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Pharmacological and therapeutic directions in ADHD: Specificity in the PFC

Pharmacological and therapeutic directions in ADHD: Specificity in the PFC Background: Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA) are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. Hypothesis: The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC) and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA) stimulation (through DAT transporter inhibition) decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists) increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC), and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance and motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety, social affect, and sedation via noradrenergic transmission. Tests of the hypothesis: At a theoretical level, the advent of possible specific alpha-2A noradrenergic therapies has posed the question of the role of working memory in ADHD. Head to head comparisons of stimulant and noradrenergic alpha-2A, alpha-2B and alpha-2C agonists, utilizing vigilance and affective measures should help to clarify pharmacological and therapeutic differences. Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 ent phasic dopamine release by increasing the tonic Background Recent directions in the treatment of ADHD have stimulation of the auto-receptor. Thus subcortical down- involved both a broadening of pharmacological perspec- regulation depends on presynaptic auto-inhibition tives to include nor-adrenergic as well as dopaminergic through autoreceptors [10,11]. This mechanism is similar agents. This offers an opportunity, in conjunction with to that proposed by Seeman and Madras, who pointed out animal studies for a better understanding of the differen- that stimulants raise extracellular levels of dopamine sev- tial selectivity of these agents in the treatment of ADHD. eral-fold, but reduce the extent to which dopamine is A number of theories have been proposed for the effect of released with nerve impulses, compared with the impulse- CNS stimulants on dopaminergic (DA) transmission in associated release in the absence of the drug. However at ADHD. higher doses, stimulants are found to produce generalised stimulation of the nervous system, as a result of very high concentrations of extracellular dopamine at rest, and Theories of cognitive processing Moghaddam and Homayoun [1] have described two dis- markedly increased release of dopamine with nerve tinct patterns of cerebral cognitive processing. A modular impulses overcoming presynaptic inhibition of dopamine view is supported by animal and neurophysiological find- release [12]. ings [2-4]. A second connectionist view emphasizes paral- lel distributed neural networks [5-7]. Contemporary Volkow et al. used positron emission tomography (PET) approaches consider both types of processing relevant and to demonstrate that extracellular DA increases in propor- generally assume that modular processing is a modifica- tion to the level of DAT blockade, and the rate of DA tion of parallel computational networks. The dorsolateral release by cell firing. The latter increases were found to be PFC (dlPFC) receives extensive innervations from the greater when methylphenidate was given concomitantly mediodorsal nucleus of the thalamus and sends promi- with a salient rather than a neutral stimulus. The authors nent projections to dorsal striatum, nucleus accumbens postulated that enhanced saliency and MP motivates the and ventral tegmental area, allowing a key role in execu- improved school performance observed with methylphe- tive functions. On the other hand the orbitofrontal cortex nidate [8]. According to Volkow et al., symptoms of inat- (OFC) receives inputs from sensory associative cortices, tention have been mainly linked with striatum and particularly olfactory, gustatory, and visual areas, as well cingulate gyrus, those of hyperactivity with striatum, and as hypothalamus and amygdala. those of impulsivity with nucleus accumbens, while impairment in executive tasks is linked with the dorsola- According to Volkow et al. [8], the processing of emotion- teral prefrontal cortex [13,14]. ally salient and behaviourally adaptive information may be at the core of response-reinforcement relations. The Dopamine and working memory role of the frontal cortex, and specifically the anterior cin- Goldman-Rakic et al. investigated the pharmacological gulate gyrus (CG), in emotional processing has been dem- actions of drugs on neurons as they are engaged in cogni- onstrated in several imaging studies. Studies indicate an tive processes in awake behaving animals [15]. They have important integrative role for the OFC and CG in the anal- shown that the 'memory fields' of the prefrontal cortex are ysis of information that carries an emotive, evaluative and modulated by neurotransmitters such as dopamine serot- in the long term, survival significance for an individual onin and gamma-amino-butyric acid (GABA) in different [8]. ways [16-18]. Goldman-Rakic et al. showed that the spa- tial tuning of prefrontal neurons engaged in spatial work- ing memory was enhanced at moderate levels of Synaptic DA transmission Seeman and Madras [9] suggested that methylphenidate occupancy, and reduced at both lower and higher levels of (MP) blocks the dopamine transporter (DAT), resulting in occupancy. The specificity of drug action on single cell increased extracellular DA, activating autoreceptors and activity was thought accounted for by the specific synaptic leading to an attenuation of DA release in response to arrangement of D receptors in spines that receive excita- phasic DA firing. On the other hand, a second hypothesis tory inputs from visual pathways carrying highly proc- by Volkow et al suggests that the blocked DAT overcomes essed visuo-spatial information. The model postulated an the inhibitory effects for activation of the autoreceptors, optimal level of D receptor occupancy for efficient physi- leading to a net effect of DA accumulation in the synapse, ological signalling and optimal performance [15]. with amplification of DA signals resulting from tonic as well as phasic DA [8]. Spatial working memory has been associated with the dorsolateral PFC, while the orbital and ventromedial PFC Grace has pointed out that by interfering with dopamine allow recognition and inhibition of emotional responses, re-uptake, stimulants allow dopamine to escape the syn- important for appropriate social behaviour [19]. Gold- aptic cleft, thereby depressing subsequent spike-depend- man-Rakic and colleagues pointed out that a full under- Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 standing of the functional capacity of even a single individuals but not in schizophrenia [27]. Thus the pyramidal cell requires knowledge not only of its biophys- COMT gene (possibly in conjunction with other DA genes) may help predict DA function in the PFC. How- ical properties but its circuitry and signalling mechanisms in vivo. Thus experimental depletion of dopamine in pre- ever, genetic studies in ADHD have shown limited associ- frontal areas of rhesus monkeys has been shown to pro- ation with ADHD [28]. This may be a developmental duce impairments in working memory performance issue related to the late development of cortical PFC con- [15,20]. Furthermore Goldman-Rakic et al. [21] and nections in adolescence, with late 'turning on' of the Lidow et al. [22] have showed that the D family of COMT gene [29]. dopamine receptors are at least 20-fold more abundant than D family of receptors in the PFC. The D receptor According to Lewis and Gonzalez-Burgos, dendritic spines 2 1 was also found to be in close proximity to putative gluta- are the principal targets of excitatory synapses to pyrami- matergic axon terminals, giving rise asymmetric synapses dal neurons [30]. Excitatory connections from the medio- on the same spine. dorsal thalamus, the principal source of inputs to the dlPFC, synapse primarily on dendritic spines. Dendritic receptor in Muly et al. also studied the distribution of D spine density on dlFPC layer 3 pyramidal neurons under- GABAergic interneurons, and shown it is preferentially goes a substantial decline during adolescence in primates. found in those subtypes of interneurons which provide Activity-dependent strengthening and pruning appears to the strongest inhibitory input to the perisomatic