the cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex

ogicalchiatry
Review Biol
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The Cognition-Enhancing Effects ofPsychostimulants Involve Direct Action in thePrefrontal CortexRobert C. Spencer, David M. Devilbiss, and Craig W. Berridge

ABSTRACTPsychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. The clinical efficacyof these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) andextended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses.Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulantshas only recently been systematically investigated. Findings from this research unambiguously demonstrate that thecognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC andthe subsequent activation of norepinephrine α2 and dopamine D1 receptors. In contrast, while the striatum is acritical participant in PFC-dependent cognition, where examined, psychostimulant action within the striatum is notsufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear toimprove PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g., workingmemory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to beassociated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidenceindicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemicalactions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependentfunction). This information has potentially important clinical implications as well as relevance for public health policyregarding the widespread clinical use of psychostimulants and for the development of novel pharmacologictreatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.

Keywords: ADHD, Cognition, Dopamine, Norepinephrine, Prefrontal cortex, Stimulants

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http://dx.doi.org/10.1016/j.biopsych.2014.09.013

Psychostimulants elicit potent arousing, behaviorally activat-ing, and reinforcing actions that are associated with significantpotential for abuse (1–6). Nonetheless, these drugs are highlyeffective in treating hyperactivity, impulsivity, and inattentionassociated with attention-deficit/hyperactivity disorder (ADHD)(7–10). Given these apparently contradictory actions, it wasinitially proposed that psychostimulants acted paradoxically inindividuals with ADHD: calming, rather than activating, behav-ior. This paradoxical hypothesis strongly influenced clinicaland basic science research into the neurobiology and phar-macology of ADHD.

A major breakthrough in our understanding of psychosti-mulant action was the demonstration in 1980 that thecognition-enhancing and behavioral-calming actions of psy-chostimulants are not unique to ADHD, with similar effectsseen in healthy human subjects (11). This and subsequentstudies unambiguously demonstrated that when used at lowand clinically relevant doses, psychostimulants improve pre-frontal cortex (PFC)-dependent behavioral/cognitive proc-esses in human subjects with and without ADHD (11–15).This ability of psychostimulants to act as cognitive enhancersdrives the recent growth in use of these drugs by the general

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SEE COMMENTA

population to improve academic and work-related perform-ance (16–18). Low-dose psychostimulant improvement inPFC-dependent function is consistent with evidence indicatingADHD involves dysregulation of the PFC and extendedfrontostriatal circuitry (19–22). Moreover, the procognitiveactions of psychostimulants are also observed in normalanimal subjects (5,6,23,24) (Figure 1), indicating an animalmodel of ADHD is not required to study the neural mecha-nisms underlying the cognition-enhancing/therapeutic effectsof psychostimulants. This is an important advantage giventhere are no animal models known to definitively mimic theneurobiology of ADHD.

Collectively, these observations indicate that the neuralmechanisms responsible for the therapeutic/cognition-enhancing effects of low-dose psychostimulants cannot beextrapolated from actions of higher doses that exert opposingbehavioral and cognitive effects. Over the past 10 years,correlative evidence has suggested the hypothesis that thePFC is a key site in the cognition-enhancing actions ofpsychostimulants [for review, (25,26)]. More recent workprovides critical, causal evidence for a role of the PFC in thecognition-enhancing effects of psychostimulants. In the

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Figure 1. Behavioral-calming andcognition-enhancing actions of clini-cally relevant doses of methylpheni-date (MPH) in rats. (A) Lack oflocomotor activation. Bars indicatemotor counts (quadrant entries 1

rears) in the 90-minute period fol-lowing subcutaneous treatment withvehicle (VEH) or varying doses ofMPH (.5, 1.0, 2.0, and 4.0 mg/kg)during the light (inactive) phase ofthe circadian cycle in rats (i.e., underlow arousal conditions). Doses thatproduce clinically relevant plasmaconcentrations (.5, 1.0 mg/kg) donot elicit significant locomotor acti-vation. Higher doses elicit dose-dependent increases in locomotoractivity. The 4.0 mg/kg dose wasperithreshold for eliciting mildstereotypy. (B) Motoric calming.When tested under conditions asso-ciated with elevated motor activity(during the dark/active phase), clini-cally relevant doses of oral MPH(1.0, 3.0 mg/kg) suppressed motoractivity, similar to that seen in atten-tion-deficit/hyperactivity disorderpatients. (C, D) Cognition enhance-ment. When administered in dosesthat elicit clinically relevant plasmaconcentrations, .5 mg/kg intraperi-toneally (I.P.) (C) or 2.0 mg/kg orally(D) administered MPH improvesworking memory performance asmeasured by percent change frombaseline performance in a delayed-

response test of working memory (T-maze). Fourfold higher doses impair or do not improve performance. All bars indicate mean 6 SEM. *p , .05, **p , .01compared with vehicle-treated animals. [Modified with permission from Devilbiss and Berridge (6), Berridge et al. (24), and Kuczenski and Segal (33).]

