The Experts below are selected from a list of 8703 Experts worldwide ranked by ideXlab platform
Stéphane Oliet - One of the best experts on this subject based on the ideXlab platform.
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Voltage-gated Ca2+ channel subtypes mediating GABAergic Transmission in the rat supraoptic nucleus.
European Journal of Neuroscience, 2005Co-Authors: Khaleel Bhaukaurally, Dominique Poulain, Aude Panatier, Stéphane OlietAbstract:The supraoptic nucleus receives an abundant gamma-aminobutyric acid (GABA)ergic input which is inhibited by activation of various presynaptic metabotropic receptors. We here analysed the subtypes of voltage-gated Ca2+ channels intervening in the control of transmitter release at these synapses. To address this issue, we tested various specific inhibitors of Ca2+ channels on evoked inhibitory postsynaptic currents (IPSCs). Blocking N- and P-type voltage-gated Ca2+ channels with 1 micromomega-conotoxin-GVIA and 20 nmomega-agatoxin-IVA, respectively, dramatically reduced IPSC amplitude. Q- and L-type Ca2+ channels also contributed to GABAergic Transmission, although to a lesser extent, as revealed by applications of 200 nmomega-agatoxin-IVA and of the dihydropyridines nifedipine (10 microm) and nimodipine (10 microm). Evoked IPSCs were insensitive to SNX-482 (300 nm), a blocker of some R-type Ca2+ channels. Analysis of selective blockade by the various antagonists suggested that multiple types of Ca2+ channels synergistically interact to trigger exocytosis at some individual GABA release sites. We next investigated whether inhibition of GABA release in response to the activation of metabotropic glutamate, GABA and adenosine receptors involved the modulation of these presynaptic Ca2+ channels. This was not the case, as the inhibitory actions of selective agonists of these receptors were unaffected by the presence of the different Ca2+ channel antagonists. This finding suggests that these metabotropic receptors modulate GABAergic Transmission through a different mechanism, downstream of Ca2+ entry in the terminals, or upstream through the activation of K+ channels.
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Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic Transmission in the rat supraoptic nucleus.
Journal of Neurophysiology, 2003Co-Authors: Karima Azdad, Richard Piet, Dominique Poulain, Stéphane OlietAbstract:The mechanism by which dopamine induces or facilitates neurohypophysial hormone release is not completely understood. Because oxytocin- and vasopressin-secreting supraoptic neurons are under the control of a prominent GABAergic inhibition, we investigated the possibility that dopamine exerts its action by modulating GABA-mediated Transmission. Whole cell voltage-clamp recordings of supraoptic neurons were carried out in acute hypothalamic slices to determine the action of dopamine on inhibitory postsynaptic currents. Application of dopamine caused a consistent and reversible reduction in the frequency, but not the amplitude, of miniature synaptic events, indicating that dopamine was acting presynaptically to reduce GABAergic Transmission. The subtype of dopamine receptor involved in this response was characterized pharmacologically. Dopamine inhibitory action was greatly reduced by two highly selective D4 receptor antagonists L745,870 and L750,667 and to a lower extent by the antipsychotic drug clozapine but was unaffected by SCH 23390 and sulpiride, D1/D5 and D2/D3 receptor antagonists, respectively. In agreement with these results, the action of dopamine was mimicked by the potent D4 receptor agonist PD168077 but not by SKF81297 and bromocriptine, D1/D5 and D2/D3 receptor agonists, respectively. Dopamine and PD168077 also reduced the amplitude of evoked inhibitory postsynaptic currents, an effect that was accompanied by an increase in paired-pulse facilitation. These data clearly indicate that D4 receptors are located on GABA terminals in the supraoptic nucleus and that their activation reduces GABA release in the supraoptic nucleus. Therefore dopaminergic facilitation of neurohypophysial hormone release appears to result, at least in part, from disinhibition of magnocellular neurons caused by the depression of GABAergic Transmission.
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Modulation of GABAergic Transmission by endogenous glutamate in the rat supraoptic nucleus.