region of underlie synapse stabilisation. It is suggested that func- cortical pyramidal cells [23]. They suggested a circuit tionally immature synapses may not be able to provide model to explain the biphasic action of D receptor stim- compensation for synaptic dysfunction prior to adoles- ulation on working memory performance and neuronal cence, because they have a very low AMPA receptor contri- delay period firing, which focuses on the interactions bution, rendering them silent at the resting memory between pyramidal and non-pyramidal neurons. The potential, and a relatively high probality of glutamate authors believe that D receptor stimulation enhances release, and thus subject to quick exhaustion of glutamate excitatory transmission to both pyramidal cells and pools after repetitive activation. It is likely that a range of interneurons, but the enhancement is more effective on factors including labour-delivery, alcohol, nicotine and pyramidal cells, because of the closer contacts with other stressors may affect the development of dlPFC cir- dopaminergic axon terminals. On pyramidal neurons, the cuitry. Dopamine is thought to exert a modulating influ- spine may act as a diffusion barrier, while on interneurons ence on the dlPFC. It is thought that prefrontal pyramidal D receptor synapses are located on the shaft allowing for neurons may directly excite mesocortical DA neurons in more diffusion of second messengers [24,25]. the ventral mesencephalon and indirectly inhibit mesotri- atal DA cells through activation of GABAergic neurons in mesencephalic cell nuclei [30]. Thus reduction in PFC cell COMT and development In humans, the catechol-O-methyltransferase (COMT) activity leads to an excess of DA receptor activation at sub- gene contains a common variation in its coding sequence, cortical nuclei. In the primate dlPFC, D1 receptors are the which translates valine (Val) to methionine (Met). At most abundant DA receptor subtype, and mediate most of room temperature the Met allele has one-fourth the the cellular effects of DA in this subtype, and mediate enzyme activity of the Val allele. It is believed that COMT most of the cellular effects of DA in this region [31]. Thus is important in the metabolism of DA in the prefrontal D1 receptors regulate sustained firing of dlPFC neurons cortex (PFC) whereas the dopamine transporter (DAT) is during the delay phase of delayed-response tasks that more important in the striatum. The Val allele associated require working memory [32,33]. DA neurons may also with high -activity COMT increases phasic and reduces have an important role in gating information loaded into tonic DA transmission sub-cortically and decreases DA working memory buffers [34-37]. concentrations cortically. This leads to an increase in D and a decrease in D receptor transmission; as a result According to Lewis and Gonzalez-Burgos, COMT is there is decreased stability of neural networks, underlying mostly an intracellular cystolic protein [38]. Therefore, working memory representations. The Met allele associ- extracellular DA must be transported through the plasma ated with low-activity COMT decreases phasic and membrane before becoming a substrate of COMT enzy- increases tonic DA transmission sub-cortically, and matic activity, raising the question of potential interaction increases DA concentrations cortically: this is associated between genetic variants of COMT and the DA trans- with increased D and decreased D transmission in the porter. However, because COMT expression levels in DA 1 2 PFC [26]. This increases the stability of networks mediat- neurons are relatively low [39,40], the availability of DA ing sustained working memory representations. A recent to be inactivated by COMT is dependent on DA transport study found a small but significant relationship between through the membrane of cortical cells that express higher Val Met genotype and executive function in healthy levels of COMT (e.g. post-synaptic neurons or glia), and Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 that may express non-specific transporters with the ability spines. This allows DA to modulate incoming informa- to uptake DA. It is thus important, according to the tion to PFC pyramidal cells [50,51]. On the other hand, authors, to note that COMT metabolises norepinephrine, supra-normal DA stimulation may impair PFC function, which heavily innervates the primate dlPFC [41] and providing an inverted-U effect. For example, Goldman- influences working memory function [42]. Rakic et al., found that the D1 message and protein in the cortex of rhesus monkeys was down-regulated by chronic Lewis and Gonzalez-Burgos [30] point out that although neuroleptic treatment, which both down-regulated D1 the interneuron depolarization and the increase in inhib- receptors and produced impairments in working memory itory currents produced by DA suggests net inhibitory performance [23]. effects in the primate dlPFC, DA also changes the response of pyramidal neurons to excitatory currents with a delayed According to Arnsten et al. electrophysiological recordings time course [32] and is consistent with other delayed D1 of PFC neurons in monkeys performing working memory receptor-mediated effects [36]. This may partly account tasks, have shown that PFC neurons are able to hold for the inverted-U dose-response effect on dlPFC firing, modality-specific information "on-line" over a delay though these effects may be complex [43] Low levels of period and use this representational information to guide DA receptor stimulation appear to selectively increase the behaviour in the absence of environmental cues. The firing of neurons that are tuned to preferred stimuli during delay-related firing is thought to arise from feed-forward tasks that require working memory [16]. microcircuits within the PFC, as cells with shared proper- ties interconnect [52]. Arnsten et al. suggest there are no drugs that distinguish between D and D receptors, and Developmental hypothesis 1 5 While an association has been proposed between DRD1 moderate levels of D /D receptor stimulation suppress 1 5 and schizophrenia, most genetic association studies in delay-related firing for non-preferred spatial directions, ADHD have been directed towards the dopamine trans- and thus enhance spatial tuning. The authors point out porter, DAT1 and the DRD4 receptor. An influential that while limited studies have been done in humans, due developmental hypothesis, the Dynamic Developmental to the lack of selective D /D compounds available for 1 5 Theory (DDT) suggested that the dopaminergic system is human use, studies with non-selective compounds sug- hypoactive in ADHD, and explains the behavioural gest that an "inverted-U" response may be evident in changes in terms of altered reinforcement and extinction humans as well as animals. They suggest that compounds processes [44]. This leaves open the question of the role of that prefer D receptors may be more helpful than D ago- 1 2 working memory in ADHD, presumably related to deficits nists in improving verbal memory [52]. in the prefrontal DRD1 system. The present developmen- tal hypothesis suggests early deficits in PFC connectivity, Alpha-2A receptor in both young children and in ADHD. In this case stimu- According to Arnsten [53], relatively high doses of alpha- lant medications may 'remediate' a deficient working 2 agonists appear to have beneficial effects on cognitive memory system, as suggested in neuropsychological stud- function, although these effects may be eroded by emerg- ies of vigilance [45,46]. ing sedative and hypotensive effects. However, Arnsten et al. [52] and Arnsten and Leslie [54] have shown that the Noradrenergic mechanisms ability of alpha-2 agonists to improve PFC function with- The above 'vigilance/working memory' hypothesis also out side effects was found to correspond with selectivity draws attention to the noradrenergic (NA) system. Opti- for the alpha-2A receptor site. A comparison between the mal prefrontal cortex function is thought to require opti- three NA alpha-2 receptors guanfacine, clonidine and mally functioning noradrenergic and dopaminergic input BHT showed guanfacine had better selectivity than cloni- to the prefrontal cortex [47,48]. A relatively recent dine, which is more selective than BHT 920. Thus open tri- approach to the treatment of ADHD has been the finding als [55-57] have shown beneficial effects of guanfacine, of