Psychostimulant Cognitive Enhancement: Role of the PFCBiologicalPsychiatry

following sections, we review the collective body of researchon the neurobiology of clinically relevant and procognitivedoses of psychostimulants.

CLINICALLY RELEVANT DOSES OFPSYCHOSTIMULANTS ELEVATE CATECHOLAMINESIGNALING PREFERENTIALLY IN THE PFC

The two most commonly used psychostimulants in the treat-ment of ADHD are methylphenidate (MPH) (e.g., Ritalin) andamphetamine (e.g., Adderall). At behaviorally activating doses,these drugs potently increase extracellular levels of norepi-nephrine (NE) and dopamine (DA) throughout the brain, largelyby blocking NE and DA reuptake (27,28). Some psychostimu-lants, particularly amphetamine, actively stimulate DA effluxthrough the DA transporter (29). Although amphetamine canalso stimulate NE efflux and block serotonin reuptake, theseactions only occur at high and clinically inappropriate doses(30). In contrast, MPH acts only to block NE and DA reuptake,neither inhibiting serotonin reuptake nor stimulating NE or DAefflux (31).

Early animal studies demonstrated a central role of DAacting in the striatal subregion, the nucleus accumbens(NAcc), in the motor activating and reinforcing effects of higherdoses of psychostimulants. Based on this, the early clinical

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literature emphasized the potential role of NAcc DA in thetherapeutic effects of psychostimulants. However, given low,clinically relevant doses of psychostimulants exert qualitativelydifferent behavioral effects versus higher, behaviorally activat-ing doses, the neurobiology of higher doses may not havestrong translational relevance. However, to study the clinicallyrelevant actions of psychostimulants in animals, it is essentialto identify doses that model clinical use. Pharmacokineticstudies identified doses of MPH in animals that elicit plasmaconcentrations associated with clinical efficacy in humans(�10–40 ng/mL) (23,24,32,33). In rats, clinically relevantplasma levels are seen following 1.0 to 3.0 mg/kg MPH givenorally and .25 to 1.0 mg/kg MPH administered intraperitoneally(24,32,33). At these doses, MPH is largely devoid of behav-iorally activating or arousing actions (24,32,33) (Figure 1).Moreover, under conditions associated with elevated locomo-tor activity, these clinically relevant doses of MPH suppressmotor activity, similar to that seen in ADHD (33) (Figure 1).Finally, these doses of MPH improve PFC-dependentcognition (working memory, sustained attention), similar tothat seen in humans (5,24,34) (Figure 1). The behavioral/cognitive effects of low and clinically relevant doses contrastwith the motor-activating, arousal-promoting, and cognition-impairing actions associated with abuse-related doses ofpsychostimulants.

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Figure 2. Clinically relevant doses of methylphenidate (MPH) preferentially increase extracellular catecholamines within the prefrontal cortex (PFC). (A–C)Shown are the mean 6 SEM catecholamine levels expressed as a percentage of baseline (6 SEM) values in 16-minute microdialysis samples collected before(negative numbers) and after (positive numbers) injection of vehicle (VEH) or MPH. Clinically relevant doses of MPH administered orally (A) (2.0 mg/kg) orintraperitoneally (I.P.) (B) (.5 mg/kg) elicited large increases in extracellular dopamine (DA) within the PFC relative to that seen in the nucleus accumbens(NAcc). (C) Similarly, for norepinephrine (NE), intraperitoneal administration of .5 mg/kg MPH elicited a large increase in extracellular NE in the PFC with littlechange in the medial septal area (MSA). For both DA and NE, although clinically relevant doses of MPH elicit smaller effects outside the PFC, these effects arenonetheless statistically significant relative to both baseline and vehicle-treated animals. (D) Bars represent effects of .5 mg/kg MPH intraperitoneallyexpressed as a % change from vehicle-treated animals (mean 6 SEM) for DA and NE over a 30-minute period beginning at 15 minutes posttreatment. *p ,

.05, **p , .01 compared with vehicle-treated animals. #p , .01 relative to PFC DA. [Reproduced with permission from Berridge et al. (24).]


