A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: Potential relevance to attention deficit hyperactivity disorder
Highlights
► AHN 2-005 is a selective dopamine reuptake inhibitor lacking reinforcing effects. ► AHN 2-005 improved prefrontal-dependent cognition. ► AHN 2-005 increased extracellular dopamine and norepinephrine in prefrontal cortex. ► These actions are similar to those produced by ADHD-related drugs.
Introduction
Attention-deficit hyperactivity disorder (ADHD) is conservatively estimated to affect 3%–5% of children and adults (Solanto, 2001; Wilens et al., 2004). Psychostimulants are currently the most effective treatment for ADHD (Greenhill, 2001). However, the abuse potential of these drugs raises significant concerns about their widespread use. Thus, there is a need for new drug treatments for ADHD that display comparable efficacy while lacking the abuse potential of psychostimulants.
Extensive studies demonstrate that ADHD-approved medications improve cognitive processes dependent on the prefrontal cortex (PFC), including working memory, planning, response inhibition and the regulation of impulsivity (Chamberlain et al., 2007; Diamond, 2005; Mehta et al., 2001; Turner et al., 2005). These observations are consistent with imaging data demonstrating ADHD is associated with PFC dysfunction (Castellanos and Tannock, 2002). Importantly, the cognition-enhancing actions of ADHD-related drugs are not limited to ADHD, with similar effects observed in both normal human and animal subjects (Arnsten and Dudley, 2005; Berridge et al., 2006; Devilbiss and Berridge, 2008; Elliott et al., 1997; Gamo et al., 2010; Mehta et al., 2001; Rapoport and Inoff-Germain, 2002). Collectively, these observations suggest that the clinical efficacy of drugs used in the treatment of ADHD involves, at least in part, an ability to improve PFC-dependent function.
Psychostimulants used in the treatment of ADHD (i.e. methylphenidate, amphetamine) act as non-selective catecholamine reuptake inhibitors (Berridge and Devilbiss, 2011). Additionally, selective norepinephrine reuptake inhibitors (SNRIs) are effective in the treatment of ADHD, though these drugs are typically viewed as less efficacious than psychostimulants (Berridge and Devilbiss, 2011). To date, selective DA reuptake inhibitors (SDRIs) have not been utilized in ADHD, largely due to a limited number of compounds that display selectivity for the DA transporter (DAT) while lacking the abuse potential of psychostimulants. However, a series of benztropine analogs has been described that display high selectivity and affinity for the DAT while lacking reinforcing effects in rodents and monkeys (Hiranita et al., 2009; Li et al., 2005; Woolverton et al., 2001, 2000). The behavioral and pharmacological profiles of these compounds suggest they may be efficacious in the treatment of ADHD while lacking significant abuse potential.
The behavioral and neurochemical actions of the benztropine analog, N-allyl-3α[bis(4fluorophenyl)methoxy]tropane (AHN 2-005), have been well-characterized. Prior work demonstrates that this compound displays high selectivity for the DAT relative to other transporters and receptors and lacks reinforcing effects as measured in conditioned place preference and self-administration paradigms at doses that produce robust increases in extracellular DA concentrations (Hiranita et al., 2009; Katz et al., 1999, 2004; Raje et al., 2005). To assess the potential use of AHN 2-005 in ADHD, we first examined the degree to which this compound improves PFC-dependent function of rats as measured in a delayed-response task of working memory. Importantly, the pharmacology of performance in this task aligns closely with the pharmacology of ADHD: all major classes of drugs used to treat ADHD (psychostimulants, SNRIs, α2-agonists) improve performance in this task (Arnsten, 2009; Berridge and Devilbiss, 2011). Thus this task is a useful preclinical screen for ADHD-related compounds. In the current studies, AHN 2-005 dose-dependently improved performance in this task, comparable to that seen with ADHD-related drugs.
Available evidence indicates that clinically-relevant, cognition-enhancing doses of psychostimulants and SNRIs simultaneously and preferentially elevate extracellular NE and DA within the PFC (Berridge et al., 2006; Bymaster et al., 2002). This has been posited to reflect, in part, a prominent role of the NET in the clearance of DA within the PFC (Berridge and Devilbiss, 2011; Carboni et al., 2006; Yamamoto and Novotney, 1998). These and other observations indicate a pivotal role of PFC catecholamines in the cognition-enhancing/therapeutic actions of ADHD-related drugs (Arnsten, 2009; Arnsten and Dudley, 2005; Devilbiss and Berridge, 2008; Spencer et al., 2012). If NE and DA binding at the NE transporter (NET) in the PFC is competitive, elevations in extracellular DA are expected to elevate extracellular NE levels. To test whether this occurs with AHN 2-005, additional microdialysis studies examined the degree to which a cognition-enhancing dose of AHN 2-005 (10 mg/kg) simultaneously impacts extracellular DA and NE within the PFC, the nucleus accumbens and the medial septal area. Similar to that seen with clinically-relevant doses of psychostimulants and SNRIs, AHN 2-005 elicited moderate increases in extracellular levels of both DA and NE within the PFC and medial septal area, and modestly higher increases in extracellular levels of DA in the nucleus accumbens. These neurochemical effects were observed in the absence of locomotor activating effects, consistent with results of earlier studies (Li et al., 2005).
Collectively, these preclinical observations suggest that AHN 2-005 and other benztropine analogs may have utility in the treatment of ADHD and other conditions associated with PFC dysfunction.
Section snippets
Animals and surgery
Male Sprague–Dawley rats (260–280 g, Charles River, Wilmington, MA) were housed in pairs with ad lib access to food and water on an 11:13 h light:dark cycle (lights on 7:00 AM). For microdialysis studies, probes were surgically implanted under isoflurane anesthesia, as previously described (Berridge et al., 2006). All procedures were in accordance with NIH guidelines and were approved by the University of Wisconsin Institutional Animal Care and Use Committee.