beneficial effects from alpha-noradrenergic agents such including improved performance on the Continuous Per- as atomoxetine and guanfacine. The molecular genetic formance Task [58]. Arnsten suggests that NA-alpha-1 and basis for the use of noradrenergic agents has been best NA-alpha-2 receptors may have opposing effects in the reviewed by Arnsten et al. [49]. They point out that it has PFC, and that alpha-2 mechanisms may predominate been appreciated for some time that dopamine (DA) is when basal NA release is moderate, as in normal attentive necessary for proper prefrontal cortex (PFC) function, but wakening, and alpha-1 mechanisms may predominate more recently a role for noradrenergic transmission has under conditions of stress with higher levels of NA release. been appreciated. According to Arnsten et al., the role of Thus alpha-2 agonists such as guanfacine may protect PFC the D receptor family in the regulation of PFC function cognitive function during stress by preventing excessive has received particular focus, particularly as D receptors NA or DA release in the PFC [53]. are found in high concentration in the PFC on dendritic Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 Easton et al. utilised phMRI BOLD (magnetic resonance prominent increase of steady-state NMDA-evoked current imaging) contrast to image the blood oxygenation level in acutely isolated PFC pyramidal neurons, and up-regu- lation of NMDA receptor activity by dopamine D recep- dependant response in rat brain regions following admin- istration of guanfacine [59]. They postulated that activa- tors suggests reciprocal interactions between D and tion of alpha-2 receptors in the dorsolateral PFC by an NMDA receptors [65]. agonist such as guanfacine might facilitate PFC neuronal activity and in turn exert an inhibitory influence on other Arnsten et al. suggest that stimulants act to enhance the cortical areas (such as premotor and motor areas) and/or release of and/or inhibit the reuptake of both DA and NE subcortical structures (such as the striatum) that are (norepinephrine) [54]. Arnsten and Dudley [66] have involved in the control of locomotion. Time-course anal- shown that the PFC-enhancing effects of methylphenidate yses of saline vs guanfacine effects were carried out, using are prevented by blockade of either NE alpha-2 or DAD1 both fixed and random effect analyses. Random effect receptors, suggesting that stimulants facilitate endog- analysis showed that guanfacine produced positive BOLD enous stimulation of D and alpha-2A receptors in the responses in frontal areas, including the frontal associa- PFC. It is thought to increase delay-related firing and tion and secondary motor cortex and prelimbic region of strengthens the functional connectivity of microcircuits in the PFC. This is consistent with single-photon emission the PFC. In children, Scahill et al. found that immediate computed tomography (SPECT) evidence, which shows release guanfacine was rated significantly better than pla- improved cognitive performance and increased rCBF (cer- cebo by teacher-rated ADHD (37% vs 8%) and subjects ebral blood flow) values in the dorsolateral PFC following performed significantly better on a Continuous Perform- guanfacine administration to young adult rhesus mon- ance Test [67]. keys, and with human positron emission tomography (PET) data showing increased regional cerebral blood Arnsten et al. also suggest that as with DA, moderate levels flow in frontal lobes following guanfacine administra- of NE are critical for proper PFC function [54]. They sug- tion. Positive BOLD changes also occurred in the dentate gest that the majority of alpha-2 receptors are localised gyrus and CA Guanfacine produced widespread negative postsynaptically to NE terminals, and that blockade of BOLD effects in the caudate, putamen, nucleus alpha-2 receptors in the PFC of monkeys erodes delay- accumbens and entorhinal cortex, suggesting decreased related cell-firing and recreates all the symptoms of dopaminergic neuronal function in this area. ADHD, with poor impulse control, impaired working memory with underlying distractibility. Easton et al. interpreted their data as suggesting that guan- facine acts on the prefrontal cortex (probably post-synap- Wang et al. have shown that spatial working memory is tically at alpha- 2 receptors) to increase cognitive and maintained by spatially tuned recurrent excitation within associated functions, known to be dysfunctional in networks of prefrontal cortical neurons [68]. They investi- ADHD sufferers, and also helps in the regulation of loco- gated monkeys performing on an oculomotor spatial motor activity via inhibitory control of subcortical brain delayed response, which required monkeys to make a regions, particularly the caudate putamen and nucleus memory-guided saccade to a visuo-spatial target. Neurons accumbens [59]. Thus guanfacine appeared to have the recorded from area 46 of the dorsolateral PFC were iso- ability to 'turn down' striatal activity, possibly of benefit lated and subjected to iontophonetic application of phar- in the treatment of motoric hyperactivity. The investiga- macological agents. Intra-PFC administration of tors also demonstrated an intense positive BOLD effect in guanfacine was shown to significantly enhance delay- the lateral hypothalamic area, which is strongly associated related activity for the 180° location (preferred direction) with feeding behaviour, perhaps a basis of appetite or gas- in 28 out of 35 cases. Studies indicated that suppression trointestinal side effects [60,61]. of cyclic AMP impaired WM performance. According to Easton et al. the alpha-2A adrenergic receptor Wang et al suggest that cAMP (cyclic AMP) has powerful subtype appears to be the site of action of the beneficial influences on Hyperpolarisation Activated Cyclic Nucle- clinical effects of alpha-2A agonists on the prefrontal cor- otide-gated (HCN) channels that pass on h current when tex (PFC) [59]. While these receptors are localized both opened [68]. They are localised on distal pyramidal den- pre- and post- synaptically, some lines of evidence are drites and according to the authors, are co-expressed with thought to suggest that their site of action is post-synaptic the alpha-2A adrenoreceptor, thus providing a potent sub- in the PFC [62]. Thus, guanfacine has been shown to dose- stratum for functional integration in the primate PFC. In dependently prevent deficits of spatial working memory, electrophysiological studies with alpha-2A adrenorecep- suggesting a role in cognitive deficits associated with tor stimulation or cAMP inhibition, HCN channel block- NMDA receptor hypofunction [63,64]. Application of the ade enhanced spatially tuned delay-related firing of PFC D receptor agonist SKF81297 has been shown to cause a neurons. Exposure to uncontrollable stress via excessive Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 catecholamine release, high levels of D receptor stimula- whereas the role of 5-HT in probabilistic learning might tion, or by activating cAMP, has been shown to impair operate according to an inverted-U function. working memory. Under these conditions, the PFC is functionally disconnected rendering it "decorticate". The Clinical implications process may be exacerbated in patients with aberrant While clinical studies of guanfacine are limited, despite genes that regulate cAMP signaling e.g. COMT [69]. This some promising results, there has been considerable inter- co-localisation of cAMP, HCN channels and D excess est in the use of atomoxetine. Despite some encouraging stimulation effects may help to explain the cross-talk trial results, [72] anecdotal clinical reports suggest limited between DA and NE receptors in the PFC discussed below. success in some children, and there have also be concerns about suicidal ideation in a small number of patients [73]. Vijayraghavan et al. showed that dopamine D receptor This raises the question of the pharmacological actions of stimulation in PFC produced an 'inverted-U' dose- atomoxetine, which also increases extrasynaptic levels of response, whereby either too little or too much D recep- NE and DA in the PFC. tor stimulation impaired spatial working memory [69]. This response has been observed across species, including The selectivity of atomoxetine for NE effects, was investi- genetic linkages with human cognitive abilities, PFC acti- gated by Bymaster et