The Journal of Neurophysiology Vol. 87 No. 3 March 2002, pp. 1206-1212
Copyright ©2002 by the American Physiological Society

Effects of Methylphenidate on the Membrane Potential and Current in Neurons of the Rat Locus Coeruleus

 ¹Department of Physiology, Kurume University School of Medicine, Kurume 830-0011; and  ²The Graduate School of Psychology, Kurume University, Kurume 839-8502, Japan

Ishimatsu, Masaru, Yuri Kidani, Akira Tsuda, and Takashi Akasu. Effects of Methylphenidate on the Membrane Potential and Current in Neurons of the Rat Locus Coeruleus. J. Neurophysiol. 87: 1206-1212, 2002. Effects of methylphenidate (MPH), a therapeutic agent used in children presenting the attention deficit hyperactivity disorder (ADHD), on the membrane potential and current in neurons of the rat locus coeruleus (LC) were examined using intracellular and whole cell patch-clamp recording techniques. Application of MPH (30 µM) to artificial cerebrospinal fluid (ACSF) produced a hyperpolarizing response with amplitude of 12 ± 1 mV (n = 29). Spontaneous firing of LC neurons was blocked during the MPH-induced hyperpolarization. Superfusion of LC neurons with ACSF containing 0 mM Ca²⁺ and 11 mM Mg²⁺ (Ca²⁺-free ACSF) produced a depolarizing response associated with an increase in spontaneous firing of the action potential. The MPH-induced hyperpolarization was blocked in Ca²⁺-free ACSF. Yohimbine (1 µM) and prazosin (10 µM), antagonists for ₂ and _2B/2C receptors, respectively, blocked the MPH-induced hyperpolarization in LC neurons. Tetrodotoxin (TTX, 1 µM) produced a partial depression of the MPH-induced hyperpolarization in LC neurons. Under the whole cell patch-clamp condition, MPH (30-300 µM) produced an outward current (I_MPH) with amplitude of 110 ± 6 pA (n = 17) in LC neurons. The I_MPH was blocked by Co²⁺ (1 mM). During prolonged application of MPH (300 µM for 45 min), the hyperpolarization gradually decreased in the amplitude and eventually disappeared, possibly because of depression of norepinephrine (NE) release from noradrenergic nerve terminals. At a low concentration (1 µM), MPH produced no outward current but consistently enhanced the outward current induced by NE. These results suggest that the MPH-induced response is mediated by NE via _2B/2C-adrenoceptors in LC neurons. I_MPH was associated with an increase in the membrane conductance of LC neurons. The I_MPH reversed its polarity at 102 ± 6 mV (n = 8) in the ACSF. The reversal potential of I_MPH was changed by 54 mV per decade change in the external K⁺ concentration. Current-voltage relationship showed that the I_MPH exhibited inward rectification. Ba²⁺ (100 µM) suppressed the amplitude and the inward rectification of the I_MPH. These results suggest that the I_MPH is produced by activation of inward rectifier K⁺ channels in LC neurons.