Spatial delayed alternation/working memory testing
Training and testing were similar to
Effects of AHN 2-005 on working memory performance
To assess the effects of AHN-2005 on working memory performance, animals were treated with vehicle (n = 8), 1.0 mg/kg AHN 2-005 (n = 7) or 10.0 mg/kg AHN 2-005 (n = 8) 20-min prior to testing in the T-maze. This dose range was based on: 1) published observations indicating behavioral and neurochemical actions of AHN 2-005 (Hiranita et al., 2009; Li et al., 2005; Raje et al., 2005); 2) limited pilot studies; 3) limited observations indicating that at 30 mg/kg locomotor-activating effects may
Discussion
Drugs used to treat ADHD have been demonstrated to improve an array of PFC-dependent processes (Chamberlain et al., 2007; Diamond, 2005; Mehta et al., 2001; Turner et al., 2005). The current studies demonstrate that the selective DA reuptake inhibitor, AHN 2-005, improves PFC-dependent cognitive function as measured in this working memory task while lacking locomotor-activating or arousal-promoting actions. This behavioral profile is similar to all drugs currently approved for use in ADHD,
Financial disclosures
Dr. Berridge has received consulting fees from Phase 2 Discovery. P2D Bioscience is developing AHN 2-005 for the treatment of attention deficit/hyperactivity disorder. FPZ is a full time employee of P2D Bioscience. Ms. Schmeichel has no financial disclosures to report.
Acknowledgments
This work was supported by PHS grants, MH081843, DA000389, and MH08138, the Wisconsin Institutes of Discovery and the University of Wisconsin Graduate School.
References (54)
- et al.
Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders
Pharmacol. Biochemistry, and Behavior
(2011) The emerging neurobiology of attention deficit hyperactivity disorder: the key role of the prefrontal association cortex
J. Pediatr.
(2009)- et al.
Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder
Biol. Psychiatry
(2011) - et al.
Contrasting effects of noradrenergic beta-receptor blockade within the medial septal area on forebrain electroencephalographic and behavioral activity state in anesthetized and unanesthetized rat
Neuroscience
(2000) - et al.
Amphetamine acts within the medial basal forebrain to initiate and maintain alert waking
Neuroscience
(1999) - et al.
Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function
Biol. Psychiatry
(2006) - et al.
Differential sensitivity to psychostimulants across prefrontal cognitive tasks: differential involvement of Noradrenergic α1- vs. α2-receptors
Biol. Psychiatry
(2012) - et al.
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder
Neuropsychopharmacology
(2002) - et al.
Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder
Biol. Psychiatry
(2007) - et al.
Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness
Biol. Psychiatry
(2008)
Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment
Brain Res.
Methylphenidate and atomoxetine enhance prefrontal function through alpha2-adrenergic and dopamine D1 receptors
J. Am. Acad. Child. Adolesc. Psychiatry
Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability
Neuroscience
Orexin-saporin lesions of the medial septum impair spatial memory
Neuroscience
Psychostimulants act within the prefrontal cortex to improve cognition function
Biol. Psychiatry
Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in attention deficit hyperactivity disorder
Behav. Brain Funct.
Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness
Cereb. Cortex
Enhancement of behavioral and electroencephalographic indices of waking following stimulation of noradrenergic beta-receptors within the medial septal region of the basal forebrain
J. Neurosci.
Differential sensitivity to the wake-promoting actions of norepinephrine within the medial preoptic area and the substantia innominata
Behav. Neurosci.
Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex
Synapse
Neural substrates of psychostimulant-induced arousal
Neuropsychopharmacology
Functional magnetic resonance imaging of methylphenidate and placebo in attention-deficit/hyperactivity disorder during the multi-source interference task
Arch. Gen. Psychiatry
Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals
J. Neurochem.
Cumulative effect of norepinephrine and dopamine carrier blockade on extracellular dopamine increase in the nucleus accumbens shell, bed nucleus of stria terminalis and prefrontal cortex
J. Neurochem.
Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes
Nat. Rev. Neurosci.
Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine
J. Neurosci.
Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): a neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity)
Dev. Psychopathol.
Cited by (37)
Attractiveness and neural processing of infant faces: effects of a facial abnormality but not dopamine
2020, Physiology and BehaviorMethylphenidate administration reverts attentional inflexibility in adolescent rats submitted to a model of neonatal hypoxia-ischemia: Predictive validity for ADHD study
2019, Experimental NeurologyCitation Excerpt :Higher pTH enzyme levels indicate higher TH activity and probably higher DA levels in the PFC, that we could presume to be associated with the improved attentional flexibility observed in this group. MPH is well recognized to increase DA levels in the PFC (Berridge et al., 2006; Devilbiss and Berridge, 2008; Schmeichel et al., 2013; Spencer et al., 2012) and we assume that an increase in the DA signaling in the PFC of HIMPH animals was responsible for their attentional improvements. Although MPH administration was able to reverse attentional impairments caused by the neonatal HI, the drug did not impact on protein levels of DA receptors and DAT.
A novel heterocyclic compound targeting the dopamine transporter improves performance in the radial arm maze and modulates dopamine receptors D1-D3
2016, Behavioural Brain ResearchCitation Excerpt :As such, increased dopamine levels are associated with cognitive improvements [14]. Selective dopamine reuptake inhibitors such as modafinil and the benztropine analog AHN 2-005 improve both, hippocampal- and prefrontal cortex- dependent cognitive functions [15–18]. In search for highly selective DAT inhibitors, we synthesized a heterocyclic compound, CE-111 and tested its blocking efficacy in HEK293-expressing DAT, NET or SERT.