2 receptors level of dopamine primarily by blocking the dopamine (on the nerve terminal) which in turn inhibits the transporter, thereby preventing the re-entry of dopam- stimulated release of additional dopamine.51,56,57 ine into the neuron.37 Although dextroamphetamine Hence, the cellular pharmacology of the stimulant (ෂ 150 nM) also inhibits the dopamine transporter, this drugs at low doses may be depicted as in Figure 3. drug directly releases dopamine.37,38 Methylphenidate Panels A and B of this figure illustrate that the normal and cocaine do not have this direct releasing action.37 resting level of extracellular dopamine (of the order of The increased output of dopamine by stimulants has 4nM27–29) transiently rises 60-fold (to about 250 nM) also been measured indirectly in human volunteers by during a normal nerve impulse.29 This transiently elev- brain PET* imaging, using the method of ligand dis- ated level of extracellular dopamine falls back to 4 nM placement from dopamine D2 receptors by endogenous in a matter of a few milliseconds, primarily by dif- dopamine.39 Such studies40–47 indicate that dextroam- fusion29 but assisted by the dopamine transporter. In phetamine40–42,45–49 appreciably elevates synaptic the presence of methylphenidate or dextroamphetam- dopamine such as to inhibit the binding of various PET ine (panels C and D), the dopamine transporter is ligands to dopamine D2 receptors by 6–48%, while blocked (step 3) and the resting extracellular level of methylphenidate43 and cocaine44 result in an inhi- dopamine rises by about 6-fold, as mentioned above. bition of about 10%, as summarized in Table 1. These In turn, the elevated resting level of dopamine acts on values indicate a considerable increase in the basal the presynaptic dopamine D2 receptors (step 4) to resting levels of dopamine in the extracellular synaptic reduce the relative rise in the impulse-triggered release space.48 However, the imaging method limits the col- of additional dopamine (step 5) to only two-fold lection of data to 30–60 s intervals, far slower than the (Table 2). rapid ms time-course of nerve-impulse-associated At higher doses of dextroamphetamine, above 1 or release of dopamine. The PET image, therefore, reflects 2mgkg−1, the magnitude of the increase markedly the time-averaged result of the competition between raises the resting level of extracellular dopamine by 14- to 35-fold,49,50,55 while raising the pulsatile output of dopamine by 7-fold.51,52 These higher doses are asso- * Positron emission tomography. ciated with generalized stimulation of the nervous sys- Anti-hyperactivity medication P Seeman and BK Madras 389

Figure 3 Cell pharmacology of stimulant drug action. (A) Normal resting level of extracellular dopamine is of the order of 4 nM.27–29 (B) The transient rise of extracellular dopamine during a normal nerve impulse returns to normal levels by diffusion and by re-uptake via the dopamine transporter. (C) In the presence of locomotor-inhibiting doses of methylphenidate or dex- troamphetamine, the dopamine transporter is blocked (step 1) and the resting extracellular level of dopamine rises about six- fold. (D) The elevated resting level of dopamine acts on presynaptic dopamine D2 receptors on the nerve terminal (step 2), resulting in an impulse-associated release of dopamine (step 3) which is less than the six-fold rise between A and C, and proportionately less than the percent rise from A to B. This lower differential rise in pulsatile dopamine acts on post-synaptic D2 dopamine receptors to result in less locomotor activity. Higher doses of stimulants markedly elevate the resting level of extracellular dopamine, and result in marked behavioral stimulation which is not overcome by the steps shown here.

Table 1 Increase in dopamine output by stimulants in humans and baboonsa

Stimulant Dose Ligand % Fall in ligand Ref.