European Journal of Neuroscience, 2003Co-Authors: Richard Piet, Dominique Poulain, Renée Bonhomme, Dionysia Theodosis, Stéphane OlietAbstract:The presence of group III metabotropic glutamate receptors on GABAergic terminals in the supraoptic nucleus suggests that the level of glutamate in the extracellular space may regulate synaptic strength at inhibitory synapses. To test this hypothesis we examined the consequences of increasing ambient glutamate on GABA-mediated synaptic activity in supraoptic neurons. The concentration of the excitatory amino acid in the extracellular space was increased pharmacologically by blocking glutamate transporters. Inhibition of the astrocyte-specific GLT-1 glutamate transporter led to a reversible decrease in evoked inhibitory postsynaptic current amplitude. This modulation had a presynaptic origin as revealed by analysis of paired-pulse ratio and miniature inhibitory currents. Furthermore, blocking group III metabotropic glutamate receptors with the specific antagonist MAP4 prevented the depression of GABAergic Transmission induced by glutamate transporter blockade. Thus, presynaptic metabotropic glutamate receptors located on inhibitory terminals in the supraoptic nucleus appear to sense changes in ambient glutamate and modify GABA release accordingly. However, it seems that such changes need to reach a certain magnitude because the discrete deficit in glutamate clearance which occurs in the supraoptic nucleus of lactating rats is not sufficient to modulate GABA-mediated Transmission. These results suggest that ambient glutamate contributes to the modulation of synaptic efficacy not only at glutamatergic synapses but also at inhibitory GABAergic synapses.
Ilsung Jang - One of the best experts on this subject based on the ideXlab platform.
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α2a adrenoceptor mediated presynaptic inhibition of GABAergic Transmission in rat tuberomammillary nucleus neurons
Journal of Neurochemistry, 2013Co-Authors: Michiko Nakamura, Ilsung JangAbstract:Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in the regulation of sleep-wakefulness. Here, we report the adrenergic modulation of GABAergic Transmission in rat TMN histaminergic neurons using a conventional whole-cell patch clamp technique. Norepinephrine (NE) reversibly decreased the amplitude of action potential-dependent GABAergic inhibitory post-synaptic currents (IPSCs) and increased the paired pulse ratio. The NE-induced inhibition of GABAergic IPSCs was mimicked by clonidine, a selective α2 adrenoceptor agonist. However, cirazoline and isoproterenol, nonselective α1 and β adrenoceptor agonists, respectively, had no effect on GABAergic IPSCs. The NE-induced inhibition of GABAergic IPSCs was significantly blocked by BRL44408, a selective α2A adrenoceptor antagonist, but not imiloxan or JP1302, a selective α2B and α2C adrenoceptor antagonists. The extent of NE-induced inhibition of GABAergic IPSCs was inversely proportional to the extracellular Ca2+ concentration. Pharmacological agents affecting the activities of adenylyl cyclase or G-protein-coupled inwardly rectifying K+ channels did not affect the NE-induced inhibition of GABAergic IPSCs. However, NE had no effect on the frequency and amplitude of GABAergic miniature IPSCs. These results suggest that NE acts on presynaptic α2A adrenoceptor to inhibit action potential-dependent GABA release via the inhibition of Ca2+ influx from the extracellular space to GABAergic nerve terminals, and that this α2A adrenoceptor-mediated modulation of GABAergic Transmission may be involved in regulating the excitability of TMN histaminergic neurons.
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muscarinic m4 receptors regulate GABAergic Transmission in rat tuberomammillary nucleus neurons
Neuropharmacology, 2012Co-Authors: Michiko Nakamura, Ilsung JangAbstract:Abstract Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole-cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M4 receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd2+, a general voltage-dependent Ca2+ channel blocker, or in a Ca2+-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K+ channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M4 receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca2+ influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M4 receptors in more physiological conditions. The M4 receptor-mediated modulation of GABAergic Transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness.
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adenosine a1 receptors inhibit GABAergic Transmission in rat tuberomammillary nucleus neurons
Journal of Neurochemistry, 2008Co-Authors: Insun Choi, Jaekap Choi, Michiko Nakamura, Byungju Choi, Ilsung JangAbstract:The adenosinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) was investigated in mechanically dissociated rat tuberomammillary nucleus (TMN) neurons using a conventional whole-cell patch clamp technique. Adenosine (100 μM) reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that adenosine acts presynaptically to decrease the probability of spontaneous GABA release. The adenosine action on GABAergic mIPSC frequency was completely blocked by 1 μM DPCPX, a selective A1 receptor antagonist, and mimicked by 1 μM CPA, a selective A1 receptor agonist. This suggests that presynaptic A1 receptors were responsible for the adenosine-mediated inhibition of GABAergic mIPSC frequency. CPA still decreased GABAergic mIPSC frequency even either in the presence of 200 μM Cd2+, a general voltage-dependent Ca2+ channel blocker, or in the Ca2+-free external solution. However, the inhibitory effect of CPA on GABAergic mIPSC frequency was completely occluded by 1 mM Ba2+, a G-protein coupled inwardly rectifying K+ (GIRK) channel blocker. In addition, the CPA-induced decrease in mIPSC frequency was completely occluded by either 100 μM SQ22536, an adenylyl cyclase (AC) inhibitor, or 1 μM KT5720, a specific protein kinase A (PKA) inhibitor. The results suggest that the activation of presynaptic A1 receptors decreases spontaneous GABAergic Transmission onto TMN neurons via the modulation of GIRK channels as well as the AC/cAMP/PKA signal transduction pathway. This adenosine A1 receptor-mediated modulation of GABAergic Transmission onto TMN neurons may play an important role in the fine modulation of the excitability of TMN histaminergic neurons as well as the regulation of sleep-wakefulness.
Dominique Poulain - One of the best experts on this subject based on the ideXlab platform.
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Voltage-gated Ca2+ channel subtypes mediating GABAergic Transmission in the rat supraoptic nucleus.
European Journal of Neuroscience, 2005Co-Authors: Khaleel Bhaukaurally, Dominique Poulain, Aude Panatier, Stéphane OlietAbstract:The supraoptic nucleus receives an abundant gamma-aminobutyric acid (GABA)ergic input which is inhibited by activation of various presynaptic metabotropic receptors. We here analysed the subtypes of voltage-gated Ca2+ channels intervening in the control of transmitter release at these synapses. To address this issue, we tested various specific inhibitors of Ca2+ channels on evoked inhibitory postsynaptic currents (IPSCs). Blocking N- and P-type voltage-gated Ca2+ channels with 1 micromomega-conotoxin-GVIA and 20 nmomega-agatoxin-IVA, respectively, dramatically reduced IPSC amplitude. Q- and L-type Ca2+ channels also contributed to GABAergic Transmission, although to a lesser extent, as revealed by applications of 200 nmomega-agatoxin-IVA and of the dihydropyridines nifedipine (10 microm) and nimodipine (10 microm). Evoked IPSCs were insensitive to SNX-482 (300 nm), a blocker of some R-type Ca2+ channels. Analysis of selective blockade by the various antagonists suggested that multiple types of Ca2+ channels synergistically interact to trigger exocytosis at some individual GABA release sites. We next investigated whether inhibition of GABA release in response to the activation of metabotropic glutamate, GABA and adenosine receptors involved the modulation of these presynaptic Ca2+ channels. This was not the case, as the inhibitory actions of selective agonists of these receptors were unaffected by the presence of the different Ca2+ channel antagonists. This finding suggests that these metabotropic receptors modulate GABAergic Transmission through a different mechanism, downstream of Ca2+ entry in the terminals, or upstream through the activation of K+ channels.
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Dopamine D4 receptor-mediated presynaptic inhibition of GABAergic Transmission in the rat supraoptic nucleus.
Journal of Neurophysiology, 2003Co-Authors: Karima Azdad, Richard Piet, Dominique Poulain, Stéphane OlietAbstract:The mechanism by which dopamine induces or facilitates neurohypophysial hormone release is not completely understood. Because oxytocin- and vasopressin-secreting supraoptic neurons are under the control of a prominent GABAergic inhibition, we investigated the possibility that dopamine exerts its action by modulating GABA-mediated Transmission. Whole cell voltage-clamp recordings of supraoptic neurons were carried out in acute hypothalamic slices to determine the action of dopamine on inhibitory postsynaptic currents. Application of dopamine caused a consistent and reversible reduction in the frequency, but not the amplitude, of miniature synaptic events, indicating that dopamine was acting presynaptically to reduce GABAergic Transmission. The subtype of dopamine receptor involved in this response was characterized pharmacologically. Dopamine inhibitory action was greatly reduced by two highly selective D4 receptor antagonists L745,870 and L750,667 and to a lower extent by the antipsychotic drug clozapine but was unaffected by SCH 23390 and sulpiride, D1/D5 and D2/D3 receptor antagonists, respectively. In agreement with these results, the action of dopamine was mimicked by the potent D4 receptor agonist PD168077 but not by SKF81297 and bromocriptine, D1/D5 and D2/D3 receptor agonists, respectively. Dopamine and PD168077 also reduced the amplitude of evoked inhibitory postsynaptic currents, an effect that was accompanied by an increase in paired-pulse facilitation. These data clearly indicate that D4 receptors are located on GABA terminals in the supraoptic nucleus and that their activation reduces GABA release in the supraoptic nucleus. Therefore dopaminergic facilitation of neurohypophysial hormone release appears to result, at least in part, from disinhibition of magnocellular neurons caused by the depression of GABAergic Transmission.
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Modulation of GABAergic Transmission by endogenous glutamate in the rat supraoptic nucleus.
European Journal of Neuroscience, 2003Co-Authors: Richard Piet, Dominique Poulain, Renée Bonhomme, Dionysia Theodosis, Stéphane OlietAbstract:The presence of group III metabotropic glutamate receptors on GABAergic terminals in the supraoptic nucleus suggests that the level of glutamate in the extracellular space may regulate synaptic strength at inhibitory synapses. To test this hypothesis we examined the consequences of increasing ambient glutamate on GABA-mediated synaptic activity in supraoptic neurons. The concentration of the excitatory amino acid in the extracellular space was increased pharmacologically by blocking glutamate transporters. Inhibition of the astrocyte-specific GLT-1 glutamate transporter led to a reversible decrease in evoked inhibitory postsynaptic current amplitude. This modulation had a presynaptic origin as revealed by analysis of paired-pulse ratio and miniature inhibitory currents. Furthermore, blocking group III metabotropic glutamate receptors with the specific antagonist MAP4 prevented the depression of GABAergic Transmission induced by glutamate transporter blockade. Thus, presynaptic metabotropic glutamate receptors located on inhibitory terminals in the supraoptic nucleus appear to sense changes in ambient glutamate and modify GABA release accordingly. However, it seems that such changes need to reach a certain magnitude because the discrete deficit in glutamate clearance which occurs in the supraoptic nucleus of lactating rats is not sufficient to modulate GABA-mediated Transmission. These results suggest that ambient glutamate contributes to the modulation of synaptic efficacy not only at glutamatergic synapses but also at inhibitory GABAergic synapses.
Michiko Nakamura - One of the best experts on this subject based on the ideXlab platform.
