Dataset Information

Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons.

ABSTRACT: Methylphenidate (MPH) has long been used to treat attention-deficit/hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established.Juvenile (postnatal day [PD] 15) and adult (PD90) Sprague Dawley rats were treated with MPH or saline. Whole-cell patch clamp recording was used to examine the neuronal excitability and synaptic transmission in pyramidal neurons of prefrontal cortex. Recovery from MPH treatment was also examined at 1, 5, and 10 weeks following drug cessation.A dose of 1 mg/kg intraperitoneal MPH, either single dose or chronic treatment (well within the accepted therapeutic range for adults), produced significant depressive effects on pyramidal neurons by increasing hyperpolarization-activated currents in juvenile rat prefrontal cortex, while exerting excitatory effects in adult rats. Minimum clinically-relevant doses (.03 to .3 mg/kg) also produced depressive effects in juvenile rats, in a linear dose-dependent manner. Function recovered within 1 week from chronic 1 mg/kg treatment, chronic treatment with 3 and 9 mg/kg resulted in depression of prefrontal neurons lasting 10 weeks and beyond.These results suggest that the juvenile prefrontal cortex is supersensitive to methylphenidate, and the accepted therapeutic range for adults is an overshoot. Juvenile treatment with MPH may result in long-lasting, potentially permanent, changes to excitatory neuron function in the prefrontal cortex of juvenile rats.

SUBMITTER: Urban KR

PROVIDER: S-EPMC3433628 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons.

Urban Kimberly R KR Waterhouse Barry D BD Gao Wen-Jun WJ

Biological psychiatry 20120519 10

<h4>Background</h4>Methylphenidate (MPH) has long been used to treat attention-deficit/hyperactivity disorder (ADHD); however, its cellular mechanisms of action and potential effects on prefrontal cortical circuitry are not well understood, particularly in the developing brain system. A clinically relevant dose range for rodents has been established in the adult animal; however, how this range will translate to juvenile animals has not been established.<h4>Methods</h4>Juvenile (postnatal day [PD ...[more]

PMID: 22609367

Similar Datasets

Project description:Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system.To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function.A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status.Treatment with either methylphenidate or a matched placebo for 16 weeks.Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses.Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P?=?.04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P?=?.03).We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up.identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.

Project description:Limited research has investigated the development of auditory ERPs in young children, and particularly how stimulus intensity may affect these auditory ERPs. Previous research has also yielded inconsistent findings regarding differences in the development of auditory ERPs in autism and typical development. Furthermore, stimulus intensity may be of particular interest in autism insofar as autistic people may have atypical experiences of sound intensity (e.g., hyperacusis). Therefore, the present study examined associations between age and ERPs evoked by tones of differing intensities (50, 60, 70, and 80 dB SPL) in a large sample of young children (2-5 years) with and without an autism diagnosis. Correlations between age and P1 latencies were examined, while cluster-based permutation testing was used to examine associations between age and neural response amplitudes, as well as group differences in amplitude, over all electrode sites in the longer time window of 1-350 ms. Older autistic participants had faster P1 latencies, but these effects only attained significance over the right hemisphere in response to soft 50 dB sounds. Autistic participants had slower P1 responses to 80 dB sounds over the right hemisphere. Over the scalp regions associated with the later N2 response, more negative response amplitudes (that is, larger N2 responses) were observed in typically-developing than autistic participants. Furthermore, continuous associations between response amplitudes and age suggested that older typically-developing participants exhibited stronger N2 responses to all intensities, though this effect may have at least in part reflected the absence of small positive voltage deflections in the N2 latency window. Age was associated with amplitudes of responses to 50 dB through 70 dB sounds in autism, but in contrast to Typical Development (TD), little evidence of relationships between age and amplitudes in the N2 latency window was found in autism in the 80 dB condition. Although caution should be exercised in interpretation due to the cross-sectional nature of this study, these findings suggest that developmental changes in auditory responses may differ across diagnostic groups in a manner that depends on perceived loudness and/or stimulus intensity.

Dataset Information

Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons.

Publications

Distinct age-dependent effects of methylphenidate on developing and adult prefrontal neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets