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1

Glutamatergic and GABAergic transmission in rat PVN is altered after acute restraint stress

100%
Kusek M., Tokarska A., Tokarski K., Hess G.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: The hypothalamic paraventricular nucleus (PVN) plays a key role in the activation of the hypothalamic-pituitary-adrenal axis (HPA). In response to stress, corticotropin releasing hormone (CRH) is released from parvocellular PVN neurosecretory neurons into hypophysial portal vessels that access the anterior pituitary gland to stimulate the production of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to produce glucocorticoid hormones.  It is known that excitatory and inhibitory inputs that regulate the activity of parvocellular PVN neurosecretory neurons may undergo stress-related modifications. However, the influence of acute restraint stress on the function of glutamatergic and GABAergic synapses in PVN is not fully understood. METHODS: Adolescent male Wistar rats were subjected to acute restraint lasting 10 min. Animals were decapitated either immediately after the stress session or 24 hours later. Whole-cell patchclamp was used to record spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs/mEPSCs, sIPSCs/ mIPSCs) from parvocellular neuroendocrine neurons of the PVN ex vivo. RESULTS: In animals decapitated immediately after the stress session, an increase in the mean frequency of sEPSCs/mEPSCs was observed. These effects were accompanied by a decrease in the mean frequency of sIPSCs/mIPSCs. The kinetics and amplitude of the currents remained unchanged. In slices prepared 24 h after the restraint there was no change in the frequency and amplitude of all recorded currents. Also the basal electrophysiological properties and the excitability of the neurosecretory parvocellular neurons remained unchanged in all tested slices. CONCLUSIONS: Acute immobilization stress results in a transient (less than 24 h) enhancement of the glutamatergic and an attenuation of the GABAergic synaptic input to neurosecretory parvocellular neurons in the rat PVN. Support: Grant 2012/07/N/NZ4/02687.
2

5-HT7 receptors medulate GABAergic transmission in the CA1 area of rat hippocampus

100%
Tokarski K., Kusek M., Hess G.
Acta Neurobiologiae Experimentalis
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2011
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tom 71
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nr S
Hippocampal GABAergic interneurons modulate the activity of principal glutamatergic cells. Hippocampus receives 5-HT innervation originating in raphe nuclei. In this study we aimed at establishing whether the 5-HT7 receptor-dependent modulation of hippocampal functions also involves local inhibitory circuits. We investigated the effects of 5-HT7 receptor activation on the glutamatergic input to stratum lacunosum moleculare GABAergic interneurons and on the GABAergic input to pyramidal cells of the CA1 area. The experiments were performed on hippocampal slices using whole-cell patch-clamp technique. Neurons were visualized and identified by the shape of the soma as well as by the spiking pattern. For the recording of sIPSCs neurons were voltage clamped at 0 mV and sEPSCs were recorded at -76 mV. The amplitude and the frequency of sIPSCs recorded from pyramidal neurons as well as the amplitude and the frequency of sEPSCs recorded from GABA interneurons were measured. To activate the 5-HT7 receptor, 5-CT (a nonselective 5-HT7 receptor agonist) was applied in the presence of WAY 100635 (the 5-HT1A receptor antagonist). The application of 5-CT increased the mean frequency of sIPSCs and sEPSCs while the mean amplitudes of sIPSCS and sEPSCs were not altered. In the presence of a nonselective glutamate receptor antagonist, kynurenic acid, 5-CTmediated increase in the sIPSCs frequency was still present. These data suggest that the activation of the 5-HT7 receptor results in an enhancement of the GABAergic transmission via two mechanisms. The first one is an enhancement of excitatory glutamatergic input to GABAergic interneurons and the second - an increase of the excitability of GABAergic cells and /or an increase of GABA release due the activation of 5-HT7 receptors located in the perisomatic region of GABAergic cells and/or on GABAergic terminals. Support: MNiSW grant 0259/B/P01/2010/38.
3