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α2a adrenoceptor mediated presynaptic inhibition of GABAergic Transmission in rat tuberomammillary nucleus neurons
Journal of Neurochemistry, 2013Co-Authors: Michiko Nakamura, Ilsung JangAbstract:Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in the regulation of sleep-wakefulness. Here, we report the adrenergic modulation of GABAergic Transmission in rat TMN histaminergic neurons using a conventional whole-cell patch clamp technique. Norepinephrine (NE) reversibly decreased the amplitude of action potential-dependent GABAergic inhibitory post-synaptic currents (IPSCs) and increased the paired pulse ratio. The NE-induced inhibition of GABAergic IPSCs was mimicked by clonidine, a selective α2 adrenoceptor agonist. However, cirazoline and isoproterenol, nonselective α1 and β adrenoceptor agonists, respectively, had no effect on GABAergic IPSCs. The NE-induced inhibition of GABAergic IPSCs was significantly blocked by BRL44408, a selective α2A adrenoceptor antagonist, but not imiloxan or JP1302, a selective α2B and α2C adrenoceptor antagonists. The extent of NE-induced inhibition of GABAergic IPSCs was inversely proportional to the extracellular Ca2+ concentration. Pharmacological agents affecting the activities of adenylyl cyclase or G-protein-coupled inwardly rectifying K+ channels did not affect the NE-induced inhibition of GABAergic IPSCs. However, NE had no effect on the frequency and amplitude of GABAergic miniature IPSCs. These results suggest that NE acts on presynaptic α2A adrenoceptor to inhibit action potential-dependent GABA release via the inhibition of Ca2+ influx from the extracellular space to GABAergic nerve terminals, and that this α2A adrenoceptor-mediated modulation of GABAergic Transmission may be involved in regulating the excitability of TMN histaminergic neurons.
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muscarinic m4 receptors regulate GABAergic Transmission in rat tuberomammillary nucleus neurons
Neuropharmacology, 2012Co-Authors: Michiko Nakamura, Ilsung JangAbstract:Abstract Histaminergic neurons within the tuberomammillary nucleus (TMN) play an important role in sleep-wakefulness regulation. Here, we report the muscarinic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat histaminergic neurons using a conventional whole-cell patch clamp technique. Muscarine, a nonselective muscarinic acetylcholine (mACh) receptor agonist, reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that muscarine acts presynaptically to decrease the probability of spontaneous GABA release. The muscarine action on GABAergic mIPSC frequency was completely blocked by atropine, a nonselective mACh receptor antagonist, and tropicamide, an M4 receptor antagonist. The muscarine-induced decrease in mIPSC frequency was completely occluded in the presence of Cd2+, a general voltage-dependent Ca2+ channel blocker, or in a Ca2+-free external solution. However, pharmacological agents affecting adenylyl cyclase or G-protein coupled inwardly rectifying K+ channel activity did not prevent the inhibitory action of muscarine on GABAergic mIPSCs. These results suggest that muscarine acts on M4 receptors on GABAergic nerve terminals projecting to histaminergic neurons to inhibit spontaneous GABA release via the inhibition of Ca2+ influx from the extracellular space. Muscarine also inhibited action potential-dependent GABA release by activating presynaptic M4 receptors in more physiological conditions. The M4 receptor-mediated modulation of GABAergic Transmission onto TMN neurons may contribute to the regulation of sleep-wakefulness.
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adenosine a1 receptors inhibit GABAergic Transmission in rat tuberomammillary nucleus neurons
Journal of Neurochemistry, 2008Co-Authors: Insun Choi, Jaekap Choi, Michiko Nakamura, Byungju Choi, Ilsung JangAbstract:The adenosinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) was investigated in mechanically dissociated rat tuberomammillary nucleus (TMN) neurons using a conventional whole-cell patch clamp technique. Adenosine (100 μM) reversibly decreased mIPSC frequency without affecting the current amplitude, indicating that adenosine acts presynaptically to decrease the probability of spontaneous GABA release. The adenosine action on GABAergic mIPSC frequency was completely blocked by 1 μM DPCPX, a selective A1 receptor antagonist, and mimicked by 1 μM CPA, a selective A1 receptor agonist. This suggests that presynaptic A1 receptors were responsible for the adenosine-mediated inhibition of GABAergic mIPSC frequency. CPA still decreased GABAergic mIPSC frequency even either in the presence of 200 μM Cd2+, a general voltage-dependent Ca2+ channel blocker, or in the Ca2+-free external solution. However, the inhibitory effect of CPA on GABAergic mIPSC frequency was completely occluded by 1 mM Ba2+, a G-protein coupled inwardly rectifying K+ (GIRK) channel blocker. In addition, the CPA-induced decrease in mIPSC frequency was completely occluded by either 100 μM SQ22536, an adenylyl cyclase (AC) inhibitor, or 1 μM KT5720, a specific protein kinase A (PKA) inhibitor. The results suggest that the activation of presynaptic A1 receptors decreases spontaneous GABAergic Transmission onto TMN neurons via the modulation of GIRK channels as well as the AC/cAMP/PKA signal transduction pathway. This adenosine A1 receptor-mediated modulation of GABAergic Transmission onto TMN neurons may play an important role in the fine modulation of the excitability of TMN histaminergic neurons as well as the regulation of sleep-wakefulness.
