Methylphenidate enhances inhibitory synaptic transmission by increasing the content of norepinephrine in the locus coeruleus of juvenile rats

The present study examined the effect of methylphenidate (MPH), a psychostimulant, on nor-adrenergic transmission in the locus coeruleus (LC) of juvenile rats. Intracellular recordings showed that MPH (>3 μM) produced a hyperpolarizing response associated with a decrease in the rate of spontaneously firing action potentials. MPH (1 μM) enhanced the amplitude of the inhibitory postsynaptic potential (IPSP) mediated by norepinephrine (NE), but did not change the excitatory postsynaptic potential (EPSP) mediated by excitatory amino acids. Whole-cell patch-clamp recordings showed that MPH (0.3-30 μM) produced an outward current (I(MPH)) and enhanced the inhibitory postsynaptic current (IPSC) in neurons of the juvenile rat LC. MPH (30 μM) enhanced the NE-induced outward current (I(NE)). Bath-application of yohimbine (1 μM) produced an inward current and blocked the MPH-induced enhancement of the IPSC. Yohimbine (1 μM) depressed not only the I(NE) but also the I(MPH) in juvenile rat LC neurons. The current-voltage relationship of the I(MPH) showed inward rectification and reversed polarity at -91.1±4.3 mV (n=5). Ba(2+) (100 μM) blocked the I(MPH), indicating that the I(MPH) is mediated by Ba(2+)-sensitive inward rectifier K(+) current. These results suggest that MPH enhances inhibitory synaptic transmission by increasing the concentration of NE at noradrenergic synapses in juvenile rat LC neurons.