al., utilising radioligands and micro- vation states and DA synthesis. According to the authors dialysis studies [74]. They showed that atomoxetine the cellular basis for the inverted U has long been sought, increased extracellular levels of NE in the prefrontal cortex with in vitro intracellular recordings supporting a variety 3-fold, but did not alter 5-HT levels. Atomoxetine also of potential mechanisms. Their study demonstrated that increased DA concentrations in the PFC 3-fold but did not the D receptor agonist inverted-U response was observed alter DA in nucleus accumbens or striatum. In contrast in PFC neurons of behaving monkeys: low levels of D methylphenidate increased DA and NE equally in PFC, receptor stimulation enhanced spatial tuning by suppress- but also increased DA in striatum and nucleus accumbens ing responses to non-preferred directions, whereas high to the same level. The authors suggest that atomoxetine is levels reduced delay-related firing for all directions, erod- thus less likely to have motoric or abuse liability. ing tuning. These actions of D receptor stimulation were mediated in monkeys and rats by cyclic AMP intracellular Arnsten and Li suggest that noradrenergic transmission signaling. The evidence for an inverted-U at the cellular has a vital beneficial effect on PFC function, particularly level in behaving animals promised to bridge in vitro via postsynaptic alpha-2-adrenoreceptors. Alpha -2 ago- molecular analyses with human cognitive experience. nists such as guanfacine have been shown to improve working memory performance in monkeys after direct Arnsten et al. have described three different subtypes of infusion into the dorsolateral PFC [75]. Blockade of alpha alpha-2 adrenoreceptors in humans, the alpha-2A alpha- -2 receptors with yohimbine infusion was shown to 2B and alpha-2C subtypes [54]. The alpha-2A and alpha- weaken working memory [76], and in addition to induce 2C subtypes are widely distributed in the brain, including motor hyperactivity [77]. Arnsten and Li have pointed out the PFC, the alpha-2B receptor is most concentrated in the that the PFC guides behaviour, thought and affect using thalamus. Guanfacine is thought to be the most selective working memory, and that these processes are the basis of agonist available for the alpha-2A subtype [70]. On the executive functions, including regulation of attention, other hand the sedating effects of clonidine are thought to planning and impulse control [75]. PFC function is involve the thalamus, basal forebrain and other alpha-2B thought to be fundamental in ADHD [48,49]. As outlined and alpha-2C effects. Atomoxetine, which also has sedat- above, stimulation of the D receptor within optimal lev- ing effects in some children, may also have alpha-2B and/ els improves working memory performance, while higher or alpha-2C effects [48]. levels may erode performance [78,79]. The role of D , D 2 3 and D receptors in the PFC are, according to Arnsten and A recent study by Chamberlain et al. suggested that NE is Li less well understood, though it is of interest that NA has more sensitive in modulating lateral compared to orbital high affinity for the D receptor, which may be considered PFC functioning [71]. They showed that atomoxetine (60 a catecholamine rather than a DA receptor [75]. mg single dose) improved response inhibition on a stop- signal task, but had no effect on a task requiring probabi- Interestingly, while it has been accepted in the past that listic learning. On the other hand administration of cita- the beneficial effect effects of stimulant medication were lopram (30 mg single dose) impaired probabilistic mediated by DA transmission, Arnsten and Li suggest that learning with no effect on response inhibition. The performance on PFC tasks in rats and mice on low oral authors concluded that finding that atomoxetine doses of methylphenidate may be mediated in part by the improved response inhibition in healthy volunteers alpha-2 adrenoreceptor [75]. Thus stimulants, atomoxet- implicated ascending noradrenergic systems in its control, ine and guanfacine may exert therapeutic actions via D Page 6 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 and alpha-2A receptor mechanisms, but under conditions tions used in the treatment of ADHD, with guanfacine of stress, guanfacine may be more protective [80], given likely to be most specific for the treatment of attentional that high doses of stimulants may impair cognition and deficits, while stimulants may have broader effects on induce perseverative or restricted thinking [81]. both vigilance and motor impulsivity depending on dose levels. Atomoxetine has effects on attention, social affect, Receptor specificity anxiety and sedation via noradrenergic systems. Head to Arnsten describes the PFC as using representational head comparisons utilizing both vigilance and affective knowledge, i.e. to guide overt responses as well as allow- measures, such as facial recognition may further elucidate ing inhibition of inappropriate behaviours by gating the differential effects. At a theoretical level, the advent of spe- processing of irrelevant stimuli. Studies in rats have cific noradrenergic therapies such as guanfacine, raises the shown that low oral doses of methylphenidate that pro- question of the role of working memory in the treatment duce plasma drug levels similar to therapeutic doses in of ADHD. Also suggested, is a possible aetiological role of humans, also improve PFC function, dependant on both developmental deficit or delay, at the prefrontal cortical dopamine D and NE- alpha-2 receptor stimulation [82]. level, in ADHD. Acccording to Arnsten, the enhancing effects of alpha-2A Competing interests agonists are most likely mediated through G-mediated The author declares that she has no competing interests. suppression of CAMP intracellular signaling. Blocking alpha-2 receptors in monkey PFC with yohimbine reduces Abreviations delay-related cell firing and impairs working memory, as D1 Dopamine D1 receptor: PFC Prefrontal cortex; OFC well as impulse control, recreating the profile of ADHD. Orbitofrontal cortex; In contrast excessive stimulants produce cognitive inflexi- bility through alpha 1, beta and high D1 stimulation [66]. DAT Dopamine transporter; COMT Catechol-O-methyl- transferase; It is still somewhat unclear whether DA effects in the PFC are exerted primarily through the DAD1 receptor, or NA Noradrenergic; NE Norepinephrine; alpha-2A receptor. Cornil et al have shown that dopamine activates noradrenergic receptors in the quail preoptic area MRI Magnetic Resonance Imaging; BOLD Blood oxygen [83]. They found that DA-induced inhibitions/excitations level dependent; were not blocked by selective dopaminergic receptor antagonists, but were suppressed by selective alpha- SPECT Single-photon emission computed tomography; noradrenergic antagonists (yohimbine/prasozin). While NMDA N-methyl D-aspartate; the mechanism of the cross-talk between DA and NE receptors was unclear, the relatively similar structure of CAMP Cyclic AMP; HCN Hyperpolarisation Activated DA and NE could potentially explain the binding of both Cyclic Nucleotide-gated amines to the two receptor subtypes, as could co-localisa- tion of cAMP, HCN channels and alpha-2A adrenorecep- References 1. Moghaddam B, Homayoun : Divergent plasticity of prefrontal tor [68]. Studies of transgenic mice demonstrated that the cortex networks. Neuropsychopharm 2008, 33:42-55. transporters for NE and DA lacked specificity, so that in 2. Mishkin M, Pribram K: Analysis of the effects of frontal lesions the prefrontal cortex, DA was mainly taken up by the NE in monkeys, I. J Comp Physiol Psychol 1955, 48:492-495. 3. Goldman P, Rosvold H: Localization of function within the dor- transporter [84]. The mechanisms and specificity in solateral prefrontal cortex of the rhesus monkey. 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Franowicz JS, Kessler L, Daily-Borja CM, Kobilka BK, Limbird LE, Arn- scientist can read your work free of charge sten AFT: Mutation of the alpha-2A adrenoreceptor impairs working memory performance and annuls cognitive "BioMed Central will be the most significant development for enhancement by guanfacine. Neurosci 2002, 22:8771-8777. disseminating the results of biomedical researc h in our lifetime." 71. Chamberlain SR, Muller U, Robbins TW, Sahakian B: Neurophar- Sir Paul Nurse, Cancer Research UK macological modulation of cognition (degenerative and cog- nitive diseases). Current Opin Neurol 2006, 19:607-612. Your research papers will be: 72. 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Pharmacological and therapeutic directions in ADHD: Specificity in the PFC

