Exposure to oral methylphenidate from adolescence through young adulthood produces transient effects on hippocampal-sensitive memory in rats

Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), Cognición, Cerebro y Conducta, Panamá, Panama.
Behavioural brain research (Impact Factor: 3.03). 09/2009; 202(1):50-7. DOI: 10.1016/j.bbr.2009.03.015
Source: PubMed


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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    • "In clinic, pharmacological stimulants such as norepinephrine agonists (Banaschewski et al., 2004) and methylphenidate (MPH) and indirect dopaminergic agonist were used to reduce the symptoms of ADHD. Of them, MPH is the most popular medication because of its effects on ADHD (Bethancourt et al., 2009). These stimulants, however, sometimes exert no effectiveness or induce side effect, often restrain their continued use (Banaschewski et al., 2004). "
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    ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of cognition. We investigated the effects of treadmill exercise on Purkinje cell and astrocytic reaction in the cerebellum of the ADHD rat. Adult male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKYR) weighing 210± 10 g were used. The animals were randomly divided into four groups (n= 15): control group, ADHD group, ADHD and methylphenidate (MPH)-treated group, ADHD and treadmill exercise group. The rats in the MPH-treated group as a positive control received 1 mg/kg MPH orally once a day for 28 consecutive days. The rats in the treadmill exercise group were made to run on a treadmill for 30 min once a day for 28 days. Motor coordination and balance were determined by vertical pole test. Immunohistochemistry for the expression of calbindinD-28 and glial fibrillary acidic protein (GFAP) in the cerebellar vermis and Western blot for GFAP, Bax, and Bcl-2 were conducted. In the present results, ADHD significantly decreased balance and the number of calbindin-positive cells, while GFAP expression and Bax/Bcl-2 ratio in the cerebellum were significantly increased in the ADHD group compared to the control group (P< 0.05, respectively). In contrast, treadmill exercise and MPH alleviated the ADHD-induced the decrease of balance and the number of calbindine-positive cells, and the increase of GFAP expression and Bax/Bcl-2 ratio in the cerebellum (P< 0.05, respectively). Therefore, the present results suggested that treadmill exercise might exert ameliorating effect on ADHD through reduction of Purkinje cell loss and astrocytic reaction in the cerebellum.
    02/2014; 10(1):22-30. DOI:10.12965/jer.140092
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    • "The first of these found no effects on any measures collected (memory, mood, or wakefulness) (Gilbert et al., 1973), whilst the second found only an increase in anxiety following MPH treatment (Gobbi et al., 2003). The use of repeated drug administration is more common in animal work with the majority of the studies outlined above using repeated administration (McFadyen et al., 2002; Zhu et al., 2007; Bethancourt et al., 2009; Galizio et al., 2009). Nevertheless, many of the studies using repeated administration in animals have administered the drug by injection which does not give comparable pharmacokinetics to the oral administration used in humans. "
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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(7):97. DOI:10.3389/fnins.2013.00097 · 3.66 Impact Factor
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    • "Evidence for enhanced vulnerability to drug-induced plasticity in adolescents has come primarily from studies in rats, where adolescence has been conservatively defined as beginning around postnatal day (P) 28 and extending to P42 [36] or perhaps as late as P60 [37] [38]. For example, studies of adults exposed to AMPH, cocaine, methylphenidate, or nicotine during adolescence have reported enduring deficits in cognitive tasks that assess attention, memory, decision making, and impulse control [39] [40] [41] [42] [43] [44] [45]. Some of these cognitive dysfunctions have been associated with alterations in multiple measures of neural function and gene expression in the PFC, dorsal striatum and nucleus accumbens [39,40,43,46–49]. "
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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; 242(1). DOI:10.1016/j.bbr.2012.12.044 · 3.03 Impact Factor
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