Tipepidine activates VTA dopamine neuron via inhibiting dopamine D2 receptor-mediated inward rectifying K+ current
Introduction
Recently, we reported that tipepidine produces an antidepressant-like effect in the forced swimming test in rats (Kawaura et al., 2009). Interestingly, this was also the case for adrenocorticotropic hormone (ACTH)-treated rats (Kawaura et al., 2011). In the rats, the immobility time in the forced swimming which is one of criteria for an antidepressant-like effect, is not affected by known antidepressants such as imipramine (Kitamura et al., 2002), suggesting that this animal may be a model of depression resistant to treatment with known antidepressants. Many currently available antidepressants from the first to the fourth generation produce an antidepressant effect by increasing the concentration of monoamines such as serotonin (5-HT) and noradrenaline (NA) in the synapse by inhibiting the 5-HT (SERT) and NA transporters (NAT). Our recent preliminary data using in vivo microdialysis showed that tipepidine increases not only 5-HT and NA, but also dopamine (DA) levels in the prefrontal cortex and nucleus accumbens (NAc) of rats (Kawaura et al., 2010, Hamao et al., 2011) despite tipepidine having a small effect on SERT, NAT and DA transporters (DAT) (Mitsubishi-Tanabe, Pharma. Corp., Japan, Personal communication). Then, it is noted that the antidepressant-like effect caused by tipepidine was effectively blocked by SCH23390, a DA D1 receptor antagonist (Kawaura et al., 2012), suggesting that the activation of dopaminergic system participates in the antidepressant-like effect of this drug in the forced swimming test. The increase of DA level in the NAc may contribute to a novel type of antidepressant effect, because recent studies have shown that modulation of the DA level in the NAc may be effective in treating depression resistant to standard treatment (Cassano et al., 2004, Higuchi et al., 2005). In addition to this, the deep brain stimulation (DBS) of the NAc is effective not only on treatment-resistant depression, but also on obsessive–compulsive disorder (OCD) (Denys et al., 2010). Tipepidine also has an inhibitory effect on marble-burying behavior (Honda et al., 2010) which is considered to be a potential model of OCD based on behavioral similarity (Njung’e and Handley, 1991, Ichimaru et al., 1995, Londei et al., 1998). This evidence also implies that the behavioral effects of tipepidine may be due to modulating mesolimbic DA pathway. Incidentally we previously reported that dextromethorphan, a centrally acting antitussive, inhibits G protein-coupled inwardly rectifying potassium (GIRK) channel currents in dorsal raphe neurons (Ishibashi et al., 2000). This was also the case for other centrally acting antitussives such as tipepidine (Takahama et al., 2009). GIRK channel subtypes are widely distributed in the brain. GIRK1, GIRK2 and GIRK3 are expressed in the locus coeruleus, GIRK2 and GIRK3 are expressed in the ventral tegmental area (VTA), and GIRK3 is expressed in the raphe nucleus (Karschin et al., 1996). GIRK channels are coupled to various G-protein-coupled receptors (GPCRs) such as the monoamine 5-HT1A, α2, and D2 receptors. GPCR-mediated activation of GIRK channels stabilize the excitation of neurons through the hyperpolarization caused by outward currents carried by K+ (North, 1989, Signorini et al., 1997, Wickman et al., 1998). Thus, some researchers have suggested that the inhibition of GIRK channels should activate neurons, facilitating the release of neurotransmitters including monoamine transmitters (North, 1989; Signorini et al., 1997, Wickman et al., 1998). Considering the circumstances, we hypothesize that tipepidine activates mesolimbic DA neurons through the direct inhibition of GIRK channels. In fact, we recently reported that tipepidine increased the expression levels of c-Fos like protein, a marker of neuronal excitation, in the VTA and NAc neurons (Kawahara et al., 2013). However, no direct electrophysiological evidence has been obtained as to whether or not tipepidine activates neurons in the VTA and NAc. In this study, we investigated the effects of tipepidine on DA D2 receptors-mediated GIRK channel currents (IDA(GIRK)) and the excitability of DA neurons acutely dissocated from the VTA in rats by using patch clamp and immunohistochemical techniques.
Section snippets
Preparation
Neurons were acutely dissociated from the VTA of rats as previously described (Kaneda et al., 1988, Arim et al., 1998, Jin and Akaike, 1998). Briefly, 8–15-day-old Wistar rats were decapitated under diethyl ether anesthesia. The brain was quickly removed from the skull and was sliced at the bregma −6.04 mm to −5.20 mm with a thickness of 375 μm by using a tissue slicer (YIS-102, ASTEC, Fukuoka, Japan) in Krebs solution containing (in mM): NaCl 124, KCl 5, KH2PO4 1.2, MgSO4 1, CaCl2 2, NaHCO3 24
DA responses
Because VTA DA neurons express an inward rectifying nonselective cation current in response to membrane hyperpolarization, termed the hyperpolarization-activated cation current (Ih) (Neuhoff et al., 2002, Liu et al., 2003, Okamoto et al., 2006, Hopf et al., 2007), we identified putative DA neurons with the presence of Ih. To activate Ih in the voltage-clamp mode, neurons were clamped at a holding potential of −60 mV, and then hyperpolarizing voltage step pulses were applied to the neurons from
Discussion
Prior to studies on the actions of tipepidine dopamine neurons in the VTA, we verified the actions of DA on VTA neurons. The present study has shown the effect of DA on acutely dissociated neurons of VTA. Because the data were obtained from DA-sensitive neurons, the DA-insensitive neurons were not considered in this study. The effect of DA on acutely dissociated neurons of the SNc was previously reported (Uchida et al., 2000). Both DA-insensitive neurons of the VTA and the SNc have almost the
Acknowledgements
This study was supported in part by a Grant-in-Aid for Scientific Research (B) from the Japanese Society for the Promotion of Science (JSPS).
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