Single and Repeated Administration of Methylphenidate Modulates Synaptic Plasticity in Opposite Directions via Insertion of AMPA Receptors in Rat Hippocampal Neurons.

Claudia Carvallo,Gonzalo Ugarte,Luis Constandil,Ricardo Delgado,Bernardo Morales,Darwin Contreras,Marc L Zeise,Floria Pancetti,Carlos Rozas,Ricardo Piña

doi:10.3389/fphar.2018.01485

Abstract

Methylphenidate (MPH) is widely used in the treatment of Attention Deficit Hyperactivity Disorder. Several lines of evidence support that MPH can modulate learning and memory processes in different ways including improvement and impairment of test performances. A relevant factor in the efficacy of treatment is whether administration is performed once or several times. In this study we demonstrate opposite effects of MPH on performance of preadolescent rats in the Morris Water Maze test. Animals treated with a single dose (1 mg/kg) performed significantly better compared to controls, while in animals treated with repetitive administration at the same concentration performance was reduced. We found that hippocampal LTP in slices from rats treated with a single dose was increased, while LTP from rats treated with repetitive injections of MPH was lower than in controls. Using Western blot of CA1 areas from potentiated slices of rats treated with a single dose we found a significant increase of phosphorylation at Ser845 of GluA1 subunits, associated to an increased insertion of GluA1-containing AMPARs in the plasma membrane. These receptors were functional, because AMPA-dependent EPSCs recorded on CA1 were enhanced, associated to a significant increase in short-term plasticity. In contrast, CA1 samples from rats injected with MPH during six consecutive days, showed a significant decrease in the phosphorylation at Ser845 of GluA1 subunits associated to a lower insertion of GluA1-containing AMPARs. Accordingly, a reduction of the AMPA-mediated EPSCs and short-term plasticity was also observed. Taken together, our results demonstrate that single and repeated doses with MPH can induce opposite effects at behavioral, cellular, and molecular levels. The mechanisms demonstrated here in preadolescent rats are relevant to understand the effects of this psychostimulant in the treatment of ADHD.

Highlights

Methylphenidate (MPH), an amphetamine derivative, is widely prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and increasingly used as a drug of abuse by students (Sahakian and Morein-Zamir, 2007; Weyandt et al, 2016)
In slices from repeatedly treated rats with MPH, AMPA-mediate excitatory postsynaptic currents (EPSCs) and short-term plasticity were significantly lower than in controls (n = 4,5; ∗p < 0.05; Figures 6D–F). This effect was reverted by superfusing those slices 7 min before until 7 min after TBS with 50 μM of forskolin (n = 3,5; #p < 0.05; Figures 6D–F). These results suggest that the increase and decrease of short-term plasticity induced by single and repeated MPH treatment, respectively, is mainly due to an increase/reduction of the AMPA currents, confirming the functionality and importance of the AMPARs for the effects observed after treatment with MPH
The results demonstrate that the clinically relevant dose of 1 mg/kg i.p. administered once improves visuo-spatial learning augmenting synaptic plasticity, whereas repeated administration caused the opposite effect, reducing LTP and learning swiftness

Summary

INTRODUCTION

Methylphenidate (MPH), an amphetamine derivative, is widely prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and increasingly used as a drug of abuse by students (Sahakian and Morein-Zamir, 2007; Weyandt et al, 2016). Chronic administration of cocaine or amphetamine in early development of rats has been found to cause functional changes in the nervous system that may translate into behavioral and cognitive deficits (Robinson and Kolb, 2004). This includes impaired performance on learning measures, such as recognition and spatial memory (Bisagno et al, 2003). In the present study we investigated the effects of a single administration of MPH (1 mg/kg) compared to a repetitive one at the same dose, demonstrating changes in visuo-spatial learning and plasticity that lasted more than 24 h. Single administration of MPH improved the learning performance, enhancing LTP by insertion of AMPA-GluA1 receptor subunits, while repeated administration impaired behavioral performance, decreasing the LTP due to a decreased number of AMPA-GluA1 receptor subunits in the plasma membrane

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION

ETHICS STATEMENT