Behavioral and Brain Functions , Volume 4 (1) – Feb 28, 2008

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References (95)

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Springer Journals
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Copyright © 2008 by Levy; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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1744-9081
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10.1186/1744-9081-4-12
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18304369
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Abstract

Background: Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA) are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. Hypothesis: The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC) and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA) stimulation (through DAT transporter inhibition) decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists) increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC), and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance and motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety, social affect, and sedation via noradrenergic transmission. Tests of the hypothesis: At a theoretical level, the advent of possible specific alpha-2A noradrenergic therapies has posed the question of the role of working memory in ADHD. Head to head comparisons of stimulant and noradrenergic alpha-2A, alpha-2B and alpha-2C agonists, utilizing vigilance and affective measures should help to clarify pharmacological and therapeutic differences. Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 ent phasic dopamine release by increasing the tonic Background Recent directions in the treatment of ADHD have stimulation of the auto-receptor. Thus subcortical down- involved both a broadening of pharmacological perspec- regulation depends on presynaptic auto-inhibition tives to include nor-adrenergic as well as dopaminergic through autoreceptors [10,11]. This mechanism is similar agents. This offers an opportunity, in conjunction with to that proposed by Seeman and Madras, who pointed out animal studies for a better understanding of the differen- that stimulants raise extracellular levels of dopamine sev- tial selectivity of these agents in the treatment of ADHD. eral-fold, but reduce the extent to which dopamine is A number of theories have been proposed for the effect of released with nerve impulses, compared with the impulse- CNS stimulants on dopaminergic (DA) transmission in associated release in the absence of the drug. However at ADHD. higher doses, stimulants are found to produce generalised stimulation of the nervous system, as a result of very high concentrations of extracellular dopamine at rest, and Theories of cognitive processing Moghaddam and Homayoun [1] have described two dis- markedly increased release of dopamine with nerve tinct patterns of cerebral cognitive processing. A modular impulses overcoming presynaptic inhibition of dopamine view is supported by animal and neurophysiological find- release [12]. ings [2-4]. A second connectionist view emphasizes paral- lel distributed neural networks [5-7]. Contemporary Volkow et al. used positron emission tomography (PET) approaches consider both types of processing relevant and to demonstrate that extracellular DA increases in propor- generally assume that modular processing is a modifica- tion to the level of DAT blockade, and the rate of DA tion of parallel computational networks. The dorsolateral release by cell firing. The latter increases were found to be PFC (dlPFC) receives extensive innervations from the greater when methylphenidate was given concomitantly mediodorsal nucleus of the thalamus and sends promi- with a salient rather than a neutral stimulus. The authors nent projections to dorsal striatum, nucleus accumbens postulated that enhanced saliency and MP motivates the and ventral tegmental area, allowing a key role in execu- improved school performance observed with methylphe- tive functions. On the other hand the orbitofrontal cortex nidate [8]. According to Volkow et al., symptoms of inat- (OFC) receives inputs from sensory associative cortices, tention have been mainly linked with striatum and particularly olfactory, gustatory, and visual areas, as well cingulate gyrus, those of hyperactivity with striatum, and as hypothalamus and amygdala. those of impulsivity with nucleus accumbens, while impairment in executive tasks is linked with the dorsola- According to Volkow et al. [8], the processing of emotion- teral prefrontal cortex [13,14]. ally salient and behaviourally adaptive information may be at the core of response-reinforcement relations. The Dopamine and working memory role of the frontal cortex, and specifically the anterior cin- Goldman-Rakic et al. investigated the pharmacological gulate gyrus (CG), in emotional processing has been dem- actions of drugs on neurons as they are engaged in cogni- onstrated in several imaging studies. Studies indicate an tive processes in awake behaving animals [15]. They have important integrative role for the OFC and CG in the anal- shown that the 'memory fields' of the prefrontal cortex are ysis of information that carries an emotive, evaluative and modulated by neurotransmitters such as dopamine serot- in the long term, survival significance for an individual onin and gamma-amino-butyric acid (GABA) in different [8]. ways [16-18]. Goldman-Rakic et al. showed that the spa- tial tuning of prefrontal neurons engaged in spatial work- ing memory was enhanced at moderate levels of Synaptic DA transmission Seeman and Madras [9] suggested that methylphenidate occupancy, and reduced at both lower and higher levels of (MP) blocks the dopamine transporter (DAT), resulting in occupancy. The specificity of drug action on single cell increased extracellular DA, activating autoreceptors and activity was thought accounted for by the specific synaptic leading to an attenuation of DA release in response to arrangement of D receptors in spines that receive excita- phasic DA firing. On the other hand, a second hypothesis tory inputs from visual pathways carrying highly proc- by Volkow et al suggests that the blocked DAT overcomes essed visuo-spatial information. The model postulated an the inhibitory effects for activation of the autoreceptors, optimal level of D receptor occupancy for efficient physi- leading to a net effect of DA accumulation in the synapse, ological signalling and optimal performance [15]. with amplification of DA signals resulting from tonic as well as phasic DA [8]. Spatial working memory has been associated with the dorsolateral PFC, while the orbital and ventromedial PFC Grace has pointed out that by interfering with dopamine allow recognition and inhibition of emotional responses, re-uptake, stimulants allow dopamine to escape the syn- important for appropriate social behaviour [19]. Gold- aptic cleft, thereby depressing subsequent spike-depend- man-Rakic and colleagues pointed out that a full under- Page 2 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 standing of the functional capacity of even a single individuals but not in schizophrenia [27]. Thus the pyramidal cell requires knowledge not only of its biophys- COMT gene (possibly in conjunction with other DA genes) may help predict DA function in the PFC. How- ical properties but its circuitry and signalling mechanisms in vivo. Thus experimental depletion of dopamine in pre- ever, genetic studies in ADHD have shown limited associ- frontal areas of rhesus monkeys has been shown to pro- ation with ADHD [28]. This may be a developmental duce impairments in working memory performance issue related to the late development of cortical PFC con- [15,20]. Furthermore Goldman-Rakic et al. [21] and nections in adolescence, with late 'turning on' of the Lidow et al. [22] have showed that the D family of COMT gene [29]. dopamine receptors are at least 20-fold more abundant than D family of receptors in the PFC. The D receptor According to Lewis and Gonzalez-Burgos, dendritic spines 2 1 was also found to be in close proximity to putative gluta- are the principal targets of excitatory