Microdialysis studies demonstrate that clinically relevantdoses of MPH elicit prominent increases in extracellular NEand DA within the PFC (100% to 250%) (Figure 2). In contrast,substantially smaller effects are observed on DA levels in theNAcc and NE levels in the medial septum, regions associatedwith psychostimulant-induced motor activation and arousal,respectively (24,32,33,35–39) (Figure 2). As with the cognitiveeffects of MPH (6,24), the preferential targeting of PFCcatecholamines is not dependent on route of administration,as long as dose is adjusted to yield similar plasma concen-trations (24). These doses of MPH increase hippocampal andsomatosensory cortical NE levels similar to that seen in themedial septal area (32,33,40), indicating the greater sensitivityof PFC catecholamines reflects a relatively unique aspect ofPFC physiology (32,33,40).

The modest actions of low-dose psychostimulants onextracellular catecholamines in subcortical regions associatedwith motor activation (e.g., accumbens) and arousal (e.g.,medial septum) appear to explain why, clinically, psychosti-mulants are devoid of the prototypical behavioral-activatingand arousal-enhancing effects of psychostimulants. Moreover,

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the fact that low-dose psychostimulants do not increase, andmay reduce, drug abuse in ADHD patients (41,42) is consistentwith a relatively modest impact of clinically relevant doses onneural circuitry posited to underlie drug abuse (e.g., NAcc DA)(39).

POTENTIAL MECHANISMS UNDERLYING THEPREFERENTIAL SENSITIVITY OF PFCCATECHOLAMINES

The above-described studies fail to identify the circuit mech-anisms associated with the preferential sensitivity of PFCcatecholamines. Recent studies using reverse microdialysisdemonstrate that when infused in low concentrations, MPHelicits significantly larger increases in extracellular NE and DAin the PFC relative to the medial septum or NAcc (43)(Figure 3). This selectivity for the PFC disappeared with higherconcentrations of MPH, similar to that seen with systemicadministration (24,31). These observations demonstrate thatthe enhanced sensitivity of PFC catecholamines reflects, atleast in part, an intrinsic property of the PFC.

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Figure 3. Pre-ferential sensitivityof prefrontal cortex(PFC) catechola-mines involves localmechanisms. Lo-cally administeredmethylphenidate(MPH) increasesdopamine (DA) andnorepinephrine (NE)preferentially withinthe prefrontal cor-tex. Shown are the

effects of local application of 1.0 mmol/L MPH on extracellular levels of DA andNE within the PFC, nucleus accumbens (NAcc), and medial septal area (MSA).Data are an average (6 SEM) of three 30-minute samples following MPHapplication and are expressed as percent above baseline. At this concentration,MPH produced only modest increases in DA and NE levels (�50% to 60%) insubcortical regions (NAcc and MSA), while eliciting significantly larger increasesin DA and NE levels (�100% to 120%) within the PFC. A similar pattern ofeffects is seen with systemic administration of clinically relevant doses of MPH(Figure 2). *p , .05 relative to NAcc DA and 1p , .05 relative to MSA NE.[Reproduced with permission from Schmeichel and Berridge (43).]

Figure 4. Similar neurochemical actions in the prefrontal cortex (PFC) of aselective norepinephrine reuptake inhibitor (SNRI) and a selective dopaminereuptake inhibitor (SDRI). Shown are the mean (6 SEM) change in extra-cellular norepinephrine (NE) in the PFC and extracellular dopamine (DA) in thePFC and nucleus accumbens (NAcc) expressed as a percent change frombaseline. Data are shown for 30-minute samples collected before (negativenumbers) and following (positive numbers) systemic treatment with either (A)the selective NE inhibitor (SNRI), atomoxetine (3 mg/kg) or (B) the selectiveDA inhibitor (SDRI), AHN 2005 (10 mg/kg). At these doses, these drugs exertcognition-enhancing effects. (A) The SNRI elicited similar increases inextracellular levels of both NE and DA (�150% above baseline), while havingno effect on DA within the NAcc. (B) The SDRI also elicited significantincreases in both extracellular DA and NE in the PFC that were comparable inmagnitude (�100% above baseline). However, in contrast to the SNRI, theSDRI elicited a relatively large increase in extracellular DA levels in the NAcc(�200% above baseline). Error bars removed for clarity. *p , .05, comparedwith vehicle-treated animals. [Panel (A) adapted by permission from Macmil-lan Publishers Ltd: [Neuropsychopharmacology] (Bymaster et al. (49)), copy-right (2002). Panel (B) adapted with permission from Schmeichel et al. (53).]


