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: WE AIMED TO INVESTIGATE THE EFFECTS OF METHYLPHENIDATE (MPH) IN HEALTHY RATS ON TWO DISTINCT RADIAL MAZE TASKS WHICH RELY ON BRAIN STRUCTURES AND NEUROTRANSMITTERS KNOWN TO BE AFFECTED BY MPH: the Random Foraging Non-Delay Task (RFNDT) and the Delayed Spatial Win Shift Task (DSWT). Hooded Lister rats were trained to complete either the RFNDT or the DSWT having received oral treatment of either a vehicle or MPH (3.0 mg/kg and 5.0 mg/kg for RFNDT, 3.0 mg/kg for DSWT). We found no effect of MPH on the RFNDT relative to the control group. However, those treated with 5.0 mg/kg MPH did take significantly longer to reach criterion performance than those treated with the 3.0 mg/kg MPH, suggesting some doses of MPH can have detrimental effects. For the DSWT, if MPH was present in both phases, performance did not differ from when it was absent in both phases. However, when present in only one phase there was an increase in errors made, although this only reached significance for when MPH was present only in the test-phase. These data suggest that MPH may have detrimental effects on task performance and can result in state-dependent effects in healthy individuals.Frontiers in Neuroscience 06/2013; 7:97. DOI:10.3389/fnins.2013.00097
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ABSTRACT: Cognitive dysfunction is a hallmark of chronic psychostimulant misuse. Adolescents may have heightened risk of developing drug-induced deficits because their brains are already undergoing widespread changes in anatomy and function as a normal part of development. To address this hypothesis, we performed two sets of experiments where adolescent and young adult rats were pre-exposed to saline or amphetamine (1 or 3mg/kg) and subsequently tested in a prefrontal cortex (PFC)-sensitive working memory task. A total of ten injections of AMPH or saline (in control rats) were given every other day over the course of 19 days. After rats reached adulthood (> 90 days old), cognitive performance was assessed using operant-based delayed matching-to-position (DMTP) and delayed nonmatching-to-position (DNMTP) tasks. DNMTP was also assessed following challenges with amphetamine (0.1-1.25mg/kg), and ketamine (5.0-10mg/kg). In experiment one, we also measured the locomotor response following the first and tenth pre-exposure to amphetamine and after an amphetamine challenge given at the conclusion of operant testing. Compared to adult-exposed groups, adolescents were less sensitive to the psychomotor effects of amphetamine. However, they were more vulnerable to exposure-induced cognitive impairments. For example, adolescent-exposed rats displayed delay-dependent deficits in accuracy, increased sensitivity to proactive interference, and required more training to reach criterion. Drug challenges produced deficits in DNMTP performance, but these were not dependent on pre-exposure group. These studies demonstrate age of exposure-dependent effects of amphetamine on cognition in a PFC-sensitive task, suggesting a heightened sensitivity of adolescents to amphetamine-induced neuroplasticity.Behavioural brain research 01/2013; DOI:10.1016/j.bbr.2012.12.044 · 3.39 Impact Factor
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ABSTRACT: Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations.Journal of Child Psychology and Psychiatry 02/2011; 52(4):476-503. DOI:10.1111/j.1469-7610.2011.02376.x · 5.67 Impact Factor