Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils

Grund, Thorsten; Teuchert-Noodt, Gertraud; Busche, Andrea; Neddens, Joerg; Brummelte, Susanne; Moll, Gunther H.; Dawirs, Ralph R.

doi:10.1016/j.brainres.2007.06.107

Cited by 15 publications

(12 citation statements)

References 59 publications

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“…Clearly, healthy adolescents have not been included in clinical trials assessing methylphenidate's effects on brain function and structure for medical ethical reasons. In a previous study in gerbils, adolescent treatment with methylphenidate normalized dopaminergic fiber density in animals with methamphetamine-lesioned brains, but it did not affect control animals (Grund et al, 2007). On the other hand, other studies have also reported long-lasting changes in healthy animals, eg, reduced striatal dopamine transporter densities (Moll et al, 2001) and altered firing rates of midbrain dopaminergic neurons (Brandon et al, 2003).…”

Section: Limited Effects Of Methylphenidate Exposure On Healthy Brainsmentioning

confidence: 93%

“…Animal models may therefore afford a well-controlled experimental setup to disentangle the effects of neuropathology and chronic psychostimulant treatment on the developing brain. Studies in rats have shown that early exposure to methylphenidate can affect midbrain dopaminergic neurons (Brandon et al, 2003), cause profound reductions in striatal dopamine transporter levels (Moll et al, 2001), but could also prevent methamphetamine-triggered suppression of dopaminergic innervation of the prefrontal cortex and amygdala (Grund et al, 2007). However, it remains unclear to what extent long-term exposure of the normally developing adolescent brain to methylphenidate-in the absence of ADHDaffects gross tissue morphology and function as observed in patient studies.…”

Section: Introductionmentioning

confidence: 99%

“…Body weight was measured daily during treatment, and following the washout period. The methylphenidate dosing regimen used in the present study was chosen to mimic clinically therapeutic doses and route of administration in rats (Gerasimov et al, 2000;Grund et al, 2007).…”

Section: Animalsmentioning

confidence: 99%

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Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Marel¹,

Klomp²,

Meerhoff³

et al. 2013

Neuropsychopharmacol

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Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamineinduced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.

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Section: Limited Effects Of Methylphenidate Exposure On Healthy Brainsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Marel¹,

Klomp²,

Meerhoff³

et al. 2013

Neuropsychopharmacol

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“…Some of the most commonly-prescribed are MPH for ADHD (Shanks et al 2015; Caprioli et al 2015; Crawford et al 2011; Gray et al 2007), and fluoxetine (FLX) for the treatment of Major Depression (Iñiguez et al 2010; Iñiguez et al 2014; Homberg et al 2011). MPH exhibits a similar pharmacological profile to amphetamines and cocaine, may modulate neurodevelopment (Grund et al 2007; Thanos et al 2007; Adriani et al 2006), and by extension, may impact learning and behavior mediated by corticostriatal circuitry. There is evidence for long-term effects of adolescent MPH on adult locomotor behavior and addiction vulnerability.…”

Section: Introductionmentioning

confidence: 99%

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Izquierdo

Pozos

Torre

et al. 2016

Behavioural Brain Research

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Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner.

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“…from P 30-60 and their brain was investigated at day P90 no changes could be observed (dopamine fiber density in the PFC or amygdala). Moreover, when the animals were pretreated with a single dose of the neurotoxine methamphetamine at day P14 MPH could prevent the usual suppressive effect of methamphetamine on the dopamine fiber density [59].…”

Section: Normal Animals Effects Of Postnatal Stimulant Treatment On Tmentioning

confidence: 99%

Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention-Deficit/Hyperactivity Disorder

Bock

Gerlach²,

Rothenberger³

2010

CPD

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In recent years an increased use of psychotropic medication in children has been observed, but little is known about the influence of this medication on brain maturation. Probably, because of methodological problems and/or ethical aspects. It means that only naturalistic observational studies might allow to get some insight in humans. But even animal studies touching this issue are scarce and heterogeneous. Nevertheless, postnatal brain development is highly sensitive to the effects of psychotropic drugs, either in the short- and/or long-term. Therefore, more and better information is needed. The main targets of psychotropic drugs are the monoaminergic transmitter systems that are related to brain networks for motor behavior, motivation, emotion, and cognition. In order to elucidate the mechanisms of drug development interactions and their long-term consequences on brain and behavior, animal studies might provide a good basis for a better understanding and guidance of research in humans. Hence, this article reviews the possible influence of those psychotropic drugs on postnatal brain development in animals (mostly rats and rodents) which are widely used to treat common psychiatric disorders in children and adolescents like depression and attention-deficit/ hyperactivity disorder (ADHD). Moreover this review refers to the obvious problems of the available animal studies (including experimental animal models of child psychiatric disorders) which seem to be of limited value in translating experimental knowledge to the complexity of clinical understanding and practice.

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Administration of oral methylphenidate during adolescence prevents suppressive development of dopamine projections into prefrontal cortex and amygdala after an early pharmacological challenge in gerbils

Cited by 15 publications

References 59 publications

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention-Deficit/Hyperactivity Disorder

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