Chronic oral methylphenidate treatment increases microglial activation in rats

Abstract

Methylphenidate (MP) is a widely prescribed psychostimulant used to treat attention deficit hyperactivity disorder. Previously, we established a drinking paradigm to deliver MP to rats at doses that result in pharmacokinetic profiles similar to treated patients. In the present study, adolescent male rats were assigned to one of three groups: control (water), low-dose MP (LD; 4/10 mg/kg), and high dose MP (HD; 30/60 mg/kg). Following 3 months of treatment, half of the rats in each group were euthanized, and the remaining rats received only water throughout a 1-month-long abstinence phase. In vitro autoradiography using [H] PK 11195 was performed to measure microglial activation. HD MP rats showed increased [H] PK 11195 binding compared to control rats in several cerebral cortical areas: primary somatosensory cortex including jaw (68.6%), upper lip (80.1%), barrel field (88.9%), and trunk (78%) regions, forelimb sensorimotor area (87.3%), secondary somatosensory cortex (72.5%), motor cortices 1 (73.2%) and 2 (69.3%), insular cortex (59.9%); as well as subcortical regions including the thalamus (62.9%), globus pallidus (79.4%) and substantia nigra (22.7%). Additionally, HD MP rats showed greater binding compared to LD MP rats in the hippocampus (60.6%), thalamus (59.6%), substantia nigra (38.5%), and motor 2 cortex (55.3%). Following abstinence, HD MP rats showed no significant differences compared to water controls; however, LD MP rats showed increased binding in pre-limbic cortex (78.1%) and ventromedial caudate putamen (113.8%). These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

“…Early-life exposure to high doses of potentially toxic chemicals (GBR12909 [92], valproate [93], methylphenidate [94], manganese [95]) impacts microglia with very similar results in the short term. Specifically, increases in cell number, amoeboid/hypertrophic morphology, and expression of activation markers (CD68) have been found across brain regions, including frontal and other cortices, HIP, AMY, striatum, thalamus, substantia nigra, and globus pallidus [92][93][94][95][96].…”

Adenosine A2A Receptor Blockade Ameliorates Mania Like Symptoms in Rats: Signaling to PKC-α and Akt/GSK-3β/β-Catenin

“…The notion of dysregulated dopaminergic neurotransmission was also established in the pathophysiology of various diseases such as schizophrenia and bipolar disorder [33]. Notably, the locomotor hyperactivity induced by MPH has been reported [11] which is associated by a robust increment in DA release in the PFC [34]. This upsurge is attributed not only to MPH ability to increase DA release but also to inhibition of dopamine transporter (DAT) [35] with subsequent decrease in DA uptake an effect mediated by PKC-α phosphorylation of N-terminal of DAT [9,36].…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…For example, there are no prominent therapies for the symptomatic relief of ASD. Methylphenidate, a drug commonly used for the treatment of ADHD, can cause hyperactivity, which is also a symptom of ADHD [ 104 ]. In the case of epilepsy, many types of anticonvulsants have been developed and are in clinical use.…”

“…On the other hand, it has been reported that methylphenidate hydrochloride (MP)-treated rats showed increased microglial activity in multiple regions of the brain (such as the insular cortex, hippocampus, and thalamus) [ 104 ]. MP is widely used in therapies for various psychiatric diseases, including ADHD and chronic sleep disorders.…”