Marisa Roberto - One of the best experts on this subject based on the ideXlab platform.
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Chronic alcohol exposure disrupts CB1 regulation of GABAergic Transmission in the rat basolateral amygdala.
Addiction biology, 2016Co-Authors: Florence P. Varodayan, Michal Bajo, Neeraj Soni, George Luu, Samuel G. Madamba, Paul Schweitzer, Marisa RobertoAbstract:The basolateral nucleus of the amygdala (BLA) is critical to the pathophysiology of anxiety-driven alcohol drinking and relapse. The endogenous cannabinoid/type 1 cannabinoid receptor (eCB/CB1 ) system curbs BLA-driven anxiety and stress responses via a retrograde negative feedback system that inhibits neurotransmitter release, and BLA CB1 activation reduces GABA release and drives anxiogenesis. Additionally, decreased amygdala CB1 is observed in abstinent alcoholic patients and ethanol withdrawn rats. Here, we investigated the potential disruption of eCB/CB1 signaling on GABAergic Transmission in BLA pyramidal neurons of rats exposed to 2-3 weeks intermittent ethanol. In the naive rat BLA, the CB1 agonist WIN 55,212-2 (WIN) decreased GABA release, and this effect was prevented by the CB1 antagonist AM251. AM251 alone increased GABA release via a mechanism requiring postsynaptic calcium-dependent activity. This retrograde tonic eCB/CB1 signaling was diminished in chronic ethanol exposed rats, suggesting a functional impairment of the eCB/CB1 system. In contrast, acute ethanol increased GABAergic Transmission similarly in naive and chronic ethanol exposed rats, via both presynaptic and postsynaptic mechanisms. Notably, CB1 activation impaired ethanol's facilitation of GABAergic Transmission across both groups, but the AM251-induced and ethanol-induced facilitation of GABA release was additive, suggesting independent presynaptic sites of action. Collectively, the present findings highlight a critical CB1 influence on BLA GABAergic Transmission that is dysregulated by chronic ethanol exposure and, thus, may contribute to the alcohol-dependent state.
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IL-1 interacts with ethanol effects on GABAergic Transmission in the mouse central amygdala.