Humans d-Amphetamine 0.3 mg kg−1 i.v. [123I]iodobenzamide 15% 32 d-Amphetamine 0.3 mg kg−1 i.v. [11C]raclopride 10–48% 33 Amphetamineb 30 mg p.o. [11C]raclopride 6–16% 34 Methylphenidate 0.5 mg kg−1 i.v. [123I]iodobenzamide 9% 35 Cocaine 48 mg i.v. [11C]raclopride 10% 36 Baboons d-Amphetamine 1 mg kg−1 i.v. [18F]N-methylspiperone 8–90% 37 d-Amphetamine 0.5–2 mg kg−1 i.v. [123I]iodobenzamide ෂ 34% h−1 38 d-Amphetamine 1 mg kg−1 i.v. [11C]raclopride 16% 39 aMeasured indirectly by the fall in ligand binding to dopamine D2 receptors in the . bAs the sulphate. Anti-hyperactivity medication P Seeman and BK Madras 390 Table 2 Extracellular levels of dopamine ated extracellular dopamine would occupy more D1 and D2 receptors during rest, reducing or desensitizing Rest During these receptors from the dopamine which arrives dur- (nM) nerve ing the nerve impulses. (One molecular mechanism of impulses such desensitization is based on the current obser- (nM) vations that dopamine receptors exist as dimers or olig- omers (to be published) which appear to behave similar Normal ෂ 427,28 ෂ 25029,28 to the interaction between oxygen and hemoglobin, d-Amphetamine ෂ 2549,50 ෂ 50051,52 −1 where the first molecule of oxygen reduces the affinity (0.5 mg kg ) of hemoglobin to bind the second molecule of oxygen.) While the steps in Figure 3 may account for the Refs 27, 49, 50 used brain microdialysis. hypolocomotor action of low doses of stimulants, high Refs 28, 29, 51, 52 used carbon fiber microelectrodes. doses of stimulants cause marked elevations in the resting and pulsatile levels of extracellular dopamine, tem, arising from the very high level of extracellular providing high enough extracellular levels of dopa- dopamine at rest and the increased release of dopamine mine to oversaturate and overstimulate postsynaptic during the nerve impulses. These high levels of resting dopamine receptors, overwhelming the presynaptic and pulsatile dopamine cause widespread stimulation inhibitory action of dopamine. These high levels are of post-synaptic dopamine receptors, overcoming the associated with hyperdopaminergic somatic, presynaptic inhibition of further dopamine release. behavioral and psychological signs and symptoms which necessitate lowering the clinical dose. Although long-term dopamine consistently The anti-hyperactivity action of stimulants is reduce the of D2 receptors,58–61 the effects of mediated via post-synaptic dopamine D1 and D2 amphetamine, methylphenidate or cocaine on the receptors density of dopamine D2 receptors depend on the As just outlined, the enhanced output of dopamine by experimental conditions used. As mentioned above in low doses of stimulant drugs reduces the impulse-asso- connection with Table 1, single doses of dextroamphet- ciated rise of dopamine, relative to the baseline. That amine, methylphenidate or cocaine increase the output is, the relative rise of dopamine during the impulse is of dopamine, thus inhibiting the binding of the benza- lowered because of this elevated baseline. mide radioligands ([123I]iodobenzamide and The smaller pulsatile surge of dopamine would [11C]raclopride) to dopamine D2 receptors62 in vivo, but result in less activation of the post-synaptic dopamine these data do not necessarily reflect changes in the den- D1 and D2 receptors, thereby resulting in reduced psy- sity of D2 receptors. chomotor activity. These psychomotor-controlling Consistent with the fact that dextroamphetamine dopamine receptors58 are hypothesized to vary their increases the output of dopamine and prolongs the response in proportion to the relative rise in pulsatile exposure and desensitization of post-synaptic dopa- dopamine, but there is not direct experimental work to mine receptors, long-term administration of dextroam- validate this particular point. For example, the elev- phetamine does lower the density of dopamine D2

Table 3 Clinical concentrations of anti-hyperactivity drugs match their dissociation constants at the dopamine transporter

Dissociation constanta, K, for inhibition of:

[3H]CFT [3H]Dopamine Clinical ([3H]WIN 35,428) uptake concentration binding (nM) in plasma (nM) at 1–3 h (nM)

Methylphenidate 3 21 21–30b d-Amphetamine 35 (35% H) 100 ෂ 150c 6900 (65% L) (−)-Cocaine 180 85 Dopamine 150 H 1700 6000 L

H: high-affinity site. L: low-affinity site. aRef 74, using human cloned dopamine transporter. bRef 76. cRef 77. Anti-hyperactivity medication P Seeman and BK Madras 391

