Sex differences in adolescent methylphenidate sensitization: Effects on glial cell-derived neurotrophic factor and brain-derived neurotrophic factor

doi:10.1016/j.bbr.2014.07.014

Behavioural Brain Research

Volume 273, 15 October 2014, Pages 139-143

https://doi.org/10.1016/j.bbr.2014.07.014 Get rights and content

Highlights

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Adolescent females demonstrated enhanced sensitization to methyphenidate (MPH).
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Only adolescent females demonstrated MPH conditioned hyperactivity.
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MPH increased striatal and accumbal glial-cell derived neurotrophic factor (GDNF).
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MPH increased striatal brain-derived neurotrophic factor (BDNF) in males.
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Increases in GDNF and BDNF were predicted by behavioral observations.

Abstract

This study analyzed sex differences in methylphenidate (MPH) sensitization and corresponding changes in glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotprhic factor protein (BDNF) in adolescent male and female rats. After habituation to a locomotor arena, animals were sensitized to MPH (5 mg/kg) or saline from postnatal day (P) 33–49, tested every second day. On P50, one group of animals were injected with saline and behavior assessed for conditioned hyperactivity. Brain tissue was harvested on P51 and analyzed for GDNF protein. A second group of animals was also sensitized to MPH from P33 to 49, and expression of behavioral sensitization was analyzed on a challenge given at P60, and BDNF protein analyzed at P61. Females demonstrated more robust sensitization to MPH than males, but only females given MPH during sensitization demonstrated conditioned hyperactivity. Interestingly, MPH resulted in a significant increase in striatal and accumbal GDNF with no sex differences revealed. Results of the challenge revealed that females sensitized and challenged with MPH demonstrated increased activity compared to all other groups. Regarding BDNF, only males given MPH demonstrated an increase in dorsal striatum, whereas MPH increased accumbal BDNF with no sex differences revealed. A hierarchical regression analysis revealed that behavioral sensitization and the conditioned hyperactivity test were reliable predictors of striatal and accumbal GDNF, whereas sensitization and activity on the challenge were reliable predictors of accumbal BDNF, but had no relationship to striatal BDNF. These data have implications for the role of MPH in addiction and dopamine system plasticity.

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Cited by (7)

Chronic administration of methylphenidate did not affect memory and GDNF levels but increase astrogliosis in adult male rat's hippocampus
2020, Journal of Chemical Neuroanatomy
Citation Excerpt :
Galvanically, Oakes H. et al.(Oakes et al. 2019) reported no significant changes in the GDNF and the BDNF levels of the hippocampus. With regard to brain regions other than the hippocampus, a significant increment in the striatal and the accumbal GDNF level has been reported (Roeding et al. 2014). We argue that this increased GDNF level is due to the secretion of these neurotrophic factors, exerting its inhibitory effect on neural regeneration caused by the reactive astrocytes.
ADHD is the most common developmental disorder affecting approximately three to seven percent of school-aged children and 2.5 percent of adults worldwide. The drug of choice for the pharmacotherapy of ADHD is Methylphenidate (MPH). However, there is growing concerns about side effects resulting from its potential interference with brain anatomical and behavioral development.
This article focuses on the adverse effects of MPH on the rat’s hippocampus.
The animals received an oral dose of 5 mg/kg MPH or normal saline, as the vehicle, on a daily basis for 30 days. Y-maze test, passive avoidance, Barnes maze and field potential recording were conducted. Western blot for detecting the neurotrophic factor of GDNF and immunohistochemistry of astrogliosis were performed.
Our results revealed that MPH treatment suppressed the willingness of rats to explore new environments. Also, it had no effect on improving long-term potentiation, long-term memory and spatial memory in the MPH group as opposed to the control group. There was also a significant increase of astrogliosis in the treated rats’ hippocampi. On the other hand, there was not a significant relationship between MPH administration and the decrement of the GDNF level.
We encourage the need to conduct more research on the adverse effects of MPH on the brain.
Prescription stimulant use is associated with earlier onset of psychosis
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Citation Excerpt :
Preclinical studies indicate that dopamine release in the nucleus accumbens is modulated by estrogen and progesterone, and estrogen enhances amphetamine-stimulated dopamine release (Becker, 1999). Female adolescent rats show stronger behavioral sensitization to methylphenidate than males (Roeding et al., 2014). A plausible mechanism for earlier AOP in those exposed to stimulants is stimulant-induced sensitization of striatal dopamine release.
A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender × stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis.
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Short communicationSex differences in adolescent methylphenidate sensitization: Effects on glial cell-derived neurotrophic factor and brain-derived neurotrophic factor

Highlights

Abstract

Pharmacol Biochem Behav

Neuropharmacology

Biol Psychiatr

Brain Res Brain Res Rev

Behav Brain Res

Pharmacol Biochem Behav

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Prog Brain Res

Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats

J Psychopharmacol

Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in human brain

Arch Gen Psychiatr

Short communication
Sex differences in adolescent methylphenidate sensitization: Effects on glial cell-derived neurotrophic factor and brain-derived neurotrophic factor