Methylphenidate Administration to Juvenile Rats Alters Brain Areas Involved in Cognition, Motivated Behaviors, Appetite, and Stress

The Rockefeller University, New York, New York, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2007; 27(27):7196-207. DOI: 10.1523/JNEUROSCI.0109-07.2007
Source: PubMed


Thousands of children receive methylphenidate (MPH; Ritalin) for attention deficit/hyperactivity disorder (ADHD), yet the long-term neurochemical consequences of MPH treatment are unknown. To mimic clinical Ritalin treatment in children, male rats were injected with MPH (5 mg/kg) or vehicle twice daily from postnatal day 7 (PND7)-PND35. At the end of administration (PND35) or in adulthood (PND135), brain sections from littermate pairs were immunocytochemically labeled for neurotransmitters and cytological markers in 16 regions implicated in MPH effects and/or ADHD etiology. At PND35, the medial prefrontal cortex (mPFC) of rats given MPH showed 55% greater immunoreactivity (-ir) for the catecholamine marker tyrosine hydroxylase (TH), 60% more Nissl-stained cells, and 40% less norepinephrine transporter (NET)-ir density. In hippocampal dentate gyrus, MPH-receiving rats showed a 51% decrease in NET-ir density and a 61% expanded distribution of the new-cell marker PSA-NCAM (polysialylated form of neural cell adhesion molecule). In medial striatum, TH-ir decreased by 21%, and in hypothalamus neuropeptide Y-ir increased by 10% in MPH-exposed rats. At PND135, MPH-exposed rats exhibited decreased anxiety in the elevated plus-maze and a trend for decreased TH-ir in the mPFC. Neither PND35 nor PND135 rats showed major structural differences with MPH exposure. These findings suggest that developmental exposure to high therapeutic doses of MPH has short-term effects on select neurotransmitters in brain regions involved in motivated behaviors, cognition, appetite, and stress. Although the observed neuroanatomical changes largely resolve with time, chronic modulation of young brains with MPH may exert effects on brain neurochemistry that modify some behaviors even in adulthood.

