• The Korean Journal of Physiology and Pharmacology
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• v.22 no.4
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• pp.419-425
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• 2018

The superficial dorsal horn of the spinal cord plays an important role in pain transmission and opioid activity. Several studies have demonstrated that opioids modulate pain transmission, and the activation of ${\mu}$-opioid receptors (MORs) by opioids contributes to analgesic effects in the spinal cord. However, the effect of the activation of MORs on GABAergic interneurons and the contribution to the analgesic effect are much less clear. In this study, using transgenic mice, which allow the identification of GABAergic interneurons, we investigated how the activation of MORs affects the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive afferent and GABAergic interneurons. We found that a selective ${\mu}$-opioid agonist, [$D-Ala^2$, $NMe-Phe^4$, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by $K^+$ channels in GABAergic interneurons. In addition, DAMGO reduced the amplitude of evoked excitatory postsynaptic currents (EPSCs) of GABAergic interneurons which receive monosynaptic inputs from primary nociceptive C fibers. Taken together, we found that DAMGO reduced the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive C fibers and GABAergic interneurons. These results suggest one possibility that suppression of GABAergic interneurons by DMAGO may reduce the inhibition on secondary GABAergic interneurons, which increase the inhibition of the secondary GABAergic interneurons to excitatory neurons in the spinal dorsal horn. In this circumstance, the sum of excitation of the entire spinal network will control the pain transmission.

• The Korean Journal of Physiology and Pharmacology
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• v.13 no.6
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• pp.461-467
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• 2009

The auditory cortex (A1) encodes the acquired significance of sound for the perception and interpretation of sound. Nitric oxide (NO) is a gas molecule with free radical properties that functions as a transmitter molecule and can alter neural activity without direct synaptic connections. We used whole-cell recordings under voltage clamp to investigate the effect of NO on spontaneous GABAergic synaptic transmission in mechanically isolated rat auditory cortical neurons preserving functional presynaptic nerve terminals. GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) in the A1 were completely blocked by bicuculline. The NO donor, S-nitroso-N-acetylpenicillamine (SNAP), reduced the GABAergic sIPSC frequency without affecting the mean current amplitude. The SNAP-induced inhibition of sIPSC frequency was mimicked by 8-bromoguanosine cyclic 3',5'-monophosphate, a membrane permeable cyclic-GMP analogue, and blocked by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a specific NO scavenger. Blockade of presynaptic $K^+$ channels by 4-aminopyridine, a $K^+$ channel blocker, increased the frequencies of GABAergic sIPSCs, but did not affect the inhibitory effects of SNAP. However, blocking of presynaptic $Ca^{2+}$ channels by $Cd^{2+}$, a general voltage-dependent $Ca^{2+}$ channel blocker, decreased the frequencies of GABAergic sIPSCs, and blocked SNAP-induced reduction of sIPSC frequency. These findings suggest that NO inhibits spontaneous GABA release by activation of cGMP-dependent signaling and inhibition of presynaptic $Ca^{2+}$ channels in the presynaptic nerve terminals of A1 neurons.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.2
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• pp.63-70
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• 2002

Cholinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) by the activation of muscarine receptors was investigated in mechanically dissociated rat nucleus basalis of the Meynert neurons using the conventional whole-cell patch recording configuration. Muscarine $(10{\mu}M)$ reversibly and concentration-dependently decreased mIPSC frequency without affecting the current amplitude distribution. Muscarine action on GABAergic mIPSCs was completely blocked by $1{\mu}M$ methoctramine, a selective $M_2$ receptor antagonist, but not by $1{\mu}M$ pirenzepine, a selective $M_1$ receptor antagonist. NEM $(10{\mu}M),$ a G-protein uncoupler, attenuated the inhibitory action of muscarine on GABAergic mIPSC frequency. Muscarine still could decrease GABAergic mIPSC frequency even in the $Ca^{2+}-free$ external solution. However, the inhibitory action of muscarine on GABAergic mIPSCs was completely occluded in the presence of forskolin. The results suggest that muscarine acts presynaptically and reduces the probability of spontaneous GABA release, and that such muscarine-induced inhibitory action seems to be mediated by G-protein-coupled $M_2$ receptors, via the reduction of cAMP production. Accordingly, $M_2$ receptor-mediated disinhibition of nBM neurons might play one of important roles in the regulation of cholinergic outputs from nBM neurons as well as the excitability of nBM neurons themselves.

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.3
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• pp.163-169
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• 2011

Corticosterone is known to modulate GABAergic synaptic transmission in the hypothalamic paraventricular nucleus. However, the underlying receptor mechanisms are largely unknown. In the anterior hypothalamic area (AHA), the sympathoinhibitory center that project GABAergic neurons onto the PVN, we examined the expression of glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) of GABAergic neurons using intact GAD65-eGFP transgenic mice, and the effects of corticosterone on the burst firing using adrenalectomized transgenic mice. GR or MR immunoreactivity was detected from the subpopulations of GABAergic neurons in the AHA. The AHA GABAergic neurons expressed mRNA of GR (42%), MR (38%) or both (8%). In addition, in brain slices incubated with corticosterone together with RU486 (MR-dominant group), the proportion of neurons showing a burst firing pattern was significantly higher than those in the slices incubated with vehicle, corticosterone, or corticosterone with spironolactone (GR-dominant group; 64 vs. 11~14%, p<0.01 by $x^2$-test). Taken together, the results show that the corticosteroid receptors are expressed on the GABAergic neurons in the AHA, and can mediate the corticosteroid-induced plasticity in the firing pattern of these neurons. This study newly provides the experimental evidence for the direct glucocorticoid modulation of GABAergic neurons in the AHA in the vicinity of the PVN.

• The Korean Journal of Physiology and Pharmacology
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• v.10 no.2
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• pp.59-64
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• 2006

The effects of $Zn^{2+}$ on spontaneous glutamate and GABA release were tested in mechanically dissociated rat CA3 pyramidal neurons which retained functional presynaptic nerve terminals. The spontaneous miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) were pharmacologically isolated and recorded using whole-cell patch clamp technique under voltage-clamp conditions. $Zn^{2+}$ at a lower concentration $(30{\mu}M)$ increased GABAergic mIPSC frequency without affecting mIPSC amplitude, but it decreased both mIPSC frequency and amplitude at higher concentrations $({\ge}300{\mu}M)$. In contrast, $Zn^{2+}$ (3 to $100{\mu}M$) did not affect glutamatergic mEPSCs, although it slightly decreased both mIPSC frequency and amplitude at $300{\mu}M$ concentration. Facilitatory effect of $Zn^{2+}$ on GABAergic mIPSC frequency was occluded either in $Ca^{2+}$-free external solution or in the presence of $100{\mu}M$ 4-aminopyridine, a non-selective $K^{+}$ channel blocker. The results suggest that $Zn^{2+}$ at lower concentrations depolarizes GABAergic nerve terminals by blocking $K^{+}$ channels and increases the probability of spontaneous GABA release. This $Zn^{2+}$-mediated modulation of spontaneous GABAergic transmission is likely to play an important role in the regulation of neuronal excitability within the hippocampal CA3 area.

• BMB Reports
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• v.54 no.12
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• pp.620-625
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• 2021

Microglia are known to be activated in the hypothalamic paraventricular nucleus (PVN) of rats with cardiovascular diseases. However, the exact role of microglial activation in the plasticity of presympathetic PVN neurons associated with the modulation of sympathetic outflow remains poorly investigated. In this study, we analyzed the direct link between microglial activation and spontaneous firing rate along with the underlying synaptic mechanisms in PVN neurons projecting to the rostral ventrolateral medulla (RVLM). Systemic injection of LPS induced microglial activation in the PVN, increased the frequency of spontaneous firing activity of PVN-RVLM neurons, reduced GABAergic inputs into these neurons, and increased plasma NE levels and heart rate. Systemic minocycline injection blocked all the observed LPS-induced effects. Our results indicate that LPS increases the firing rate and decreases GABAergic transmission in PVN-RVLM neurons associated with sympathetic outflow and the alteration is largely attributed to the activation of microglia. Our findings provide some insights into the role of microglial activation in regulating the activity of PVN-RVLM neurons associated with modulation of sympathetic outflow in cardiovascular diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.8 no.3
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• pp.129-132
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• 2004

Single unit responses of the ventral posterior medial (VPM) thalamic neurons to stimulation were monitored in anesthetized rats during activation of contralateral primary somatosensory (SI) cortex by GABA antagonist. The temporal changes of afferent sensory transmission were quantitatively analyzed by poststimulus time histogram (PSTH). Mainly, afferent sensory transmission to VPM thalamus was facilitated (15 neurons of total 23) by GABA antagonist (bicuculline) applied to contralateral cortex, while 7 neurons were suppressed. However, when ipsilateral cortex was inactivated by GABA agonist, musimol, there was significant suppression of afferent sensory transmission of VPM thalamus. This suppressed responsiveness by ipsilateral musimol was not affected by bicuculline applied to contralateral cortex. These results suggest that afferent transmission to VPM thalamus may be subjected to the interhemispheric modulation via ipsilateral cortex during inactivation of GABAergic neurons in contralateral SI cortex.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.3
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• pp.127-132
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• 2010