synapses to pyrami- matergic axon terminals, giving rise asymmetric synapses dal neurons [30]. Excitatory connections from the medio- on the same spine. dorsal thalamus, the principal source of inputs to the dlPFC, synapse primarily on dendritic spines. Dendritic receptor in Muly et al. also studied the distribution of D spine density on dlFPC layer 3 pyramidal neurons under- GABAergic interneurons, and shown it is preferentially goes a substantial decline during adolescence in primates. found in those subtypes of interneurons which provide Activity-dependent strengthening and pruning appears to the strongest inhibitory input to the perisomatic region of underlie synapse stabilisation. It is suggested that func- cortical pyramidal cells [23]. They suggested a circuit tionally immature synapses may not be able to provide model to explain the biphasic action of D receptor stim- compensation for synaptic dysfunction prior to adoles- ulation on working memory performance and neuronal cence, because they have a very low AMPA receptor contri- delay period firing, which focuses on the interactions bution, rendering them silent at the resting memory between pyramidal and non-pyramidal neurons. The potential, and a relatively high probality of glutamate authors believe that D receptor stimulation enhances release, and thus subject to quick exhaustion of glutamate excitatory transmission to both pyramidal cells and pools after repetitive activation. It is likely that a range of interneurons, but the enhancement is more effective on factors including labour-delivery, alcohol, nicotine and pyramidal cells, because of the closer contacts with other stressors may affect the development of dlPFC cir- dopaminergic axon terminals. On pyramidal neurons, the cuitry. Dopamine is thought to exert a modulating influ- spine may act as a diffusion barrier, while on interneurons ence on the dlPFC. It is thought that prefrontal pyramidal D receptor synapses are located on the shaft allowing for neurons may directly excite mesocortical DA neurons in more diffusion of second messengers [24,25]. the ventral mesencephalon and indirectly inhibit mesotri- atal DA cells through activation of GABAergic neurons in mesencephalic cell nuclei [30]. Thus reduction in PFC cell COMT and development In humans, the catechol-O-methyltransferase (COMT) activity leads to an excess of DA receptor activation at sub- gene contains a common variation in its coding sequence, cortical nuclei. In the primate dlPFC, D1 receptors are the which translates valine (Val) to methionine (Met). At most abundant DA receptor subtype, and mediate most of room temperature the Met allele has one-fourth the the cellular effects of DA in this subtype, and mediate enzyme activity of the Val allele. It is believed that COMT most of the cellular effects of DA in this region [31]. Thus is important in the metabolism of DA in the prefrontal D1 receptors regulate sustained firing of dlPFC neurons cortex (PFC) whereas the dopamine transporter (DAT) is during the delay phase of delayed-response tasks that more important in the striatum. The Val allele associated require working memory [32,33]. DA neurons may also with high -activity COMT increases phasic and reduces have an important role in gating information loaded into tonic DA transmission sub-cortically and decreases DA working memory buffers [34-37]. concentrations cortically. This leads to an increase in D and a decrease in D receptor transmission; as a result According to Lewis and Gonzalez-Burgos, COMT is there is decreased stability of neural networks, underlying mostly an intracellular cystolic protein [38]. Therefore, working memory representations. The Met allele associ- extracellular DA must be transported through the plasma ated with low-activity COMT decreases phasic and membrane before becoming a substrate of COMT enzy- increases tonic DA transmission sub-cortically, and matic activity, raising the question of potential interaction increases DA concentrations cortically: this is associated between genetic variants of COMT and the DA trans- with increased D and decreased D transmission in the porter. However, because COMT expression levels in DA 1 2 PFC [26]. This increases the stability of networks mediat- neurons are relatively low [39,40], the availability of DA ing sustained working memory representations. A recent to be inactivated by COMT is dependent on DA transport study found a small but significant relationship between through the membrane of cortical cells that express higher Val Met genotype and executive function in healthy levels of COMT (e.g. post-synaptic neurons or glia), and Page 3 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 that may express non-specific transporters with the ability spines. This allows DA to modulate incoming informa- to uptake DA. It is thus important, according to the tion to PFC pyramidal cells [50,51]. On the other hand, authors, to note that COMT metabolises norepinephrine, supra-normal DA stimulation may impair PFC function, which heavily innervates the primate dlPFC [41] and providing an inverted-U effect. For example, Goldman- influences working memory function [42]. Rakic et al., found that the D1 message and protein in the cortex of rhesus monkeys was down-regulated by chronic Lewis and Gonzalez-Burgos [30] point out that although neuroleptic treatment, which both down-regulated D1 the interneuron depolarization and the increase in inhib- receptors and produced impairments in working memory itory currents produced by DA suggests net inhibitory performance [23]. effects in the primate dlPFC, DA also changes the response of pyramidal neurons to excitatory currents with a delayed According to Arnsten et al. electrophysiological recordings time course [32] and is consistent with other delayed D1 of PFC neurons in monkeys performing working memory receptor-mediated effects [36]. This may partly account tasks, have shown that PFC neurons are able to hold for the inverted-U dose-response effect on dlPFC firing, modality-specific information "on-line" over a delay though these effects may be complex [43] Low levels of period and use this representational information to guide DA receptor stimulation appear to selectively increase the behaviour in the absence of environmental cues. The firing of neurons that are tuned to preferred stimuli during delay-related firing is thought to arise from feed-forward tasks that require working memory [16]. microcircuits within the PFC, as cells with shared proper- ties interconnect [52]. Arnsten et al. suggest there are no drugs that distinguish between D and D receptors, and Developmental hypothesis 1 5 While an association has been proposed between DRD1 moderate levels of D /D receptor stimulation suppress 1 5 and schizophrenia, most genetic association studies in delay-related firing for non-preferred spatial directions, ADHD have been directed towards the dopamine trans- and thus enhance spatial tuning. The authors point out porter, DAT1 and the DRD4 receptor. An influential that while limited studies have been done in humans, due developmental hypothesis, the Dynamic Developmental to the lack of selective D /D compounds available for 1 5 Theory (DDT) suggested that the dopaminergic system is human use, studies with non-selective compounds sug- hypoactive in ADHD, and explains the behavioural gest that an "inverted-U" response may be evident in changes in terms of altered reinforcement and extinction humans as well as animals. They suggest that compounds processes [44]. This leaves open the question of the role of that prefer D receptors may be more helpful than D ago- 1 2 working memory in ADHD, presumably related to deficits nists in improving verbal memory [52]. in the prefrontal DRD1 system. The present developmen- tal hypothesis suggests early deficits in PFC connectivity, Alpha-2A receptor in both young children and in ADHD. In this case stimu- According to Arnsten [53], relatively high doses of alpha- lant medications may 'remediate' a deficient working 2 agonists appear to have beneficial effects on cognitive memory system, as suggested in neuropsychological stud- function, although these effects may be eroded by emerg- ies of vigilance [45,46]. ing sedative and hypotensive effects. However, Arnsten et al. [52] and Arnsten and Leslie [54] have shown that the Noradrenergic mechanisms ability of alpha-2 agonists to improve PFC function with- The