Exposure to oral methylphenidate from adolescence through young adulthood produces transient effects on hippocampal-sensitive memory in rats.
ABSTRACT Methylphenidate (MPH) is the most commonly prescribed medication used to treat the symptoms associated with attention-deficit hyperactivity disorder (ADHD). The increase in ADHD diagnosis and MPH use has raised concerns regarding the long-term consequences of early exposure to psychostimulants. Animals studies indicate that early developmental MPH treatment produces enduring changes in hippocampal-sensitive tasks, including novel object recognition (NOR) and long-term retention of contextual fear. We administered oral MPH to male Wistar rats at a therapeutically relevant dose (2 or 5 mg/kg) twice daily for 7 weeks beginning on post-natal day (PN) 27 through PN 71 (i.e., periadolescence through young adulthood). Behavioral tests began 18 days following the last MPH administration. MPH (5 mg/kg) produced an increase in the latency to reach criterion for sample object exploration during the first of two NOR tests, but did not produce memory deficits at either dose. MPH (5 mg/kg) enhanced freezing during the 24 h retention test, but did not affect responding at 48 h. Taken together, the results of both tasks suggest that treatment with MPH in a manner that approximates clinical exposure patterns transiently modifies hippocampal-sensitive learning in rats but does not produce cognitive impairments. We suggest that the effects of prolonged exposure to MPH treatment on cognitive processes vary as a function of the duration and pattern of drug administration, as well as task complexity, which may account for differences among studies regarding its long-term behavioral effects. Future preclinical studies examining the effects of early psychostimulant treatment should include different periods of exposure and assessment, as well as clinically relevant doses and routes of drug administration, in order to better understand the impact of pediatric medications on adult cognition.
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ABSTRACT: Neurotransmission at most excitatory synapses in the brain operates through two types of glutamate receptor termed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors; these mediate the fast and slow components of excitatory postsynaptic potentials respectively. Activation of NMDA receptors can also lead to a long-lasting modification in synaptic efficiency at glutamatergic synapses; this is exemplified in the CA1 region of the hippocampus, where NMDA receptors mediate the induction of long-term potentiation (LTP). It is believed that in this region LTP is maintained by a specific increase in the AMPA receptor-mediated component of synaptic transmission. We now report, however, that a pharmacologically isolated NMDA receptor-mediated synaptic response can undergo robust, synapse-specific LTP. This finding has implications for neuropathologies such as epilepsy and neurodegeneration, in which excessive NMDA receptor activation has been implicated. It adds fundamentally to theories of synaptic plasticity because NMDA receptor activation may, in addition to causing increased synaptic efficiency, directly alter the plasticity of synapses.Nature 02/1991; 349(6305):156-8. · 38.60 Impact Factor
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ABSTRACT: Methylphenidate (MPH), a dopamine reuptake inhibitor, is used increasingly to treat attention deficit and hyperactivity disorders in children. Given that dopaminergic mechanisms, contribute to the structural and functional maturation of brain circuitry, consideration of the potential influence of MPH in disrupting such processes seems warranted. Following a similar logic regarding the relevance of glutamate neurotransmission in mediating aspects of brain maturation, we and others have previously utilized in vivo and in vitro studies of the developing rodent brain to establish that MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist has both neuroprotective and pro-apoptotic actions. In this study we used a neonatal murine model of excitotoxin-induced cortical injury to compare such actions between MPH and MK-801, and found that MPH shared some biological properties with MK-801. Specifically, both drugs were neuroprotective against excitotoxic challenge resulting in neonatal brain lesions and in vitro neuronal death, but both drugs also exacerbated programmed neural cell death. However, this profile of action was not shared by the dopamine reuptake blocker GBR-12783, a molecule which like MPH binds to and blocks the dopamine transporter, but which is structurally dissimilar to MPH, suggesting that inhibition of dopamine reuptake alone cannot explain the results from our MPH studies. The implications of our findings are that when studied in our developmental mouse model both drugs demonstrate similar capacities to be either neuroprotective or pro-apoptotic, depending on the specific biologic setting in which they act. Additional studies to identify some potential positive as well as negative consequences of exposure to these drugs during brain development in clinical settings are warranted.Neuroscience 02/2004; 125(1):163-70. · 3.12 Impact Factor
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ABSTRACT: Methylphenidate (MP) (ritalin) is widely used in the treatment of children and adolescents with attention deficit hyperactivity disorder, but little is known about therapeutic mechanisms or about possible consequences of long-term exposure. To more closely simulate the clinical use of the drug, we orally administered MP to adolescent rats during the dark-active phase of the circadian cycle at doses (0.75-3.0 mg/kg) below threshold for locomotor activation. We found that doses in this range increased extracellular norepinephrine in hippocampus without affecting dopamine in nucleus accumbens. These results suggest that norepinephrine systems may play an important role in the therapeutic action of this drug. To examine one potential consequence of long-term exposure to MP, i.e., the development of locomotor sensitization, an adaptational change that has been implicated in drug abuse liability, animals received three daily oral administrations of these doses of MP for up to 4 weeks through adolescence. The animals were then challenged with methamphetamine (0.5 mg/kg). We found that the behavioral response to MP did not change during the course of chronic treatment and that MP-pretreated animals did not exhibit a sensitized locomotor response to the methamphetamine challenge. We propose that, to the extent that this treatment protocol more closely reflects clinical exposure patterns, the relative insensitivity of accumbens dopamine to the acute administration of these MP doses, and the corresponding absence of evidence for the development of locomotor sensitization, supports one clinical view that there is little abuse liability associated with low dose, long-term MP treatment.Journal of Neuroscience 09/2002; 22(16):7264-71. · 6.91 Impact Factor