The mechanisms within the PFC responsible for theincreased sensitivity of PFC catecholamines are less clear.However, this may involve the fact that the density of DAtransporters (DAT) is sparse in the PFC relative to the striatum(44,45), largely consistent with the reduced density of DAinnervation of the PFC relative to the striatum [except see(45)]. Moreover, the NE transporter (NET) displays a high affinityfor DA and plays a prominent role in PFC DA clearance (46–48).Consistent with this, selective NET inhibitors effective in ADHDincrease both NE and DA in the PFC without altering striatal DA(49,50) (Figure 4). It is important to note that limited DAT densityin the PFC (relative to the striatum) does not indicate anabsence of functional DAT. Indeed, evidence demonstratesmeasurable DAT in the medial PFC of rats (44,45). Further, DATinhibitors are known to elevate extracellular DA levels in thisregion (43,51,52). Moreover, recent studies demonstrate thatwhen administered at a cognition-enhancing dose, a selectiveDAT inhibitor increases both extracellular DA and NE in the PFCsimilar to cognition-enhancing doses of psychostimulants (53)(Figure 4). The elevation in NE is posited to result indirectly fromdrug-induced increases in extracellular DA that compete withNE at the NET, resulting in an increase in extracellular NE.

Collectively, these observations suggest that in the PFC,NE and DA competitively bind to the NET, with elevations inone transmitter increasing extracellular levels of the other. Weposit that this feed-forward mechanism contributes to thepreferential sensitivity of PFC catecholamines to clinicallyrelevant doses of psychostimulants. These observations fur-ther indicate a close relationship between drug-inducedincreases in PFC catecholamines and the cognition-enhancing effects of a variety of drug classes, includingpsychostimulants, NET inhibitors, and DAT inhibitors. Specif-ically, at cognition-enhancing doses, all of these drugs elicitmoderate elevations in PFC NE and DA of �100% to 250%.In contrast, the effects of these drugs on striatal DA fail topredict their cognition-enhancing effects (a range of 0% to200%) (Figures 2 and 4).

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DO THE COGNITION-ENHANCING EFFECTS OFPSYCHOSTIMULANTS INVOLVE DIRECT ACTIONWITHIN THE PFC?

Though correlative in nature, the neurochemical effects of low-dose psychostimulants reviewed above suggest the hypoth-esis that the PFC is an important site of action in thecognition-enhancing properties of these drugs. As in primates,the rat medial PFC is functionally and anatomically heteroge-neous, with the dorsomedial PFC (dmPFC) (i.e., dorsal anteriorcingulate, dorsal prelimbic PFC) associated with flexiblecognitive function and the ventromedial PFC (i.e., infralimbicPFC, ventral prelimbic PFC) associated with affective/motiva-tion-related processes (54–57). Recent studies demonstrate



Figure 5. Cognition-enhancing eff-ects of methylphenidate (MPH) involveactions within the prefrontal cortex(PFC). Shown are the effects of intra-PFC infusion of MPH on performance ina test of working memory expressed aspercent change from baseline (mean 6

SEM). Top panels: Infusion of methyl-phenidate into the dorsomedial PFC(dmPFC) (A) but not ventromedial PFC(vmPFC) (B) improved working memoryin an inverted-U dose-dependent man-ner, with .125 μg/hemisphere producingmaximal improvement. The magnitudeof MPH-induced improvement in perfor-mance was comparable with that seenwith systemic administration of clinicallyrelevant doses (Figure 1). Note thatdoses 4-fold and 16-fold higher thanan optimal dose infused into the dmPFCdo not impair performance as seen withsystemic administration. Bottom panels:Schematic diagram indicating all .125μg infusion sites into the dmPFC (A) andvmPFC (B). Numbers represent ante-rior-posterior (AP) level. *p , .05 relativeto vehicle treatment. dAcg, dorsal ante-rior cingulate; IL, infralimbic; PL, pre-limbic.


that when infused directly into the rat dmPFC, but notventromedial PFC, MPH facilitates working memory in aninverted-U shaped manner, comparable with systemic admin-istration (58) (Figure 5). Thus, MPH action in the dmPFC issufficient to elicit cognitive improvement.

In contrast to the cognition-enhancing effects of systemi-cally administered clinically relevant doses of MPH, fourfold toeightfold higher doses impair working memory (Figure 1).Thus, it is surprising that intra-PFC MPH fails to impairperformance, even at concentrations 16-fold and 32-foldhigher than a performance-improving concentration (58)(Figure 5). These observations indicate: 1) there is a mecha-nism within the PFC that drives the descending limb of theinverted-U curve (to zero); and 2) the cognition-impairingactions of systemically administered psychostimulants involvedrug action outside the PFC. A possible candidate system forthe cognition-impairing effects of psychostimulants is thehypothalamic-pituitary-adrenal axis. Thus, behaviorally acti-vating doses of psychostimulants activate the hypothalamic-pituitary-adrenal axis, elevating circulating glucocorticoids (59)and impairing spatial working memory through glucocorticoidreceptor activation within the PFC (60). Clinically, it wouldlikely be beneficial to extend the effective dose range ofpsychostimulants, particularly in patients that do not respondoptimally to lower doses. Understanding the neural mecha-nisms responsible for the cognition-impairing actions ofpsychostimulants is a translationally important area for futureresearch.