Figure 4 The A1 and A2 variants of the dopamine D2 receptor , as cut or not cut (at position 15 700 bases) by the restriction enxyme, TaqI. This cuts the full-length gene to yield fragment A1 with 6600 bases or fragment A2 with 3700 bases.86–93 Although it is unclear whether there is an association between the frequency of these fragments and attention deficit hyperactivity syndrome,86–93 the coding region of the dopamine D2 receptor itself is identical. receptors.63 Paradoxically, however, short-term dex- extracellular dopamine, therefore, stimulant drugs troamphetamine (from 5 min to 24 h before the could alter the proportion of spare receptors, but there radioligand) actually increased the binding of [3H]spip- is no information yet on this point. erone to D2 receptors in animal brain striata.61,63–69 However, because D2 receptors can exist as monomers The occupancy of the dopamine transporter by or dimers, with -like molecules preferring the the stimulant drugs monomer,70 this apparently paradoxical rise in [3H]spi- perone binding to D2 receptors may reflect a rise in the Do the clinical concentrations of methylphenidate and density of D2 monomers following short-term exposure dextroamphetamine in plasma correspond to the con- to dextroamphetamine. Altogether, although the dopa- centrations which occupy the main clinical target for mine D1 and D2 receptors are important components these medications, the dopamine transporter? of the final path for controlling locomotor activity, Although there is a wide range of published values there is at present no clear relation between the density for the concentration of methylphenidate which occu- of dopamine receptors and the immediate clinical pies 50% of the dopamine transporter sites in native action of the stimulants. tissues in vitro,* reasonably consistent values are In addition to the density of receptors, the functional emerging from work with the cloned dopamine trans- activity of dopamine receptors must be considered. porter.74,75 At present there is only one study74 which The dopamine receptors can exist in either a state of examined all three stimulants (methylphenidate, dex- high or low affinity for dopamine.5 The high-affinity troamphetamine and cocaine) on the cloned dopamine state is the functional state for both the D1 and D2 transporter, and a summary of these data is given in receptors. Thus, by raising the extracellular level of Table 3. dopamine, the stimulants could alter the balance From a clinical point of view, it is important to note between the high- and low-affinity states. In fact, early that the plasma concentration of methylphenidate in evidence71,72 indicates that a single dose of dextroam- children at the peak action between 1 and 3 h76 closely phetamine (7.5 mg kg−1) to rodents reduces the binding matches the concentration which occupies the dopa- of [3H]dopamine to the high-affinity state of D1 recep- mine transporter,74 namely, between 20 and 30 nM, as tors (in the presence of 20 nM spiperone to occlude D2 given in Table 3. This is compatible with the view that receptors) by 30%.71 In addition, multiple injections of the dopamine transporter is the main target for the dextroamphetamine (2.5 mg kg−1 every 4 h over 5 days) clinical action of methylphenidate. results in a 27% reduction in the binding of [3H]N-pro- The situation with dextroamphetamine is generally pylnorapomorphine,72 a ligand which binds to the similar, because the clinical concentrations of dex- high-affinity states of both D1 and D2 receptors, but troamphetamine in plasma (ෂ 150 nM77) are sufficient mostly the latter. These reductions in the proportion to occupy a significant proportion of the dopamine of high-affinity states for dopamine at the D1 and D2 transporters (Table 3). receptors reflect a desensitization of these receptors. Further support that the dopamine transporter is the This process alone, however, is not sufficient to main target for the stimulant drugs comes from genetic account for a biphasic action of the stimulants on knockout experiments. Mice which are genetically behavior, unless very high concentrations of extra- bred without the dopamine transporter do not display cellular dopamine activate both the high- and low- increases in dopamine in response to cocaine.21 affinity states of dopamine receptors or alter the cycling Although such animals would presumably not exhibit between the high- and low-affinity states of the recep- tors. In addition, a proportion of post-synaptic dopamine * From 9.8–34 nM, using [3H]WIN 35,428 ([3H]CFT; Madras et al, D1 and D2 receptors may be ‘spare receptors’ and not to be published) or [3H]cocaine,24 to 1200 nM, using [3H]threo- required for the full action of dopamine. By raising the (±)-methylphenidate.73 Anti-hyperactivity medication P Seeman and BK Madras 392

Figure 5 The dopamine D4 receptor contains a variable number of repeat units in the human population, where each unit has 16 amino acids. About 60% of the North American population has four repeats (the dopamine D4.4 receptor). There is a statistically significant association between attention deficit hyperactivity disorder with the D4.7 receptor, which has seven repeats. The amino group of dopamine (in red) attaches to (labeled D), while the two hydroxyls of dopamine attach to the two serines (labeled S). Yellow: Phospholipid bilayer region of the cell membrane. Pink: Extracellular side of the membrane. Green: Cytoplasmic side of the cell membrane. A: alanine. C: cysteine. E: . F: . G: . H: histidine. I: isoleucine. K: . L: leucine. M: methionine. N: asparagine. P: . Q: glutamine. R: arginine. T: threonine. V: valine. W: . Y: .

