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: IMPORTANCE Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described. OBJECTIVE To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction. DESIGN Randomized, placebo-controlled, before-after, crossover study. SETTING Clinical research center. PARTICIPANTS Eighteen nonabstaining individuals with cocaine use disorders. INTERVENTIONS Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects). MAIN OUTCOMES AND MEASURES Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire. RESULTS Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections. CONCLUSIONS AND RELEVANCE These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.JAMA Psychiatry 06/2013; · 12.01 Impact Factor
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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 01/2013; 7:97.
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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.Journal of exercise rehabilitation. 02/2014; 10(1):22-30.