Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons

Brandon, Cindy L.; Marinelli, Michela; White, Francis J.

doi:10.1016/s0006-3223(03)00787-x

Cited by 99 publications

(56 citation statements)

References 40 publications

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“…In light of these findings, it is not surprising that differences in the effects of drugs of abuse in adolescent rodents, as compared to adult rodents, have been reported. For example, younger animals have been shown to develop less sensitization than adult animals following repeated exposure to stimulants such as cocaine [14], [29], amphetamine [28], and methylphenidate [9,10]. Similar results have been observed for alcohol [12], [39].…”

Section: Introductionmentioning

confidence: 61%

“…Similar to ethanol, toluene interacts with GABA A receptors [1,2], suggesting that this mechanism may also contribute to the age differences observed in the present study. In addition, younger animals have been shown to develop less locomotor sensitization than adult animals following repeated exposure to other drugs of abuse such as alcohol [12], [39], cocaine [14], [29], amphetamine [28], and methylphenidate [9,10]. Together, these results suggest that initial sensitivity to the acute locomotor effects of toluene (and perhaps those of other inhalants) follows a developmental time-course in which sensitivity increases as rats leave adolescence and enter adulthood.…”

Section: Discussionmentioning

confidence: 94%

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Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

Bowen¹,

Charlesworth²,

Tokarz³

et al. 2007

Neurotoxicology and Teratology

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Volatile organic solvent (inhalant) abuse continues to be a major health concern throughout the world. Of particular concern is the abuse of inhalants by adolescents because of its toxicity and link to illicit drug use. Toluene, which is found in many products such as glues and household cleaners, is among the most commonly abused organic solvents. While studies have assessed outcomes of exposure to inhalants in adult male animals, there is little research on the neurobehavioral effects of inhalants in female or younger animals. In attempt to address these shortcomings, we exposed male and female Long-Evans rats to 20 min of 0, 2,000, 4,000, or 8,000 parts per million (ppm) inhaled toluene for 10 days in rats aged postnatal (PN) day 28-39 (adolescent), PN44-PN55, or >PN70 (adult). Animals were observed individually in 29-l transparent glass cylindrical jars equipped with standard photocells that were used to measure locomotor activity. Toluene significantly increased activity as compared to air exposure in all groups of male and female rats with the magnitude of locomotor stimulation produced by 4000 ppm toluene being significantly greater for female adults than during any age of adolescence. The results demonstrate that exposure to abuse patterns of high concentrations of toluene through inhalation can alter spontaneous locomotor behavior in rats and that the expression of these effects appears to depend upon the postnatal age of testing and sex of the animal.

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Section: Introductionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 94%

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

Bowen¹,

Charlesworth²,

Tokarz³

et al. 2007

Neurotoxicology and Teratology

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“…In a previous study in gerbils, adolescent treatment with methylphenidate normalized dopaminergic fiber density in animals with methamphetamine-lesioned brains, but it did not affect control animals (Grund et al, 2007). On the other hand, other studies have also reported long-lasting changes in healthy animals, eg, reduced striatal dopamine transporter densities (Moll et al, 2001) and altered firing rates of midbrain dopaminergic neurons (Brandon et al, 2003). In line with this, behaviorally, pre-adolescent treatment with methylphenidate increased aversion to cocaine and reduced response to its rewarding properties in adult rats (Andersen et al, 2002), while long-term oral treatment during adolescence hardly affected measures of anxietylike behavior in otherwise healthy rats (Britton and Bethancourt, 2009).…”

Section: Limited Effects Of Methylphenidate Exposure On Healthy Brainsmentioning

confidence: 85%

“…Animal models may therefore afford a well-controlled experimental setup to disentangle the effects of neuropathology and chronic psychostimulant treatment on the developing brain. Studies in rats have shown that early exposure to methylphenidate can affect midbrain dopaminergic neurons (Brandon et al, 2003), cause profound reductions in striatal dopamine transporter levels (Moll et al, 2001), but could also prevent methamphetamine-triggered suppression of dopaminergic innervation of the prefrontal cortex and amygdala (Grund et al, 2007). However, it remains unclear to what extent long-term exposure of the normally developing adolescent brain to methylphenidate-in the absence of ADHDaffects gross tissue morphology and function as observed in patient studies.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Marel¹,