Frontiers in pharmacology, 2015Co-Authors: Michal Bajo, Florence P. Varodayan, Samuel G. Madamba, Amanda J. Robert, Lindsey M. Casal, Christopher S. Oleata, George R. Siggins, Marisa RobertoAbstract:Neuroinflammation is hypothesized to enhance alcohol consumption and contribute to the development of alcoholism. GABAergic Transmission in the central amygdala (CeA) plays an important role in the transition to alcohol dependence. Therefore, we studied the effects of interleukin-1β (IL-1β) a proinflammatory cytokine mediating ethanol-induced neuroinflammation, and its interaction with ethanol on CeA GABAegic Transmission in B6129SF2/J mice. We also assessed ethanol intake in B6129SF2/J mice. Intake with unlimited (24 hours) ethanol access was 9.2-12.7 g/kg (3-15% ethanol), while limited (2 hours) access produced an intake of 4.1±0.5 g/kg (15% ethanol). In our electrophysiology experiments, we found that recombinant IL-1β (50 and 100 ng/ml) significantly decreased the amplitude of evoked inhibitory postsynaptic potentials (eIPSPs), with no significant effects on paired-pulse facilitation (PPF). IL-1beta (50 ng/ml) had dual effects on spontaneous miniature inhibitory postsynaptic currents (mIPSCs): increasing mIPSC frequencies in most CeA neurons, but decreasing both mIPSC frequencies and amplitudes in a few cells. The IL-1β receptor antagonist (IL-1ra; 100 ng/ml) also had dual effects on mIPSCs and prevented the actions of IL-1β on mIPSC frequencies. These results suggest that IL-1β can alter CeA GABAergic Transmission at pre- and postsynaptic sites. Ethanol (44 mM) significantly increased eIPSP amplitudes, decreased PPFs, and increased mIPSC frequencies. IL-1β did not alter ethanol’s enhancement of the eIPSP amplitude, but, in IL-1β-responsive neurons, the ethanol effects on mIPSC frequencies were lost. Overall, our data suggest that the IL-1 system is involved in basal GABAergic Transmission and that IL-1β interacts with the ethanol-induced facilitation of CeA GABAergic Transmission.
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Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic Transmission in the central amygdala
Brain behavior and immunity, 2014Co-Authors: Michal Bajo, Florence P. Varodayan, Samuel G. Madamba, Christopher S. Oleata, Melissa A. Herman, R. A. Harris, Yuri A. Blednov, Marisa RobertoAbstract:Abstract The IL-1 receptor antagonist (IL-1ra), encoded by the Il1rn gene, is an endogenous antagonist of the IL-1 receptor. Studies of Il1rn knockout (KO) and wild type (WT) mice identified differences in several ethanol-related behaviors, some of which may be mediated by GABAergic Transmission in the central nucleus of the amygdala (CeA). In this study we examined phasic (both evoked and spontaneous) and tonic GABAergic Transmission in the CeA of Il1rn KO and WT mice and the ethanol sensitivity of these GABAergic synapses. The mean amplitude of baseline evoked GABAA-inhibitory postsynaptic potentials (IPSPs), and the baseline frequency of spontaneous GABAA-inhibitory postsynaptic currents (sIPSCs), but not the frequency of miniature GABAA-IPSCs (mIPSCs), were significantly increased in KO compared to WT mice, indicating enhanced presynaptic action potential-dependent GABA release in the CeA of KO mice. In KO mice, we also found a cell-type specific switch in the ongoing tonic GABAA receptor conductance such that the tonic conductance in low threshold bursting (LTB) neurons is lost and a tonic conductance in late spiking (LS) neurons appears. Notably, the ethanol-induced facilitation of evoked and spontaneous GABA release was lost in most of the CeA neurons from KO compared to WT mice. Ethanol superfusion increased the sIPSC rise and decay times in both KO and WT mice, suggesting ethanol-induced postsynaptic effects. The pretreatment of CeA slices with exogenous IL-1ra (Kineret; 100 ng/ml) returned sIPSC frequency in KO mice to the levels found in WT. Importantly, Kineret also restored ethanol-induced potentiation of the sIPSC frequency in the KO mice. These results show that IL-1ra regulates baseline GABAergic Transmission in the CeA and is critical for the ethanol effects at these synapses.
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Acute morphine alters GABAergic Transmission in the central amygdala during naloxone-precipitated morphine withdrawal: role of cyclic AMP.
