Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects

LeBlanc-Duchin, Denise; Taukulis, Harald K.

doi:10.1016/j.nlm.2007.04.010

Cited by 42 publications

(24 citation statements)

References 43 publications

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“…40 This finding is in line with animal studies that reported increased anxiety and depression scores in juvenile methylphenidate-treated rats 41 and memory impairments. 42 In addition, cohort investigations have provided evidence for age-dependent effects. For example, adult ADHD is associated with a high rate of substance abuse, 43 but ADHD stimulant medication use in childhood does not increase this risk 44,45 and may even decrease such vulnerability.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

et al. 2016

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IMPORTANCE 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. OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES 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. RESULTS 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). CONCLUSIONS AND RELEVANCE 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. TRIAL REGISTRATION identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103.

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Section: Discussionmentioning

confidence: 99%

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

et al. 2016

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“…Several of these studies injected MP either subcutaneously or intraperitoneally, which differs significantly from oral administration, specifically with respect to time to peak serum concentration, half-life, and rate of elimination (Kuczenski and Segal, 2001), as well as absolute magnitude and time course of increases in extracellular DA and locomotor responses (Gerasimov et al, 2000; Kuczenski and Segal, 2001). Studies that have used oral dosing have done so by gavage (Kuczenski and Segal, 2001; Justo et al, 2010), which is stressful and can cause injury (Brown et al, 2000; Balcombe et al, 2004), or by administering MP on an oyster cracker or by mixing with chow (LeBlanc-Duchin and Taukulis, 2007; Zhu et al, 2010). Although the latter is less stressful and dangerous, oral administration results in peak serum concentration 15 min post-administration, and this concentration has been shown to drop by half within an additional 5 min (Patrick et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

Robison

Michaelos

Gandhi

et al. 2017

Front. Behav. Neurosci.

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Methylphenidate (MP) is a psychostimulant prescribed for Attention Deficit Hyperactivity Disorder. Previously, we developed a dual bottle 8-h-limited-access-drinking-paradigm for oral MP treatment of rats that mimics the pharmacokinetic profile of treated patients. This study assessed sex differences in response to this treatment. Male and female Sprague Dawley rats were assigned to one of three treatment groups at 4 weeks of age (n = 12/group): Control (water), low dose (LD) MP, and high dose (HD) MP. Rats drank 4 mg/kg MP (LD) or 30 mg/kg MP (HD) during the first hour, and 10 mg/kg (LD) or 60 mg/kg MP (HD) for the remaining 7 h each day. Throughout 3 months of treatment, rats were monitored for body weight, food intake, and fluid intake; as well as tested for open field behavior, circadian activity, novel object recognition, and social interaction. Chronic MP treated rats exhibited reduced fluid intake during distinct treatment weeks to a greater extent in males, and reduced total fluid intake in males only. HD MP treatment decreased body weight in both sexes, while HD MP increased total food intake in females only, likely to offset energy deficits resulting from MP-induced hyperactivity. LD and HD MP increased locomotor activity in the open field, particularly in females and during later treatment weeks. MP dose-dependently increased activity during the dark cycle of circadian testing in females, while in males hyperactivity was only exhibited by HD rats. HD MP increased center activity to a greater extent in males, while MP increased rearing behavior in females only. MP had no effect on social behavior or novel object recognition in either sex. This study concludes that chronic oral MP treatment at clinically-relevant dosages has significant effects on food intake, body weight, open field behavior, and wake cycle activity. Particularly marked sex differences were apparent for locomotor activity, with females being significantly more sensitive to the hyperactivating effects of the drug. These findings suggest that chronic MP exposure beginning in adolescence can have significant behavioral effects that are both dose- and sex-dependent, and raise concerns regarding the reversibility of these effects post-discontinuation of treatment.

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“…Additionally, many studies that have aimed to explore the effects of oral MP utilize the gavage method (Kuczenski and Segal, 2002; Justo et al, 2010), which can result in a significant stress response, as well as aspiration, and/or pulmonary injury in rats (Brown et al, 2000; Balcombe et al, 2004). Other studies have utilized voluntary oral consumption of MP (administered on oyster crackers or mixed with chow) to avoid these issues (LeBlanc-Duchin and Taukulis, 2007; Zhu et al, 2010); however, these methods also have some limitations. Oral administration results in peak serum concentration 15 min post-administration, and this concentration has been shown to drop by half within an additional 5 min (Patrick et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior

Thanos

Robison

Steier

et al. 2015

Pharmacology Biochemistry and Behavior

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Most animal studies using methylphenidate (MP) do not administer it the same way it is administered clinically (orally), but rather by injection, resulting in an altered pharmacokinetic profile (i.e. quicker and higher peak concentrations). Here, we evaluated several oral-dosing regimens in rats, including dual-dose drinking, to mimic the clinical drug delivery profile. Using an 8-hour-limited-access-drinking-paradigm, MP solutions were delivered at different doses (20, 30, or 60 mg/kg/day; as well as dual-dosages of 4 and 10 mg/kg/day, 20 and 30 mg/kg/day, or 30 and 60 mg/kg/day, in which the low dose was administered in the first hour of drinking followed by 7 h of drinking the high dose). Blood was sampled and plasma was assayed for MP levels at many time points. Results showed that an 8-hour limited drinking of a dual-dosage 30/60 mg/kg MP solution achieved a pharmacokinetic profile similar to clinically administered doses of MP at the high end of the spectrum (peaking at ~30 ng/mL), while the 4/10 mg/kg MP dual-dosage produced plasma levels in the range produced by typically prescribed clinical doses of MP (peaking at ~8 ng/mL). Treatment with the higher dual-dosage (HD: 30/60 mg/kg) resulted in hyperactivity, while the lower (LD: 4/10 mg/kg) had no effect. Next, chronic effects of these dual-dosages were assessed on behavior throughout three months of treatment and one month of abstinence, beginning in adolescence. MP dose-dependently decreased body weight, which remained attenuated throughout abstinence. MP decreased food intake during early treatment, suggesting that MP may be an appetite suppressant and may also speed metabolism and/or suppress growth. Chronic HD MP resulted in hyperactivity limited during the dark cycle; decreased exploratory behavior; and increased anxiolytic behavior. These findings suggest that this dual-dosage-drinking-paradigm can be used to examine the effects of clinically relevant pharmacokinetic doses of MP, and that chronic treatment with such dosages can result in long-lasting developmental and behavioral changes.

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Chronic oral methylphenidate administration to periadolescent rats yields prolonged impairment of memory for objects

Cited by 42 publications

References 43 publications

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder

Sex Differences in the Physiological and Behavioral Effects of Chronic Oral Methylphenidate Treatment in Rats

A pharmacokinetic model of oral methylphenidate in the rat and effects on behavior

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