Repeated restraint stress alters glutamatergic but not gabaergic transmission within the paraventricular nucleus of the hypothalamus

100%
Kusek M., Tokarski K., Gadek-Michalska A., Hess G.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr Suppl.1
The hypothalamic paraventricular nucleus (PVN) plays a key role in the activation of the hypothalamic-pituitary-adrenal axis (HPA) in response to stressors. Wistar rats were subjected to restraint lasting 10 min and repeated twice daily for 3 days. Brain slices were prepared 24 h after the last restraint session and studied ex vivo. Whole-cell patch-clamp method was used to record spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) from presumed parvocellular neurosecretory neurons in slices containing a part of the PVN. Repeated restraint stress resulted in an increase in the mean frequency of sEPSCs and in a decrease in the rise time and the decay time constant of sEPSCs. There were no changes in the mean amplitude of sEPSC. All measured parameters of sIPSCs remained unaltered. The relationship between the injected current and the spiking rate of parvocellular neurons was reduced. These data indicate that restraint stress, repeated for 3 days, selectively enhances the excitatory inputs to parvocellular neurons of the PVN, most likely via a combination of pre- and postsynaptic mechanisms. These changes are accompanied by a decrease in the intrinsic excitability of PVN neurons. Support: “DeMeTer” and statutory funds from the Institute of Pharmacology.
4
Content available remote

5-HT7 receptors modulate GABAergic transmission in rat hippocampal CA1 area

100%
Tokarski K., Kusek M., Hess G.
Journal of Physiology and Pharmacology
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2011
|
tom 62
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nr 5
5
Content available remote

Impaired effect of activation of rat hippocampal 5-HT7 receptors, induced by treatment with the 5-HT7 receptor antagonist SB 269970

100%
Kusek M., Sowa J., Tokarski K., Hess G.
Journal of Physiology and Pharmacology
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2015
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tom 66
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nr 2
6
Content available remote

The 5-HT7 receptor antagonist SB 269970 counteracts restraint stress-induced attenuation of long-term potentiation in rat frontal cortex

100%
Tokarski K., Bobula B., Kusek M., Hess G.
Journal of Physiology and Pharmacology
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2011
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tom 62
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nr 6
7
Content available remote

Repeated blockade of 5-HT7 receptors depresses glutamatergic transmission in the rat frontal cortex

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Tokarski K., Kusek M., Hess G.
Journal of Physiology and Pharmacology
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2012
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tom 63
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nr 2
8
Content available remote

Repeated restraint stress enhances glutamatergic transmission in the paraventricular nucleus of the rat hypothalamus

100%
Kusek M., Tokarski K., Hess G.
Journal of Physiology and Pharmacology
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2013
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tom 64
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nr 5
9

5-HT7 receptor-dependent modulation of gabaergic and glutamatergic transmission in the dorsal raphe nucleus of the rat

100%
Tokarski K., Kusek M., Sowa J. G., Hess G.
Acta Neurobiologiae Experimentalis
|
2017
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tom 77
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nr Suppl.1
The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN are localized on the GABAergic interneurons and glutamatergic terminals which modulate the activity of 5-HT DRN projection neurons. The present study was aimed at finding how the 5‑HT7 receptor modulates the GABAergic and glutamatergic synaptic inputs to 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5‑HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist SB 269970, which induced an increase in the levels of 5-HT and its metabolite, 5 hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out from DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5‑HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of a selective 5-HT1A receptor antagonist WAY100635. Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Application of 5-CT induced a concentration-dependent increase in the frequency of sIPSCs and a decrease in sEPSCs frequency in recorded neurons. Blockade of 5‑HT7 receptors caused opposite effects. FINANCIAL SUPPORT: Supported by the grant DEC‑2013/11/B/NZ4/04743, financed by the National Science Center, Poland, and by statutory funds from the Institute of Pharmacology Polish Academy of Sciences, Krakow, Poland.
10

