Caffeine regulates frontocorticostriatal dopamine transporter density and improves attention and cognitive deficits in an animal model of attention deficit hyperactivity disorder

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Abstract

Attention deficit hyperactivity disorder (ADHD) likely involves dopaminergic dysfunction in the frontal cortex and striatum, resulting in cognitive and motor abnormalities. Since both adenosine and dopamine modulation systems are tightly intertwined, we tested if caffeine (a non-selective adenosine receptor antagonist) attenuated the behavioral and neurochemical changes in adolescent spontaneously hypertensive rats (SHR, a validated ADHD animal model) compared to their control strain (Wistar Kyoto rats, WKY). SHR were hyperactive and had poorer performance in the attentional set-shifting and Y-maze paradigms and also displayed increased dopamine transporter (DAT) density and increased dopamine uptake in frontocortical and striatal terminals compared with WKY rats. Chronic caffeine treatment was devoid of effects in WKY rats while it improved memory and attention deficits and also normalized dopaminergic function in SHR. Additionally, we provide the first direct demonstration for the presence of adenosine A2A receptors (A2AR) in frontocortical nerve terminals, whose density was increased in SHR. These findings underscore the potential for caffeine treatment to normalize frontocortical dopaminergic function and to abrogate attention and cognitive changes characteristic of ADHD.

Introduction

Attention deficit and hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children (Polanczyk et al., 2007) and is characterized primarily by a triad of symptoms constituted of hyperactivity, inattention and impulsivity (Biederman and Faraone, 2005). Dysfunction of dopamine signaling in the frontal cortex and striatum has been identified as a major trait associated with behavioral changes in patients with ADHD (reviewed in Biederman and Faraone, 2005, Arnsten, 2006). Accordingly, the main therapeutic option to manage ADHD patients is the use of methylphenidate, a blocker of monoamine re-uptake, namely of dopamine transporters (DAT) (Wilens, 2008). Thus, methylphenidate improves the triad of ADHD symptoms in approximately 70% of patients (Wilens, 2008), which appears to be related to a normalization of the under-functioning brain regions involved in motor and executive functions, such as anterior cingulate/medial frontal cortex and the inferior and ventromedial frontocorticostriatal connections (e.g. Jonkman et al., 2007, Rubia et al., 2011). Although methylphenidate is the first-choice drug for ADHD (Wilens, 2008), it is frequently associated with side effects such as weight loss, insomnia and reduced appetite, as well as a high risk of drug addiction (MTA Cooperative Group, 2004, Vitiello et al., 2001). Thus, therapeutic alternatives to manage ADHD are warranted.

Adenosine neuromodulation has emerged as a putative novel candidate target in view of its ability to control the dopamine system at different levels (reviewed in Fredholm and Svenningsson, 2003). Thus, the better characterized adenosine A1 and A2A receptors (A2AR) are located in dopaminergic terminals and can modulate dopamine release (Borycz et al., 2007, Gomes et al., 2009) as well as its extracellular levels (Quarta et al., 2004). Adenosine receptors also functionally antagonize dopaminergic responses, namely through A2A–D2 receptor heteromers, which have been demonstrated to influence behavioral responses such as psychostimulant sensitization or locomotor deficits associated with Parkinson's disease (Schiffmann et al., 2007, Ferré et al., 2008). Therefore, there is interest in the manipulation of adenosine receptors to manage conditions traditionally associated with dopaminergic dysfunction, such as drug addiction, schizophrenia and mood disorders (Lara and Souza, 2000, Ferré et al., 2007, Cunha et al., 2008). While manipulation of the adenosine modulation system has not yet been probed as a potential intervention for the cardinal symptoms of ADHD, nevertheless we have recently shown that it controls memory impairment associated with ADHD (Prediger et al., 2005a, Pires et al., 2009, Pires et al., 2010).

This study was designed to test if caffeine (an adenosine receptor antagonist) could counteract the aberrant sustained attention and/or hyperlocomotion characteristic of ADHD. This was carried out using spontaneously hypertensive rats (SHR), which are the most widely accepted animal model of ADHD. SHR display the behavioral modifications and dopaminergic changes in frontocorticostriatal circuits that are characteristic of ADHD (Arnsten, 2006, Sagvolden et al., 2005, Sagvolden et al., 2009). Using this model, caffeine pharmacotherapy was applied during adolescence when corticostriatal circuits underlying executive processes undergo critical maturation (Teicher et al., 1995).

Section snippets

Subjects and treatment

Adolescent male inbred SHR (n=16) and WKY (n=16) rats, substrains NCrl and NIcoCrl respectively, were purchased from Charles River Laboratories (Germany). Rats were individually housed in plastic cages and were maintained under controlled temperature (22±2 °C) on a 12/12-h light/dark cycle (lights on at 7:00 am). Rats were considered adolescent at days 24 to 45 post-natal (Spear, 2000). Rats from each strain were randomly divided into a control group that received saline (NaCl 0.9%) and another

Attention set-shifting task

We first tested the impact of the chronic treatment with caffeine during adolescence (compared to vehicle) on the performance of SHR and WKY rats in the attention set-shifting task. The number of animals was 8 in the WKY control group, 8 in the WKY caffeine-treated group, 7 in the SHR control group and 7 in the SHR caffeine-treated group. For the response discrimination phase (Fig. 1A), which requires learning of a simple egocentric strategy, the two-way ANOVA analysis revealed a significant

Discussion

The present study reports two major intertwined findings that provide novel insights into the adenosine neuromodulation system and its potential relevance as a new therapeutic target to manage conditions of attention deficit and hyperactivity disorder (ADHD). Moreover, in the hypertensive rat (SHR) model of ADHD, we show for the first time that the chronic consumption of caffeine controls sustained attention as well as attenuating accompanying maladaptive changes in the density and function of

Role of the funding source

This work was supported by Fundação para a Ciência e a Tecnologia (PTDC/SAU-NSC/122254/2010), DARPA (DARPA-09-68-ESR-FP-010) and a CAPES-FCT grant program; they had no further role in the study design; in the collection, the analysis and the interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Pablo Pandolfo designed the study, managed the literature searches and analyses, performed experiments and wrote the manuscript. Nuno Machado performed the experiments. Attila Kofalvi undertook the statistical analysis and wrote the manuscript. Reinaldo N. Takahashi designed the study and wrote the manuscript. Rodrigo A. Cunha managed the literature searches, designed the study and wrote the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

The authors declare that there are no financial or other relationships related with this manuscript that might lead to a conflict of interest. The work described has not been submitted elsewhere for publication, in whole or in part, and all the authors listed have approved the manuscript that is enclosed. We have read and have abided by the statement of ethical standards for manuscripts submitted to European Neuropsychopharmacology.

Acknowledgments

This work was supported by Fundação para a Ciência e a Tecnologia (PTDC/SAU-NEU/108668/2008), DARPA (DARPA-09-68-ESR-FP-010) and a CAPES-FCT Grant program. P.P. is supported by scholarship from CAPES-Brazil. A.K. received support from the FCT project PTDC/SAU-NEU/100729/2008 of the Portuguese Government. R.N.T. is supported by a research fellowship from CNPq—Brazil. We thank Dr. John Jones (CNC) for kindly reviewing the MS.

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