above 'vigilance/working memory' hypothesis also out side effects was found to correspond with selectivity draws attention to the noradrenergic (NA) system. Opti- for the alpha-2A receptor site. A comparison between the mal prefrontal cortex function is thought to require opti- three NA alpha-2 receptors guanfacine, clonidine and mally functioning noradrenergic and dopaminergic input BHT showed guanfacine had better selectivity than cloni- to the prefrontal cortex [47,48]. A relatively recent dine, which is more selective than BHT 920. Thus open tri- approach to the treatment of ADHD has been the finding als [55-57] have shown beneficial effects of guanfacine, of beneficial effects from alpha-noradrenergic agents such including improved performance on the Continuous Per- as atomoxetine and guanfacine. The molecular genetic formance Task [58]. Arnsten suggests that NA-alpha-1 and basis for the use of noradrenergic agents has been best NA-alpha-2 receptors may have opposing effects in the reviewed by Arnsten et al. [49]. They point out that it has PFC, and that alpha-2 mechanisms may predominate been appreciated for some time that dopamine (DA) is when basal NA release is moderate, as in normal attentive necessary for proper prefrontal cortex (PFC) function, but wakening, and alpha-1 mechanisms may predominate more recently a role for noradrenergic transmission has under conditions of stress with higher levels of NA release. been appreciated. According to Arnsten et al., the role of Thus alpha-2 agonists such as guanfacine may protect PFC the D receptor family in the regulation of PFC function cognitive function during stress by preventing excessive has received particular focus, particularly as D receptors NA or DA release in the PFC [53]. are found in high concentration in the PFC on dendritic Page 4 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 Easton et al. utilised phMRI BOLD (magnetic resonance prominent increase of steady-state NMDA-evoked current imaging) contrast to image the blood oxygenation level in acutely isolated PFC pyramidal neurons, and up-regu- lation of NMDA receptor activity by dopamine D recep- dependant response in rat brain regions following admin- istration of guanfacine [59]. They postulated that activa- tors suggests reciprocal interactions between D and tion of alpha-2 receptors in the dorsolateral PFC by an NMDA receptors [65]. agonist such as guanfacine might facilitate PFC neuronal activity and in turn exert an inhibitory influence on other Arnsten et al. suggest that stimulants act to enhance the cortical areas (such as premotor and motor areas) and/or release of and/or inhibit the reuptake of both DA and NE subcortical structures (such as the striatum) that are (norepinephrine) [54]. Arnsten and Dudley [66] have involved in the control of locomotion. Time-course anal- shown that the PFC-enhancing effects of methylphenidate yses of saline vs guanfacine effects were carried out, using are prevented by blockade of either NE alpha-2 or DAD1 both fixed and random effect analyses. Random effect receptors, suggesting that stimulants facilitate endog- analysis showed that guanfacine produced positive BOLD enous stimulation of D and alpha-2A receptors in the responses in frontal areas, including the frontal associa- PFC. It is thought to increase delay-related firing and tion and secondary motor cortex and prelimbic region of strengthens the functional connectivity of microcircuits in the PFC. This is consistent with single-photon emission the PFC. In children, Scahill et al. found that immediate computed tomography (SPECT) evidence, which shows release guanfacine was rated significantly better than pla- improved cognitive performance and increased rCBF (cer- cebo by teacher-rated ADHD (37% vs 8%) and subjects ebral blood flow) values in the dorsolateral PFC following performed significantly better on a Continuous Perform- guanfacine administration to young adult rhesus mon- ance Test [67]. keys, and with human positron emission tomography (PET) data showing increased regional cerebral blood Arnsten et al. also suggest that as with DA, moderate levels flow in frontal lobes following guanfacine administra- of NE are critical for proper PFC function [54]. They sug- tion. Positive BOLD changes also occurred in the dentate gest that the majority of alpha-2 receptors are localised gyrus and CA Guanfacine produced widespread negative postsynaptically to NE terminals, and that blockade of BOLD effects in the caudate, putamen, nucleus alpha-2 receptors in the PFC of monkeys erodes delay- accumbens and entorhinal cortex, suggesting decreased related cell-firing and recreates all the symptoms of dopaminergic neuronal function in this area. ADHD, with poor impulse control, impaired working memory with underlying distractibility. Easton et al. interpreted their data as suggesting that guan- facine acts on the prefrontal cortex (probably post-synap- Wang et al. have shown that spatial working memory is tically at alpha- 2 receptors) to increase cognitive and maintained by spatially tuned recurrent excitation within associated functions, known to be dysfunctional in networks of prefrontal cortical neurons [68]. They investi- ADHD sufferers, and also helps in the regulation of loco- gated monkeys performing on an oculomotor spatial motor activity via inhibitory control of subcortical brain delayed response, which required monkeys to make a regions, particularly the caudate putamen and nucleus memory-guided saccade to a visuo-spatial target. Neurons accumbens [59]. Thus guanfacine appeared to have the recorded from area 46 of the dorsolateral PFC were iso- ability to 'turn down' striatal activity, possibly of benefit lated and subjected to iontophonetic application of phar- in the treatment of motoric hyperactivity. The investiga- macological agents. Intra-PFC administration of tors also demonstrated an intense positive BOLD effect in guanfacine was shown to significantly enhance delay- the lateral hypothalamic area, which is strongly associated related activity for the 180° location (preferred direction) with feeding behaviour, perhaps a basis of appetite or gas- in 28 out of 35 cases. Studies indicated that suppression trointestinal side effects [60,61]. of cyclic AMP impaired WM performance. According to Easton et al. the alpha-2A adrenergic receptor Wang et al suggest that cAMP (cyclic AMP) has powerful subtype appears to be the site of action of the beneficial influences on Hyperpolarisation Activated Cyclic Nucle- clinical effects of alpha-2A agonists on the prefrontal cor- otide-gated (HCN) channels that pass on h current when tex (PFC) [59]. While these receptors are localized both opened [68]. They are localised on distal pyramidal den- pre- and post- synaptically, some lines of evidence are drites and according to the authors, are co-expressed with thought to suggest that their site of action is post-synaptic the alpha-2A adrenoreceptor, thus providing a potent sub- in the PFC [62]. Thus, guanfacine has been shown to dose- stratum for functional integration in the primate PFC. In dependently prevent deficits of spatial working memory, electrophysiological studies with alpha-2A adrenorecep- suggesting a role in cognitive deficits associated with tor stimulation or cAMP inhibition, HCN channel block- NMDA receptor hypofunction [63,64]. Application of the ade enhanced spatially tuned delay-related firing of PFC D receptor agonist SKF81297 has been shown to cause a neurons. Exposure to uncontrollable stress via excessive Page 5 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 catecholamine release, high levels of D receptor stimula- whereas the role of 5-HT in probabilistic learning might tion, or by activating cAMP, has been shown to impair operate according to an inverted-U function. working memory. Under these conditions, the PFC is functionally disconnected rendering it "decorticate". The Clinical implications process may be exacerbated in patients with aberrant While clinical studies of guanfacine are limited, despite genes that regulate cAMP signaling e.g. COMT [69]. This some promising results, there has been considerable inter- co-localisation of cAMP, HCN channels and D excess est in the use of atomoxetine. Despite some encouraging stimulation effects may help to explain the cross-talk trial results, [72] anecdotal clinical reports suggest limited between DA and NE receptors in the PFC discussed