Mechanisms responsible for 5-HT7 receptor-mediated effects in the rat hippocampus

88%
Siwiec M., Sowa J. E., Kusek M., Hess G., Tokarski K.
Acta Neurobiologiae Experimentalis
|
2018
|
tom 78
|
nr Suppl.1
The 5‑HT7 receptor has been implicated in mood reg‑ ulation, circadian rhythmicity, and sleep, the disturbances of which are evident in the course of depressive disorders. Research into 5‑HT7 receptor signalling in the hippocam‑ pus has indicated that activation of the 5‑HT7 receptor increases the excitability of pyramidal neurons of the CA1 and CA3 areas. The aim of our study was to investigate ionic mechanisms underlying this effect. We performed whole‑cell current clamp recordings from rat CA1 pyrami‑ dal cells and tested the effects of 5‑HT7 agonists on neu‑ ronal excitability and spiking dynamics. Voltage clamp recordings were used to determine changes in voltage‑de‑ pendent currents following 5‑HT7 receptor activation. Finally, we stimulated Schaffer collaterals and recorded evoked AMPA currents to examine whether these newly discovered ionic mechanisms influence synaptic transmis‑ sion. Administration of 5‑HT7 receptor agonists increased the excitability of CA1 pyramidal neurons, in line with pre‑ vious findings. This was accompanied by a significant de‑ crease in the time needed for the cell to fire the first action potential following a depolarizing current pulse. Voltage clamp recordings confirmed that 5‑HT7 receptor activation significantly attenuated the A‑type current. Pharmacolog‑ ical block of Kv4.2/4.3 channel subunits prevented the in‑ crease in neuronal excitability and spiking latency, as well as the 5‑HT7‑mediated increase in evoked AMPA current amplitude. In the present study we demonstrate that the 5‑HT7 receptor‑mediated effects on excitability, spiking latency and synaptic transmission are directly associated with inhibition of the A‑type potassium current, which is a mechanism not previously associated with this receptor.
11

Restraint stress enhances excitatory but not inhibitory synaptic transmission in the paraventricular hypothalamic nucleus of the rat

88%
Kusek M., Tokarski K., Bobula B., Godek-Michalska A., Hess G.
Acta Neurobiologiae Experimentalis
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2012
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tom 72
|
nr 2
The paraventricular nucleus of the hypothalamus (PVN) is the main regulatory center of the hypothalamic-pituitary-adrenal (HPA) axis. One important function of PVN neurosecretory neurons is the release of corticotropin releasing hormone (CRH) to the pituitary gland. This study was aimed at establishing the effects of restraint stress on GABAergic and glutamatergic inputs to parvocellular neurons of the PVN. Male adult rats were subjected to restraint in metal tubes lasting for 10 min, 2 times daily (repeated for 3 consecutive days). Whole-cell recording were performed from parvocellular neurons. Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded from cells which were voltage clamped at 0 mV and spontaneous excitatory postsynaptic currents (sEPSCs) were recorded at −76 mV. The amplitude and the frequency of sIPSCs and sEPSCs were measured. Restraint stress resulted in an increase in the frequency of sEPSCs while the amplitude of sEPSCs was not altered. Also the parameters characterizing sIPSCs remained unaltered. Thus, restraint stress selectively enhances excitatory input to the paraventricular nucleus of the rat, most likely via a presynaptic mechanism. Support: POIG 01.01.02-12-004/09-00 awarded by the European Regional Development Fund
12

The effects of restraint stress on GABAergic and glutamatergic inpusts to the paraventricular nucleus of the rat