PSYCHOSTIMULANT ACTION OUTSIDE THE PFC:STRIATUM

The above reviewed information unambiguously demon-strates the PFC is a key region for the cognition-enhancing/therapeutic effects of psychostimulants. Nonetheless, thePFC does not act in isolation to support higher cognitivefunction, representing one node in a broader corticothalamo-cortical circuit. As part of this, the PFC extends topograph-ically organized projections to the striatum (61,62), a regionthat plays a prominent role in cognitive processes historicallyassociated with the PFC, and dysregulation of frontostriatalcircuitry is implicated in ADHD (20). Thus, it is of interest thatclinically relevant doses of MPH increase striatal DA signalingin both humans and animals (24,63,64), albeit to a lesserdegree than in the PFC (24) (Figure 2). Furthermore, inhumans, cognition-enhancing actions of MPH are associatedwith changes in DA signaling in both the dorsal and ventralstriatum (63,65). However, an important caveat to theseimaging studies is that catecholamine signaling in the PFCwas not measured. Based on the observations reviewedabove (Figure 2), it is likely that a similar, if not stronger,relationship exists between drug-induced changes in cogni-tion and catecholamine signaling in the PFC. Nonetheless,collectively, these observations suggest that psy-chostimulant-induced increases in DA in the striatum couldcontribute to the cognition-enhancing effects of psy-chostimulants.

In rats, the dorsomedial and ventromedial striatum receivedirect projections from the dmPFC (57,58,66), a region associated

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with the cognition-enhancing actions of MPH (see above).Inactivation or lesion of either the dorsomedial or ventromedialstriatum significantly impairs working memory (58,67) (Figure S1 inSupplement 1). Nonetheless, MPH infusion into either of thesestriatal regions (58) (Figure S1 in Supplement 1) has no effect onworking memory performance. Thus, unlike the dmPFC, psychos-timulant action within the striatum is not sufficient for the workingmemory enhancing effects of MPH. Nonetheless, drug-inducedalterations in PFC neuronal function are likely relayed to down-stream targets, altering the overall function/activity offrontostriatal-thalamocortical networks. Additionally, it remainspossible that although action in the striatum is not sufficient forthe procognitive effects of psychostimulants, combined actions inthe PFC and striatum may contribute to the maximal therapeuticeffects of these drugs.

CLINICALLY RELEVANT DOSES OFPSYCHOSTIMULANTS STRENGTHEN NEURONALSIGNALING IN THE PFC

A number of imaging studies indicate that cognition-enhancingdoses of psychostimulants normalize ADHD-related hypoactivitywithin frontostriatal circuitry (12,68–70). However, additional evi-dence indicates that clinically relevant doses of psychostimulantsexert a more complex pattern of actions on frontostriatal activitythat are task-, region-, and hemisphere-dependent (13,71–74).Currently, there exists only limited information regarding theelectrophysiological mechanisms that underlie the cognition-enhancing effects of psychostimulants. In unanesthetized ani-mals, cognition-enhancing doses of MPH increase the respon-siveness of PFC neurons to afferent signals while exertingminimal effects on spontaneous discharge rates (6) (Figure S2in Supplement 1). Similar to that seen neurochemically (Figure 2),these doses of MPH do not alter neuronal discharge properties ofcortical neurons outside the PFC (e.g., somatosensory cortex)(6,40). A similar improvement in PFC signal processing isobserved with cognition-enhancing doses of the NET inhibitor,atomoxetine (34).

Combined, these observations suggest that the procogni-tive/therapeutic effects of psychostimulants involve strength-ening of signal processing within the PFC. This action maybias neuronal activation to salient, task-related informationwhile simultaneously reducing responding to less salient orirrelevant stimuli. Conversely, the cognition-impairing effectsof higher, motorically activating doses of psychostimulantslikely involve suppression of neuronal signal processing in thePFC. A similar pattern of low-dose and high-dose effects onPFC reactivity has been observed in human imaging studies(75–77). Finally, as reviewed above, psychostimulant action inthe PFC is expected to alter signal processing broadly withincorticostriatal-thalamocortical loops. Further studies will needto explore how MPH alters signal processing within thisbroader circuitry that regulates flexible goal-directed behavior.