below. success in some children, and there have also be concerns about suicidal ideation in a small number of patients [73]. Vijayraghavan et al. showed that dopamine D receptor This raises the question of the pharmacological actions of stimulation in PFC produced an 'inverted-U' dose- atomoxetine, which also increases extrasynaptic levels of response, whereby either too little or too much D recep- NE and DA in the PFC. tor stimulation impaired spatial working memory [69]. This response has been observed across species, including The selectivity of atomoxetine for NE effects, was investi- genetic linkages with human cognitive abilities, PFC acti- gated by Bymaster et al., utilising radioligands and micro- vation states and DA synthesis. According to the authors dialysis studies [74]. They showed that atomoxetine the cellular basis for the inverted U has long been sought, increased extracellular levels of NE in the prefrontal cortex with in vitro intracellular recordings supporting a variety 3-fold, but did not alter 5-HT levels. Atomoxetine also of potential mechanisms. Their study demonstrated that increased DA concentrations in the PFC 3-fold but did not the D receptor agonist inverted-U response was observed alter DA in nucleus accumbens or striatum. In contrast in PFC neurons of behaving monkeys: low levels of D methylphenidate increased DA and NE equally in PFC, receptor stimulation enhanced spatial tuning by suppress- but also increased DA in striatum and nucleus accumbens ing responses to non-preferred directions, whereas high to the same level. The authors suggest that atomoxetine is levels reduced delay-related firing for all directions, erod- thus less likely to have motoric or abuse liability. ing tuning. These actions of D receptor stimulation were mediated in monkeys and rats by cyclic AMP intracellular Arnsten and Li suggest that noradrenergic transmission signaling. The evidence for an inverted-U at the cellular has a vital beneficial effect on PFC function, particularly level in behaving animals promised to bridge in vitro via postsynaptic alpha-2-adrenoreceptors. Alpha -2 ago- molecular analyses with human cognitive experience. nists such as guanfacine have been shown to improve working memory performance in monkeys after direct Arnsten et al. have described three different subtypes of infusion into the dorsolateral PFC [75]. Blockade of alpha alpha-2 adrenoreceptors in humans, the alpha-2A alpha- -2 receptors with yohimbine infusion was shown to 2B and alpha-2C subtypes [54]. The alpha-2A and alpha- weaken working memory [76], and in addition to induce 2C subtypes are widely distributed in the brain, including motor hyperactivity [77]. Arnsten and Li have pointed out the PFC, the alpha-2B receptor is most concentrated in the that the PFC guides behaviour, thought and affect using thalamus. Guanfacine is thought to be the most selective working memory, and that these processes are the basis of agonist available for the alpha-2A subtype [70]. On the executive functions, including regulation of attention, other hand the sedating effects of clonidine are thought to planning and impulse control [75]. PFC function is involve the thalamus, basal forebrain and other alpha-2B thought to be fundamental in ADHD [48,49]. As outlined and alpha-2C effects. Atomoxetine, which also has sedat- above, stimulation of the D receptor within optimal lev- ing effects in some children, may also have alpha-2B and/ els improves working memory performance, while higher or alpha-2C effects [48]. levels may erode performance [78,79]. The role of D , D 2 3 and D receptors in the PFC are, according to Arnsten and A recent study by Chamberlain et al. suggested that NE is Li less well understood, though it is of interest that NA has more sensitive in modulating lateral compared to orbital high affinity for the D receptor, which may be considered PFC functioning [71]. They showed that atomoxetine (60 a catecholamine rather than a DA receptor [75]. mg single dose) improved response inhibition on a stop- signal task, but had no effect on a task requiring probabi- Interestingly, while it has been accepted in the past that listic learning. On the other hand administration of cita- the beneficial effect effects of stimulant medication were lopram (30 mg single dose) impaired probabilistic mediated by DA transmission, Arnsten and Li suggest that learning with no effect on response inhibition. The performance on PFC tasks in rats and mice on low oral authors concluded that finding that atomoxetine doses of methylphenidate may be mediated in part by the improved response inhibition in healthy volunteers alpha-2 adrenoreceptor [75]. Thus stimulants, atomoxet- implicated ascending noradrenergic systems in its control, ine and guanfacine may exert therapeutic actions via D Page 6 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2008, 4:12 http://www.behavioralandbrainfunctions.com/content/4/1/12 and alpha-2A receptor mechanisms, but under conditions tions used in the treatment of ADHD, with guanfacine of stress, guanfacine may be more protective [80], given likely to be most specific for the treatment of attentional that high doses of stimulants may impair cognition and deficits, while stimulants may have broader effects on induce perseverative or restricted thinking [81]. both vigilance and motor impulsivity depending on dose levels. Atomoxetine has effects on attention, social affect, Receptor specificity anxiety and sedation via noradrenergic systems. Head to Arnsten describes the PFC as using representational head comparisons utilizing both vigilance and affective knowledge, i.e. to guide overt responses as well as allow- measures, such as facial recognition may further elucidate ing inhibition of inappropriate behaviours by gating the differential effects. At a theoretical level, the advent of spe- processing of irrelevant stimuli. Studies in rats have cific noradrenergic therapies such as guanfacine, raises the shown that low oral doses of methylphenidate that pro- question of the role of working memory in the treatment duce plasma drug levels similar to therapeutic doses in of ADHD. Also suggested, is a possible aetiological role of humans, also improve PFC function, dependant on both developmental deficit or delay, at the prefrontal cortical dopamine D and NE- alpha-2 receptor stimulation [82]. level, in ADHD. Acccording to Arnsten, the enhancing effects of alpha-2A Competing interests agonists are most likely mediated through G-mediated The author declares that she has no competing interests. suppression of CAMP intracellular signaling. Blocking alpha-2 receptors in monkey PFC with yohimbine reduces Abreviations delay-related cell firing and impairs working memory, as D1 Dopamine D1 receptor: PFC Prefrontal cortex; OFC well as impulse control, recreating the profile of ADHD. Orbitofrontal cortex; In contrast excessive stimulants produce cognitive inflexi- bility through alpha 1, beta and high D1 stimulation [66]. DAT Dopamine transporter; COMT Catechol-O-methyl- transferase; It is still somewhat unclear whether DA effects in the PFC are exerted primarily through the DAD1 receptor, or NA Noradrenergic; NE Norepinephrine; alpha-2A receptor. Cornil et al have shown that dopamine activates noradrenergic receptors in the quail preoptic area MRI Magnetic Resonance Imaging; BOLD Blood oxygen [83]. They found that DA-induced inhibitions/excitations level dependent; were not blocked by selective dopaminergic receptor antagonists, but were suppressed by selective alpha- SPECT Single-photon emission computed tomography; noradrenergic antagonists (yohimbine/prasozin). 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Michelson D, Faires D, Wernicke J, Kelsey D, Kendrick K, Sallee R, available free of charge to the entire biomedical community Spenser T: Atomoxetine in the treatment of children and ado- lescents with Attention-Deficit/Hyperactivity Disorder: A peer reviewed and published immediately upon acceptance randomised placebo-controlled dose response study. Pediatr cited in PubMed and archived on PubMed Central 2001, 108:E83. 73. Bangs MS, Tauscher-Wisniewski S, Polzer J, et al.: Meta-analysis of yours — you keep the copyright suicide-related events in atomoxetine-treated patients. Pre- BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 9 of 9 (page number not for citation purposes)

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