88%
Tokarski K., Kusek M., Bobula B., Gadek-Michalska A., Hess G.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Chronic stress and resulting from it, prolonged hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis and elevated level of glucocorticoids in the circulatory system, have been linked to the pathophysiology of depressive disorders. Dysregulation of the HPA axix is characteristic for individuals with depression. The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses acting via the release of corticotropin releasing hormone (CRH) to the pituitary gland. This study was aimed at establishing the effects of restraint stress on GABAergic and glutamatergic inputs to the paraventricular nucleus of the rat. Male adult rats were subjected to restraint in metal tubes lasting for 10 min (2 times daily, repeated for 3 consecutive days). Control animals were kept in home cages. Twenty-four hour after the last stress session rats were decapitated, their brains were removed and slices containing a part of PVN (420 µm thick) were cut using a vibrating microtome. Neurons were visualized using Zeiss Axioskop upright microscope using Nomarski optics, a 40× water immersion lens and an infrared camera parvocellular neurons of PVN were selected based on the morphology of the soma and on the response to depolarizing current pulses. Spontaneous IPSCs were recorded from parvocellular neurons which were voltage clamped at 0 mV and sEPSCs were recorded at -76 mV. The amplitude and the frequency of sIPSCs and sEPSCs were recorded. Obtained data indicate that the restraint stress resulted in an increase in the mean frequency of sEPSCs while the mean amplitude of sEPSCs was not altered. The restraint stress had no effect on frequency and amplitude of sIPSCs. Thus, restraint stress enhances glutamatergic, but not GABAergic, inputs to the paraventricular nucleus of the rat. Grant: POIG 01.01.02-12-004/09-00 financed by European Regional Development Fund.
13

5-HT7 receptor increases gabaergic transmission in mouse basolateral amygdala

88%
Sowa J. E., Kusek M., Siwiec M., Hess G., Tokarski K.
Acta Neurobiologiae Experimentalis
|
2018
|
tom 78
|
nr Suppl.1
The amygdala is a part of the limbic system involved in emotional processing, which is highly connected with other areas of the brain. Its basolateral region (BLA) re‑ ceives many inputs, including those from prefrontal cor‑ tex, hippocampus, and thalamus. Moreover, the amygdala receives robust innervation from the raphe nuclei. The last serotonin receptor to be discovered, 5-HT7, is highly expressed in the amygdala, suggesting a possibly strong influence on amygdala function. The 5-HT7 receptor is involved in modulation of many physiological processes, such as learning, pain sensation, and mood regulation. Functions of the 5-HT7 receptor at the cellular and net‑ work level have been studied in the hippocampus, dorsal raphe nuclei, and frontal cortex. However, very little is known about the physiological role of 5-HT7 receptors in the amygdala. Our study aimed to elucidate the effect of 5-HT7 receptor activation on synaptic transmission, elec‑ trophysiological properties, and excitability of neurons in the BLA. Whole-cell patch-clamp recordings were made primarily from principal neurons in the BLA of mice, using acute brain slices(300 μm). Afterrecording a baseline, 5-CT (250 nM) in the presence of WAY 100635 (2 µM), a 5-HT1A receptor antagonist, was bath-applied. Both inhibitory and excitatory synaptic transmission were measured by recording spontaneous (sIPSC/sEPSC), miniature (mIPSC/ mEPSC) or evoked (eEPSC/eIPSC) postsynaptic currents. Moreover, excitability, input resistance, and membrane voltage were measured. Specificity of the observed effects was further investigated using the same experimental protocols with the 5-HT7 antagonist SB269970. Our results show an increase in excitability in fast-spiking interneu‑ rons in the amygdala. Regarding inhibitory transmission, 5-HT7 activation increased the amplitude and frequency of spontaneous, but not miniature, IPSC in the principal cells, which suggests that this effect was network-dependent. These effects were abolished in the presence of the 5-HT7 antagonist SB269970. Our data suggest that 5-HT7 activa‑ tion increases GABAergic synaptic transmission onto BLA principal neurons. This is probably due to increased GABA release from local interneurons, where 5-HT7 receptors may be localized. Together, these results suggest that the 5-HT7 receptor may act as a potent modulator of BLA in‑ hibitory transmission. Supported by National Science Cen‑ tre, grant 2016/21/B/NZ4/03618.
14