RECEPTOR MECHANISMS IN THE PFC: NE a2 ANDDA D1 RECEPTORS

DA and NE exert an inverted-U shaped facilitation of both PFCdependent working memory and PFC neuronal signaling. In thecase of DA, these actions involve inverted-U shaped

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modulatory actions of D1 receptors (78). For NE, high-affinitypostsynaptic α2 receptors improve, whereas lower affinity α1receptors engaged at higher rates of NE release impair, workingmemory and PFC neuronal signaling (79). Importantly, α2-agonists are efficacious in the treatment of ADHD and improvePFC-dependent function in healthy animal and human subjects(80–84), similar to that seen with psychostimulants and selec-tive NE reuptake blockers used in ADHD. Moreover, similar toMPH, α2-agonist infusion into the PFC improves workingmemory performance and PFC neuronal signaling (85).

This evidence suggests that PFC α2 and/or D1 receptors playa prominent role in the cognition-enhancing actions of low-dosepsychostimulants. Consistent with this, the working memoryeffects of both low-dose MPH and the selective NET inhibitor,atomoxetine, are prevented with systemically administered α2and D1 antagonists (5,34) (Figure S3 in Supplement 1). More-over, we recently observed that the cognition-enhancing effectsof intra-PFC infusion of MPH are blocked by co-infusion of α2and D1 antagonists (86).

The neurophysiological actions of clinically relevant doses ofpsychostimulants described above likely involve catecholamine-dependent modulation of amino acid signaling. Thus, catechol-amines exert receptor-dependent modulation of excitatory andinhibitory amino acid signaling in a variety of brain regions (87–89),including the PFC (90,91). In the PFC, N-methyl-D-aspartatereceptor-mediated excitatory postsynaptic currents are potenti-ated by a cognition-enhancing dose of MPH, an action thatinvolves D1 receptors (89–91). Moreover, at least a subset ofcatecholamine actions in the PFC is linked to the modulation ofhyperpolarization-activated cyclic nucleotide (HCN) channels (92).Of particular relevance to the current discussion, stimulation ofcognition-enhancing postsynaptic α2 receptors in the PFC inhibitHCN channels, increasing neuronal responsiveness to behaviorallysalient signals (92). Thus, this mechanism may contribute topsychostimulant-induced strengthening of PFC neuronal respond-ing. In contrast, suppressive effects of high-dose psychostimulanton evoked discharge of PFC neurons (reduced by �80%) (6)(Figure S2 in Supplement 1) involve D1-mediated activation ofHCN channels and/or α1-mediated activation of small conduc-tance, calcium-activated potassium channels (92). Additionally,psychostimulant-driven reductions in evoked discharge mayinvolve suppression of glutamatergic signaling, as high doses ofMPH (8.0 mg/kg) suppress both N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor-mediated excitatory postsynaptic currents (89).

Combined, the available evidence indicates that the pro-cognitive and enhanced neuronal signal processing actions ofpsychostimulants (and selective NE reuptake blockers and α2agonists) involve moderate increases in NE α2 and/or DA D1receptor activation in the PFC. Conversely, the cognition-impairing actions of higher doses of psychostimulants likelyinvolve suppression of signal processing in the PFC via highrates of α1 and D1 receptor activation.

DIFFERING DOSE-RESPONSE CURVES ACROSSCOGNITIVE TASKS REFLECT DIFFERINGNORADRENERGIC RECEPTOR ACTION

In 1977, Sprague and Sleator (93) reported that in ADHDchildren, MPH elicited a narrow inverted-U shaped facilitation




of performance in a cognition/learning task, while classroombehavior was improved across a wider dose range. However,subsequent studies generally failed to observe differentialsensitivity to MPH dose across a range of cognitive tasksversus overt behavior in ADHD patients (94–96). Importantly,Sprague and Sleator (93) used a memory task that involvedshort delays (seconds), typical of PFC-dependent workingmemory tasks, while subsequent studies examined otherforms of cognition (94). MPH was also observed to producea narrow inverted-U shaped improvement in a PFC-dependenttest of response inhibition in ADHD patients while eliciting agenerally linear dose-dependent improvement in behavioral/motor activity (96).