Reactive oxygen species (ROS), which include hydrogen peroxide ($H_2O_2$), the superoxide anion (${O_2}^-{\cdot}$), and the hydroxyl radical ($OH{\cdot}$), are generated as by-products of oxidative metabolism in cells. The cerebral cortex has been found to be particularly vulnerable to production of ROS associated with conditions such as ischemia-reperfusion, Parkinson's disease, and aging. To investigate the effect of ROS on inhibitory GABAergic synaptic transmission, we examined the electrophysiological mechanisms of the modulatory effect of $H_2O_2$ on GABAergic miniature inhibitory postsynaptic current (mIPSCs) in mechanically isolated rat cerebral cortical neurons retaining intact synaptic boutons. The membrane potential was voltage-clamped at -60 mV and mIPSCs were recorded and analyzed. Superfusion of 1-mM $H_2O_2$ gradually potentiated mIPSCs. This potentiating effect of $H_2O_2$ was blocked by the pretreatment with either 10,000-unit/mL catalase or $300-{\mu}M$ N-acetyl-cysteine. The potentiating effect of $H_2O_2$ was occluded by an adenylate cyclase activator, forskolin, and was blocked by a protein kinase A inhibitor, N -(2-[p-bromocinnamylamino] ethyl)-5-isoquinolinesulfonamide hydrochloride. This study indicates that oxidative stress may potentiate presynaptic GABA release through the mechanism of cAMP-dependent protein kinase A (PKA)-dependent pathways, which may result in the inhibition of the cerebral cortex neuronal activity.

• Biomolecules & Therapeutics
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• v.15 no.3
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• pp.175-181
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• 2007

Zizyphi Spinosi Semen (ZSS), a traditional Chinese folk medicine, has been used for treatment of insomnia and anxiety. This experiment was performed to investigate the anxiolytic-like effect of methanol extract of ZSS (MEZSS) in mice by using the experimental paradigms of anxiety and compared with that of a known anxiolytic, diazepam. In the elevated plus-maze test, it showed that MEZSS (100 mg/kg, p.o.) and diazepam (2.0 mg/kg, p.o.) increased the percentage of time spent on the open arms and the number of open arms entries. MEZSS (50, 100 and 200 mg/kg, p.o.) and diazepam (0.5 mg/kg, p.o.) significantly increased the number of head dips compared with that of control group in the hole-board test. However, MEZSS has no effect on decreasing the locomotor activity, while diazepam (2.0 mg/kg, p.o.) significantly inhibited locomotor activity. MEZSS did not decrease the strength force in the grip strength test, either. In addition, GABAergic involvements were also investigated to understand the possible mechanisms. $GABA_{A}$ receptors subunits and glutamic acid decarboxylase (GAD) were not over expressed, compared with that of the saline group. We also found that MEZSS did not increase chloride influx in cultured cerebellar granule cells. It is concluded that MEZSS might have anxiolytic-like effects, but these effects might not be mediated by GABAergic transmission.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.307-312
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• 2022

It is well known that dopamine transmission from the ventral tegmental area (VTA) modulates motivated behavior and reinforcement learning. Although dopaminergic neurons are the major type of VTA neurons, recent studies show that a significant proportion of the VTA contains GABAergic and type 2 vesicular glutamate transporter (VGLUT2)-positive neurons. The non-dopaminergic neurons are also critically involved in regulating motivated behaviors. Some VTA neurons appear to co-release two different types of neurotransmitters. They are VGLUT2-DA neurons, VGLUT2-GABA neurons and GABA-DA neurons. These co-releasing neurons show distinct features compared to the neurons that release a single neurotransmitter. Here, we review how VTA cell populations wire to the other brain regions and how these projections differentially contribute to motivated behavior through the distinct molecular mechanism. We summarize the activities, projections and functions of VTA neurons concerning motivated behavior. This review article discriminates VTA cell populations related to the motivated behavior based on the neurotransmitters they release and extends the classical view of the dopamine-mediated reward system.