any locomotor slowing upon administration of low Stimulant drugs and variants of transporters and doses of stimulant drugs, this has apparently not yet dopamine receptors been directly examined. In humans, moreover, the onset of clinical symptoms The human dopamine transporter has different forms with intravenous methylphenidate or cocaine parallels in different individuals wherein the transporter has the onset of occupancy of the dopamine transporter by between three and 11 copies of a 40-base unit in the tracer amounts of [11C]cocaine or [11C]methylphenid- noncoding region of the transporter.80–82 In addition, it ate;78,79 such occupancy studies have not yet been done has been reported that there is an association between using oral methylphenidate. Although these findings attention deficit hyperactivity disorder and a variant of generally support the view that stimulant drugs prim- the dopamine transporter gene.83,84 If this association arily act on the dopamine transporter, such tracer radi- is supported by additional family linkage studies, it oligands may also bind to other sites in the brain. may be possible to identify variants of the dopamine Anti-hyperactivity medication P Seeman and BK Madras 393 transporter which may have an altered sensitivity to amplitude of impulse-associated dopamine would endogenous dopamine. At present, however, no such result in less activation of post-synaptic dopamine variations in the coding sequence of the dopamine receptors which drive psychomotor activity. In transporter have been found. Whether such variants in addition, the elevated extracellular dopamine appears the dopamine transporter exist or not, the stimulant to reduce the number of D1 and D2 receptors which drugs slow down both hyperactive and control individ- are in the functional high-affinity state for dopamine. uals. Hence, there is no reason to think at present that At higher doses, stimulants produce generalized stimu- such transporter variants, should they exist in the lation of the nervous system, as a result of the very population, would have a significantly different phar- high concentrations of extracellular dopamine at rest, macology with respect to the stimulant drugs. and the markedly increased release of dopamine with Although post-synaptic dopamine D1 and D2 recep- nerve impulses. These high levels of resting and pulsa- tors are considered to be the major target for response tile dopamine cause widespread stimulation of post- to the stimulant-induced alterations in dopamine synaptic dopamine receptors, overcoming any con- release,85 it is unsettled as to whether variants of the comitant presynaptic inhibition of dopamine release. full-length gene for the dopamine D2 receptor are asso- ciated with impulsive-addictive-compulsive behav- iour.86–93 A diagram of the two variations of the full- Acknowledgements length gene for the dopamine D2 receptor is shown in Supported by Mr and Mrs Robert Peterson of The Peter- Figure 4.86 It may be seen that the single base change son Foundation (University Park, FL, USA) and NAR- is far removed from the coding region of the D2 recep- SAD (National Alliance for Research in tor itself. Hence, the stimulant pharmacology on D2 and Depression), the Ontario Mental Health Foun- would be identical for these two variants. dation, the Medical Research Council of Canada, the The dopamine D4 receptor, however, has many vari- Medland family (J Aubrey and Helen Medland, Pamela ations in the human population.94,95 One form (with and Desmond O’Rorke, Janet Marsh and David seven 16-amino-acid repeats, termed the D4.7 receptor, Medland), the National Institute on Drug Abuse, USA as illustrated in Figure 5) occurs more frequently in (NIDA DA07223; P Seeman) (NIDA DA00304, attention deficit hyperactivity disorder.96,97 There is a DA09462, DA06303; New England Regional Primate tendency for the D4.7 receptor to be slightly less sensi- Research Center RR00168; BK Madras), the Stanley tive to dopamine than the shorter D4.2 receptor,98 Foundation of the NAMI Research Institute, and Nov- although more research needs to clarify this particular artis (Sandoz Pharma Ltd), Basel, . point. If the disease linkage to the D4.7 receptor is con- firmed, if the D4.7 receptor is significantly less sensi- tive to dopamine, and if this receptor turns out to have References a central role in the action of stimulant medications, then, according to HHM Van Tol (personal communi- 1 Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliott G, cation, 1997), it may be possible to develop dopamine Greenhill LL et al. National Institute of Mental Health collaborative multimodal treatment study of children with ADHD (the MTA)— stimulants which are selective for the dopa- design challenges and choices. Arch Gen Psychiatry 1997; 54: mine D4 receptor. 865–870. Although the present review emphasizes the role of 2 Stevenson RD, Wolraich ML. Stimulant medication of chil- the dopamine system in mediating the anti-hyperactiv- dren with attention deficit hyperactivity disorder. Ped Clin North Am 1989; 36: 1183–1197. ity action of the methylphenidate and dextroampheta- 3 Wilens TE, Biederman J. 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