These observations could suggest that psychostimulantsexert differential dose-dependent effects on PFC-dependentversus PFC-independent processes. However, when thedose-dependent actions of MPH were compared acrossworking memory and sustained attention tasks, two PFC-dependent tasks (97) (Figure S2 in Supplement 1), a narrower,left-shifted inverted-U curve was observed for working mem-ory versus sustained attention (98) (Figure 6). A similar shift indose response curves across these tasks occurs with MPHinfusion directly into the dmPFC (99). Prior studies havesuggested that PFC NE may differentially regulate flexibleversus focused attention (100,101). Sustained attentionrequires little cognitive flexibility, relative to working memory.

Figure 6. Different prefrontal cortex dependent cognitive tasks showdifferential sensitivity to methylphenidate (MPH). Methylphenidate exerts arelatively narrow inverted-U shaped facilitation of working memory perfor-mance (A), with maximal improvement seen following .5 mg/kg intraperito-neal. In contrast, MPH exerts a right-shifted dose-dependent facilitation ofsustained attention (A) and attentional set shifting (B). Importantly, doses thatimprove sustained attention and attentional set shifting impair performance inworking memory (2.0 mg/kg). *p , .05; **p , .01 compared with vehicle(VEH) treatment. [Data reproduced with permission from Berridge et al. (98).]


However, when examined in a PFC-dependent attentionalset-shifting task typically used to measure flexible attention(102,103), MPH elicited dose-dependent improvements inperformance identical to sustained attention (98) (Figure 6).Collectively, these observations indicate that differing PFC-dependent cognitive processes display differing dose sensi-tivity to MPH that are not predicted by the degree to whichthey are associated with cognitive flexibility.

As reviewed above, noradrenergic α2 receptors improve,while α1 receptors impair, working memory (104). In contrast,α1 receptors improve attentional set shifting, while α2receptors have little impact in this task (100). These observa-tions suggest the hypothesis that the narrow versus broadinverted-U shaped actions of psychostimulants describedabove involve differential activation of α2 receptors versusα1 receptors, respectively. Consistent with this, MPH-inducedimprovement in working memory is dependent on α2-recep-tors [see above (104)], while MPH-induced improvement insustained attention is dependent on α1 receptors (98).

IMPLICATIONS FOR DIVERGENT DOSE-RESPONSECURVES ACROSS PFC-DEPENDENT PROCESSES

Preclinically, the differential dose sensitivity of PFC-dependenttasks to psychostimulants suggests that not all PFC-depen-dent tasks are well suited for ADHD-focused drug discoveryprograms. Extensive evidence demonstrates that the pharma-cology of working memory mirrors the pharmacology ofADHD: all approved ADHD-related drugs, including α2 ago-nists (105), low-dose psychostimulants (5,25), and selectiveNE reuptake blockers (e.g., atomoxetine) (34) improve workingmemory. For psychostimulants, their beneficial effects onworking memory only occur across a narrow range of dosesthat produce clinically relevant plasma concentrations (32,33,37,105,106). Thus, delayed response tests of working memoryare a well-suited preclinical tool for identifying potentiallyefficacious compounds for use in ADHD and possibly otherclinical conditions associated with PFC dysfunction.

In contrast, in sustained attention, attentional set shifting, andfive-choice serial reaction time tests, MPH exerts maximal bene-ficial actions at higher, behaviorally activating, and impulsivity-promoting doses that result in blood concentrations that exceedthe clinically relevant range (33,37,107,108) (Figure 1). Moreover,limited observations indicate that α2 agonists lack beneficial effectson attentional set shifting (100), as well as sustained attention(JL Berkowitz, Ph.D., BD Waterhouse, Ph.D., JS Shumsky, Ph.D.,unpublished observations, 2011). Thus, the potential utility of thesetests in an ADHD-focused preclinical program is less clear.

Clinically, as suggested by Sprague and Sleator (93) andTannock et al. (96), differential actions of psychostimulantsacross cognitive processes raise the question of whetherdoses that are optimal for controlling classroom behaviorimpair, or no longer improve, cognitive/behavioral processesimportant for other functional domains. For example, largelyanecdotal evidence suggests that cognitive constriction oroverfocusing can be a side effect of psychostimulant treat-ment (96). This action may be related to the ability of higherdoses of MPH to improve attentional processes while impair-ing certain forms of cognitive flexibility evinced in tests ofworking memory and response inhibition (96,98,107). If so, the

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results reviewed above could suggest the use of α1 antago-nists as an adjunct treatment for ADHD. Given α1 receptors inthe PFC are necessary for the motor-activating and reinforcingeffects of psychostimulants, α1 antagonists may also lessencertain adverse actions of psychostimulants, including abuseliability. Further studies are needed to better understand thedegree to which the dose-dependent actions of psychostimu-lants across PFC-dependent processes relate to clinical,social, and academic outcomes and role of α1 receptors inthese actions.