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    • "Attention deficit and hyperactivity of PI3Kc KO mice are rescued by MPH These behavioral phenotypes of PI3Kc KO mice mimic the core symptoms of ADHD, one of the most prevalent human psychiatric disorders, more recently attributed also to an impairment of LC function (Biederman & Spencer, 1999; Berridge & Waterhouse, 2003). Thus, we hypothesized that methylphenidate (MPH), the drug of choice for the symptomatic treatment of ADHD (Mehta et al, 2004) that rescues as well the corresponding behavior in animal models of ADHD (Gray et al, 2007; Cao et al, 2012) would normalize the phenotype of PI3Kc KO mice. We found that MPH significantly improved the attention deficit of PI3Kc KO mice, as evaluated in the ASS test (Fig 1B and C). "
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    ABSTRACT: Although PI3Kγ has been extensively investigated in inflammatory and cardiovascular diseases, the exploration of its functions in the brain is just at dawning. It is known that PI3Kγ is present in neurons and that the lack of PI3Kγ in mice leads to impaired synaptic plasticity, suggestive of a role in behavioral flexibility. Several neuropsychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD), involve an impairment of behavioral flexibility. Here, we found a previously unreported expression of PI3Kγ throughout the noradrenergic neurons of the locus coeruleus (LC) in the brainstem, serving as a mechanism that regulates its activity of control on attention, locomotion and sociality. In particular, we show an unprecedented phenotype of PI3Kγ KO mice resembling ADHD symptoms. PI3Kγ KO mice exhibit deficits in the attentive and mnemonic domains, typical hyperactivity, as well as social dysfunctions. Moreover, we demonstrate that the ADHD phenotype depends on a dysregulation of CREB signaling exerted by a kinase-independent PI3Kγ-PDE4D interaction in the noradrenergic neurons of the locus coeruleus, thus uncovering new tools for mechanistic and therapeutic research in ADHD.
    EMBO Molecular Medicine 04/2015; 7(7). DOI:10.15252/emmm.201404697 · 8.67 Impact Factor
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    • "In addition, in adult ADHD several reports on grey matter reductions were not able to distinguish between ADHD and psychostimulant effects [101,102]. However, reports on greater rates of depression and anxiety in the treated groups of the MTA study sample and in several studies involving rats indicate that effects of MPH treatment may have mixed positive and negative effects [9,10,103]. Our main outcome parameter phMRI may be able to shed more light on the effects of MPH on the development of the DAergic system. "
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    ABSTRACT: Animal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different approaches to determine whether there are related findings in humans. Animal studies were carried out to investigate age-related effects of psychotropic drugs and to validate new neuroimaging techniques. In addition, we set up two double-blind placebo controlled clinical trials with MPH in 50 boys (10-12 years) and 50 young men (23-40 years) suffering from ADHD (ePOD-MPH) and with FLX in 40 girls (12-14 years) and 40 young women (23-40 years) suffering from depression and anxiety disorders (ePOD-SSRI). Trial registration numbers are: Nederlands Trial Register NTR3103 and NTR2111. A cross-sectional cohort study on age-related effects of these psychotropic medications in patients who have been treated previously with MPH or FLX (ePOD-Pharmo) is also ongoing. The effects of psychotropic drugs on the developing brain are studied using neuroimaging techniques together with neuropsychological and psychiatric assessments of cognition, behavior and emotion. All assessments take place before, during (only in case of MPH) and after chronic treatment. The combined results of these approaches will provide new insight into the modulating effect of MPH and FLX on brain development.
    BMC Psychiatry 02/2014; 14(1):48. DOI:10.1186/1471-244X-14-48 · 2.21 Impact Factor
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    • "Higher doses (doses greater than those given to treat ADHD) increase locomotor activity and impair attention and performance on prefrontal cortexdependent cognitive tasks; however, lower doses (those equivalent to the range given to ADHD patients) improve cognitive performance and reduce locomotor activity in healthy individuals [18] [19] [25] [35]. Likewise, lower doses of methylphenidate (0.25– 1 mg/kg, intraperitoneal, i.p.) in normal adult rats resulted in increased performance on attention tasks along with no effect on locomotor activity, while higher doses impaired performance and induced hyperactivity; doses beyond 10 mg/kg resulted in ''stereotypies'' (repetitive, fine motor movements similar to the tics seen in disorders like Tourette's syndrome) [25] [36] [37]. Why might a medication that is reportedly a stimulant result in increased focus and attention while reducing locomotor hyperactivity? "
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    ABSTRACT: Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug for juveniles and adolescents. Used to treat attention-deficit/hyperactivity disorder (ADHD) and for cognitive enhancement in healthy individuals, it has been regarded as a relatively safe medication for the past several decades. However, a thorough review of the literature reveals that the age-dependent activities of the drug, as well as potential developmental effects, are largely ignored. In addition, the diagnosis of ADHD is subjective, leaving open the possibility of misdiagnosis and excessive prescription of the drug. Recent studies have suggested that early life exposure of healthy rodent models to methylphenidate resulted in altered sleep/wake cycle, heightened stress reactivity, and, in fact, a dosage previously thought of as therapeutic depressed neuronal function in juvenile rats. Furthermore, juvenile rats exposed to low-dose methylphenidate displayed alterations in neural markers of plasticity, indicating that the drug might alter the basic properties of prefrontal cortical circuits. In this review of the current literature, we propose that juvenile exposure to methylphenidate may cause abnormal prefrontal function and impaired plasticity in the healthy brain, strengthening the case for developing a more thorough understanding of methylphenidate's actions on the developing, juvenile brain, as well as better diagnostic measures for ADHD.
    Medical Hypotheses 09/2013; 81(6). DOI:10.1016/j.mehy.2013.09.009 · 1.07 Impact Factor
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