Klomp²,

Meerhoff³

et al. 2013

Neuropsychopharmacol

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Methylphenidate is a widely prescribed psychostimulant for treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents, which raises questions regarding its potential interference with the developing brain. In the present study, we investigated effects of 3 weeks oral methylphenidate (5 mg/kg) vs vehicle treatment on brain structure and function in adolescent (post-natal day [P]25) and adult (P65) rats. Following a 1-week washout period, we used multimodal magnetic resonance imaging (MRI) to assess effects of age and treatment on independent component analysis-based functional connectivity (resting-state functional MRI), D-amphetamineinduced neural activation responses (pharmacological MRI), gray and white matter tissue volumes and cortical thickness (postmortem structural MRI), and white matter structural integrity (postmortem diffusion tensor imaging (DTI)). Many age-related differences were found, including cortical thinning, white matter development, larger dopamine-mediated activation responses and increased striatal functional connectivity. Methylphenidate reduced anterior cingulate cortical network strength in both adolescents and adults. In contrast to clinical observations from ADHD patient studies, methylphenidate did not increase white matter tissue volume or cortical thickness in rat. Nevertheless, DTI-based fractional anisotropy was higher in the anterior part of the corpus callosum following adolescent treatment. Furthermore, methylphenidate differentially affected adolescents and adults as evidenced by reduced striatal volume and myelination upon adolescent treatment, although we did not observe adverse treatment effects on striatal functional activity. Our findings of small but significant age-dependent effects of psychostimulant treatment in the striatum of healthy rats highlights the importance of further research in children and adolescents that are exposed to methylphenidate.

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“…Previous studies reporting chronic effects in rats resulting from administration of MPH employed various routes, durations, and age intervals of administration (Greeley and Kizer, 1980;Bolanos et al, 2003;Carlezon et al, 2003;Brandon et al, 2003). Greeley and Kizer (1980) investigated the effects on growth and endocrine function in Sprague-Dawley rats of administering MPH via twice daily subcutaneous injections to male and females for 21 days beginning on 5-7 days of age at daily doses of 1, 3, 10, 35, or 100 mg/ kg, or for 18 days beginning on 18-21 days of age at daily doses of 35 or 100 mg/kg, twice daily, and to females for 30 days beginning on 21-23 days of age at daily doses of 35 or 100 mg/kg.…”

Section: Introductionmentioning

confidence: 99%

Juvenile toxicity assessment of d,l‐methylphenidate in rats

Beckman¹,

Schneider²,

Youreneff³

et al. 2008

Birth Defects Research Pt B

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BACKGROUND:The oral administration of d,l-methylphenidate (MPH) was designed to encompass the major part of postnatal development in the rat and to evaluate potential chronic effects. METHODS: Wistar Hannover rats were crossfostered on postpartum day 0 (day of birth) and were administered MPH at doses of 5, 50, and 100 mg/kg/day (mpkd) on postpartum days 7 to 70. Clinical signs, body weight, food consumption, developmental, behavioral, clinical/ anatomic pathology, toxicokinetic, and fertility evaluations were conducted. RESULTS: MPH-related effects on clinical signs, body weight, and behavior tests were noted. Increased locomotor activity and cage biting/chewing occurred at Z 5 mpkd (females) and Z 50 mpkd (males) and were absent after dosing ceased. Body weight parameters were decreased at Z 50 mpkd and were comparable to controls at 5 weeks' recovery. Open field motor activity tests conducted 2 weeks after dosing ceased revealed decreased peripheral beam breaks at Z 50 mpkd. Passive avoidance tests conducted 3 weeks after dosing ceased indicated decreased females reaching learning criterion at 100 mpkd. This is considered of nominal significance as there were no effects in the water maze test or retention in passive avoidance test. After multiple doses, females exhibited higher exposures than males and exposures were reduced in all groups in comparison to those after a single dose. CONCLUSIONS: These results suggest that MPH can produce enduring behavioral effects in rats. The no-toxicologic-effect-level was 5 mpkd, associated with AUC (0-24 h) racemate values in males and females, respectively, of 101 and 153 ng.h/mL after chronic dosing. Birth Defects Res (Part B) 83: 48-67, 2008.

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Adolescent exposure to methylphenidate alters the activity of rat midbrain dopamine neurons

Cited by 99 publications

References 40 publications

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

Long-Term Oral Methylphenidate Treatment in Adolescent and Adult Rats: Differential Effects on Brain Morphology and Function

Juvenile toxicity assessment of d,l‐methylphenidate in rats

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