SUMMARY AND IMPLICATIONS

Low-dose psychostimulants are the first-line treatment forADHD. At clinically relevant doses, these drugs improvefrontostriatal cognitive function in ADHD patients and healthyindividuals. The procognitive and behavioral calming actionsof psychostimulants are in stark contrast to the behaviorallyactivating and cognition-impairing effects seen with higherdoses. For much of the history of psychostimulant treatmentof ADHD, there has been an emphasis on the possibleinvolvement of striatal DA signaling in the therapeutic actionsof these drugs. Much of this view was driven by the knownneurobiological actions of high and behaviorally activatingdoses. However, research over the past 10 years has providedsignificant insight into the neural mechanisms that support theprocognitive/therapeutic effects of psychostimulants. In par-ticular, evidence demonstrates that the cognition-enhancingeffects of psychostimulants involve an elevation in catechol-amine signaling at α2 and D1 receptors preferentially within thePFC. The regionally selective action of low-dose psychosti-mulants contrasts with the widespread and uniform actions ofhigher doses of these drugs. This regional selectivity appearsto explain why the clinical use of psychostimulants is notassociated with the pronounced arousal, motor activation, andabuse liability of higher doses. Evidence also indicates PFC D1and/or α2 receptors contribute to the therapeutic actions ofthe two other Food and Drug Administration approved treat-ments: selective NE reuptake inhibitors and α2 agonists.Collectively, this indicates a prominent role of PFC catechol-amines in the pharmacology of ADHD. In identifying the PFCas a key site of action in the procognitive effects of psychos-timulants, this research provides important guiding informationfor future drug discovery research focused on ADHD. It ishoped further understanding of the neurobiology of the PFCwill lead to the identification of novel, noncatecholaminetargets for ADHD and other disorders of frontostriatal function.

From a public policy perspective, there has been significantconcern about the widespread use of psychostimulants in thetreatment of ADHD. In the discussion of this issue, the term“psychostimulant” often carries strong negative connotationsthat are associated with the arousing, activating, and abuseliability of these drugs. However, information reviewed abovedemonstrates that at low and clinically relevant doses, psy-chostimulants do not exert behavioral and neurochemicalactions that define this class of drugs. Instead, at these lowerdoses, these drugs act as cognitive enhancers that improvefrontostriatal cognitive function while exerting only modesteffects in neural circuits associated with psychostimulant-related arousal, motor activation, and abuse. While this does

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not indicate these drugs are devoid of risk, it is importantinformation for policy-based discussions regarding the appro-priateness of the clinical use of psychostimulants. One impor-tant caveat to this discussion is that the vast majority of studieson the neural and behavioral actions of clinically relevant dosesof psychostimulants in both humans and animals have largelyinvolved male subjects. Extending this work to female subjectsis an important area for future research.

Finally, it is now clear that psychostimulants do not exert auniform facilitation of PFC-dependent processes. In particular,in both animals and humans, lower doses maximally improveperformance in tests of working memory and responseinhibition, whereas maximal suppression of overt behaviorand facilitation of attentional processes occurs at higherdoses. These differing sensitivities of PFC-dependent proc-esses appear to depend on the differential involvement of α2versus α1 receptors. These observations raise a number ofclinical and preclinical questions regarding the degree towhich higher doses that maximally control classroom behaviormay exert detrimental actions in other functional domains viaactivation of α1 receptors.

ACKNOWLEDGMENTS AND DISCLOSURESThis work was supported by Public Health Service Grants MH098631,MH081843, and DA000389; the National Science Foundation (NSF0918555); the Wisconsin Institutes of Discovery; and the University ofWisconsin Graduate School.

Mr. Spencer and Dr. Berridge report no biomedical financial interests orpotential conflicts of interest. Dr. Devilbiss is the founder of NexStepBiomarkers, LLC. NexStep Biomarkers had no role in study design, datacollection and analysis, decision to publish, or preparation of the manu-script. NexStep Biomarkers does not employ anyone who worked on thisproject, hold patents related to this project, sell products related to thisproject, or provide consultation on this project. This manuscript provides nofinancial gain for NexStep Biomarkers.

ARTICLE INFORMATIONFrom the Department of Psychology, University of Wisconsin, Madison,Wisconsin.

Address correspondence to Craig W. Berridge, Ph.D., University ofWisconsin, Department of Psychology, 1202 W Johnson Street, Madison,WI 53706; E-mail: [email protected].

Received May 29, 2014; revised Sep 16, 2014; accepted Sep 18, 2014.

Supplementary material cited in this article is available online at http://dx.doi.org/10.1016/j.biopsych.2014.09.013.

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the cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex

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