[Effects of milnacipran on neuronal excitability and synaptic transmission in neurons of the rat locus coeruleus].
Effects of milnacipran (MIL), a selective serotonin and noradrenaline (NA) reuptake inhibitor, on the neuronal excitability and synaptic transmission in the rat locus coeruleus (LC) were examined by intracellular and whole-cell patch-clamp recording techniques. We compared MIL and methylphenidate (MPH), a selective NA and dopamine reuptake inhibitor, as a therapeutic agent for attention deficit/hyperactivity disorder. Application of MPH (1-100 microM) and MIL (1-100 microM) to artificial cerebrospinal fluid (ACSF) produced a hyperpolarizing response in LC neurons in a concentration-dependent manner. Spontaneous firing of LC neurons was blocked during the hyperpolarization. The MIL-induced hyperpolarization was blocked by yohimbine (1 microM), an antagonist for alpha-adrenoceptors. These results suggest that the MIL-induced hyperpolarization is mediated by NA via alpha2-adrenoceptors in LC neurons. Under the whole-cell patch-clamp condition, prolonged application of MIL produced an outward current which lasted as long as MIL existed in the ACSF. The outward current induced by NA was enhanced by MIL in LC neurons. MIL enhanced the amplitude and duration of the inhibitory postsynaptic potential, while it depressed the excitatory postsynaptic potential. The results indicated that both MIL and MPH showed almost the same effects on neuronal activity and synaptic transmission in the rat LC. These results suggest that MIL increases the concentration of NA at synaptic clefts by inhibiting the NA reuptake system in the rat LC.
Kidani
Yuri
Y
Department of Physiology, Kurume University School of Medicine, Kurume, Fukuoka.
Ishimatsu
Masaru
M
Kuwahata
Takashi
T
Yamashita
Yushiro
Y
Akasu
Takashi
T
Matsuishi
Toyojiro
T
D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D000078764:Milnacipran; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*
D003521:Cyclopropanes; D008774:Methylphenidate; D000078764:Milnacipran; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors