RESUMEN
Methylphenidate (MPH, Ritalin©) is widely used in the treatment of Attention Deficit Hyperactivity Disorder and recently as a drug of abuse. Although the effect of MPH has been studied in brain regions such as striatum and prefrontal cortex (PFC), the hippocampus has received relatively little attention. It is known that MPH increases the TBS-dependent Long Term Potentiation (LTP) in the CA1 area. However, the cellular and molecular mechanisms involved in this process are still unknown. Using field potential recordings and western blot analysis in rat hippocampal slices of young rats, we found that acute application of MPH enhances LTP in CA3-CA1 synapses in a dose-dependent manner with an EC50 of 73.44±6.32 nM. Using specific antagonists and paired-pulse facilitation protocols, we observed that the MPH-dependent increase of LTP involves not only ß-adrenergic receptors activation but also post-synaptic D1/D5 dopamine receptors. The inhibition of PKA with PKI, suppressed the facilitation of LTP induced by MPH consistent with an involvement of the adenyl cyclase-cAMP-PKA dependent cascade downstream of the activation of D1/D5 receptors. In addition, samples of CA1 areas taken from slices potentiated with MPH presented an increase in the phosphorylation of the Ser845 residue of the GluA1 subunit of AMPA receptors compared to control slices. This effect was reverted by SCH23390, antagonist of D1/D5 receptors, and PKI. Moreover, we found an increase of surface-associated functional AMPA receptors. We propose that MPH increases TBS-dependent LTP in CA3-CA1 synapses through a polysynaptic mechanism involving activation of ß-adrenergic and D1/D5 dopaminergic receptors and promoting the trafficking and insertion of functional AMPA receptors to the plasma membrane.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Metilfenidato/farmacología , Animales , Transporte Biológico Activo/efectos de los fármacos , Membrana Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/metabolismo , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de TejidosRESUMEN
Methylphenidate (MPH) is widely used as a "nootropic" agent and in the treatment of disorders of attention, and has been shown to modulate synaptic plasticity in vitro. Here we present in vivo evidence that this MPH-induced metaplasticity can last long after the end of treatment. MPH (0, 0.2, 1 and 5mg/kg) was administered daily to male rats from postnatal day 42 for 15 days. The animals were tested daily in a radial maze. Long-term potentiation (LTP), a marker of neural plasticity, was induced in vivo in the prefrontal cortex after 2-3h, 15-18 days or 5 months without treatment. The behavioral performance of the 1mg/kg group improved, while that of animals that had received 5mg/kg deteriorated. In the 1 and 5mg/kg groups LTP induced 2-3h after the last MPH treatment was twice as large as in the controls. Further, 15-18 days after the last MPH administration, in groups receiving 1 and 5mg/kg, LTP was about fourfold higher than in controls. However, 5 months later, LTP in the 1mg/kg group was similar to controls and in the 5mg/kg group LTP could not be induced at all. No significant changes of LTP were seen in the low-dose group of animals (0.2mg/kg). Thus, firstly, doses of MPH that improve learning coincide approximately with those that augment LTP. Secondly, MPH-induced increases in LTP can last for several weeks, but these may disappear over longer periods or deteriorate at high doses.
Asunto(s)
Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Metilfenidato/farmacología , Nootrópicos/farmacología , Corteza Prefrontal/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Relación Dosis-Respuesta a Droga , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Microelectrodos , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/fisiología , Ratas Sprague-DawleyRESUMEN
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a drug of abuse that induces learning and memory deficit. However, there are no experimental data that correlate the behavioral evidence with models of synaptic plasticity such as long-term potentiation (LTP) or long-term depression (LTD). Using field potential recordings in rat hippocampal slices of young rats, we found that acute application of MDMA enhances LTP in CA3-CA1 synapses without affecting LTD. Using specific antagonists and paired-pulse facilitation protocols we observed that the MDMA-dependent increase of LTP involves presynaptic 5-HT2 serotonin receptors and postsynaptic D1/D5 dopamine receptors. In addition, the inhibition of PKA suppresses the MDMA-dependent increase in LTP, suggesting that dopamine receptor agonism activates cAMP-dependent intracellular pathways. We propose that MDMA exerts its LTP-altering effect involving a polysynaptic interaction between serotonergic and dopaminergic systems in hippocampal synapses. Our results are compatible with the view that the alterations in hippocampal LTP could be responsible for MDMA-dependent cognitive deficits observed in humans and animals.