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

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.

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus

“…However, PNE animals treated with a single oral dose of MPH show a complete recovery of LTP (PNE: 127.8 ± 1.75 n = 10.15; PNE + MPH: 151.6 ± 3.246 n = 9.14). As we have previously reported [20], a single dose of MPH increases hippocampal LTP in control no−PNE by about 50%. To determine whether the recovery of LTP by MPH was due to presynaptic or rather postsynaptic changes, we used a paired-pulse facilitation protocol that allows us to study the facilitation of synaptic response as the ratio of onset slopes of first and second evoked responses.…”

“…We have demonstrated that, at the hippocampal CA3/CA1 synapse, MPH induces a DA-and NE-receptor-dependent increase of LTP due to the postsynaptic insertion of AMPA receptors (AMPAR) [19]. Furthermore, we have shown that MPH augments hippocampal CA3/CA1 LTP depending on alpha1 and D1/D5 receptor activation via the intracellular messenger chain involving the cAMP/PKA/PSer845 pathway [20].…”

“…Several phosphorylation events occur in AMPA receptors induced by TBS during LTP development. It has been documented that, during hippocampal LTP, CaMKII/PKCdependent and PKA-dependent phosphorylation of residues Ser845 and Ser831 (among others) occur at the GluA1 subunit of AMPA receptors, associated to the translocation and fusion of receptor-containing vesicles into the postsynaptic membrane [20].…”

Cumulative exposure to ADHD medication is inversely related to hippocampus subregional volume in children

“…The authors proposed that the volumetric reductions were caused by neuronal atrophy within the subregions ( Al-Amin et al, 2018 ). Moreover, chronic methylphenidate (MPH) exposure at high doses has been shown to induce neuronal cell death in the rat hippocampus CA1 regions ( Carvallo et al, 2018 , Schmitz et al, 2017 ).…”

“…Pharmacological studies conducted in rodents have found that psychostimulants increased synaptic levels of DA and NE in several brain regions, notably the prefrontal cortex, a region robustly associated with ADHD, and the hippocampus ( Berridge and Devilbiss, 2011 , Carvallo et al, 2018 , Kuczenski and Segal, 2001 ). Changes in the hippocampus induced by psychostimulants have been implicated in the therapeutic response and as a potential side-effect ( Britton & Bethancourt, 2009 ).…”