Frontiers in integrative neuroscience, 2014Co-Authors: Michal Bajo, Samuel G. Madamba, Marisa Roberto, George R. SigginsAbstract:The central amygdala (CeA) plays an important role in opioid addiction. Therefore, we examined the effects of naloxone-precipitated morphine withdrawal (WD) on GABAergic Transmission in rat CeA neurons using whole-cell recordings with naloxone in the bath. The basal frequency of miniature inhibitory postsynaptic currents (mIPSCs) increased in CeA neurons from WD compared to placebo rats. Acute morphine (10 M) had mixed effects (> 20% change from baseline) on mIPSCs in placebo and WD rats. In most CeA neurons (64%) from placebo rats, morphine significantly decreased mIPSC frequency and amplitude. In 32% of placebo neurons, morphine significantly increased mIPSC amplitudes but had no effect on mIPSC frequency. In WD rats, acute morphine significantly increased mIPSC frequency but had no effect on mIPSC amplitude in 41% of CeA neurons. In 45% of cells, acute morphine significantly decreased mIPSC frequency and amplitude. Pre-treatment with the cyclic AMP inhibitor (R)-adenosine, cyclic 3’,5’-(hydrogenphosphorothioate) triethylammonium (RP), prevented acute morphine-induced potentiation of mIPSCs. Pre-treatment of slices with the Gi/o G-protein subunit inhibitor pertussis toxin (PTX) did not prevent the acute morphine-induced enhancement or inhibition of mIPSCs. PTX and RP decreased basal mIPSC frequencies and amplitudes only in WD rats. The results suggest that inhibition of GABAergic Transmission in the CeA by acute morphine is mediated by PTX-insensitive mechanisms, although PTX-sensitive mechanisms cannot be ruled out for non-morphine responsive cells; by contrast, potentiation of GABAergic Transmission is mediated by activated cAMP signaling that also mediates the increased basal GABAergic Transmission in WD rats. Our data indicate that during the acute phase of WD, the CeA opioid and GABAergic systems undergo neuroadaptative changes conditioned by a previous chronic morphine exposure and dependence.
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Innate immune factors modulate ethanol interaction with GABAergic Transmission in mouse central amygdala
Brain behavior and immunity, 2014Co-Authors: Michal Bajo, Samuel G. Madamba, Marisa Roberto, Yuri A. Blednov, Vasudeva Naidu Sagi, Edward Roberts, Kenner C. Rice, R. Adron Harris, George R. SigginsAbstract:Abstract Excessive ethanol drinking in rodent models may involve activation of the innate immune system, especially toll-like receptor 4 (TLR4) signaling pathways. We used intracellular recording of evoked GABAergic inhibitory postsynaptic potentials (eIPSPs) in central amygdala (CeA) neurons to examine the role of TLR4 activation by lipopolysaccharide (LPS) and deletion of its adapter protein CD14 in acute ethanol effects on the GABAergic system. Ethanol (44, 66 or 100 mM) and LPS (25 and 50 μg/ml) both augmented eIPSPs in CeA of wild type (WT) mice. Ethanol (44 mM) decreased paired-pulse facilitation (PPF), suggesting a presynaptic mechanism of action. Acute LPS (25 μg/ml) had no effect on PPF and significantly increased the mean miniature IPSC amplitude, indicating a postsynaptic mechanism of action. Acute LPS pre-treatment potentiated ethanol (44 mM) effects on eIPSPs in WT mice and restored ethanol’s augmenting effects on the eIPSP amplitude in CD14 knockout (CD14 KO) mice. Both the LPS and ethanol (44–66 mM) augmentation of eIPSPs was diminished significantly in most CeA neurons of CD14 KO mice; however, ethanol at the highest concentration tested (100 mM) still increased eIPSP amplitudes. By contrast, ethanol pre-treatment occluded LPS augmentation of eIPSPs in WT mice and had no significant effect in CD14 KO mice. Furthermore, (+)-naloxone, a TLR4-MD-2 complex inhibitor, blocked LPS effects on eIPSPs in WT mice and delayed the ethanol-induced potentiation of GABAergic Transmission. In CeA neurons of CD14 KO mice, (+)-naloxone alone diminished eIPSPs, and subsequent co-application of 100 mM ethanol restored the eIPSPs to baseline levels. In summary, our results indicate that TLR4 and CD14 signaling play an important role in the acute ethanol effects on GABAergic Transmission in the CeA and support the idea that CD14 and TLR4 may be therapeutic targets for treatment of alcohol abuse.