GABAergic transmission in the rat dorsal raphe nucleus is moduated by the 5-HT 7 receptor

76%
Sowa J., Kusek M., Kaminska M., Golembiowska K., Tokarski K., Hess G.
Acta Neurobiologiae Experimentalis
|
2015
|
tom 75
|
nr Supl.
BACKGROUND AND AIMS: The 5-HT7 receptor is one of the several 5-HT receptor subtypes which are expressed in DRN neurons. Some previous findings suggested that 5-HT7 receptors in the DRN are localized on local GABAergic interneurons, which modulate the activity of 5-HT projection neurons. The aims of this study were to determine how the 5-HT7 receptor activation and blockade influence the GABAergic synaptic input to presumed 5-HT DRN neurons and whether blockade of the 5-HT7 receptor would affect the release and metabolism of 5-HT in the prefrontal cortex in vivo. METHODS: Male Wistar rats, with microdialysis probes implanted in the PFC, received ip injections of 5-HT7 receptor antagonist, SB 269970. 5-HT and 5-HIAA, were analyzed by HPLC. In another set of experiments whole-cell recordings were carried out from DRN slices. SB 269970 was used to block the 5-HT7 receptor. To activate the 5-HT7 receptor 5-CT was applied in the presence of WAY 100635. RESULTS: Ip administration of SB269970 induced an increase in the level of 5-HT and 5-HIAA in PFC. SB 269970 application resulted in a depolarization of presumed DRN projection neurons and in an increase in the spontaneous firing frequency. A hyperpolarization of the cells and a decrease in the spontaneous firing frequency were observed after activation of the 5-HT7 receptor. Blockade of the 5-HT7 receptor caused a decrease in the mean frequency of sIPSCs, while its activation induced an increase. CONCLUSIONS: These results show that blockade of the 5-HT7 receptor enhances the release and metabolism of 5-HT in the PFC. This effect appears to be mediated by depolarization and enhanced firing of DRN serotonergic neurons resulting from a decreased inhibitory synaptic input received by the projection cells. Activation of the 5-HT7 receptor caused opposite effects on activity and the inhibitory input to putative DRN projection neurons. Support: National Science Centre Poland grant DEC-2013/11/B/ NZ4/04743.
15

5‑HT7 receptors on GABAergic neurons modulate the inhibitory tone to principal cells in the mouse basal amygdala

76%
Ciurej I., Kusek M., Siwiec M., Sowa J. E., Bilecki W., Mackowiak M., Tokarski K.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: The amygdala mediates unconscious reactions and is responsible for emotional memory formation and attachment of subjective emotional valence to various stimuli. The amygdala complex expresses 5-HT7 receptors in a high density, however, their function in this structure remains poorly investigated. AIM(S): The present experiments were aimed at determining the effects of 5-HT7 receptor activation on membrane properties and synaptic transmission in pyramidal‑like basal amygdala (BA) neurons. METHOD(S): Whole-cell patch clamp recordings were performed on the brain slices containing a part of the amygdala. Spontaneous excitatory and miniature postsynaptic currents (sEPSCs and mEPSCs) were recorded at a holding potential of ‑70 mV. Spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) were recorded at a holding potential of 0 mV with pipette filled with cesium gluconate-containing solution. RESULTS: Activation of 5-HT7 receptors decreased the mean frequency of sEPSCs without changing sEPSCs amplitude. The mean frequency and amplitude of sIPSCs were enhanced after 5-HT7 receptor activation. Administration of 5-HT7 receptors agonist 5-CT induced a hyperpolarization and an increase of the membrane resistance in a majority of recorded cells. The frequency and amplitude of mEPSCs and mIPSCs were not changed after 5‑CT administration. The observed effects of 5‑HT7 receptors activation were absent in the presence of the 5-HT7 receptor antagonist SB 269970. The application of 5-CT had no effect in slices prepared from 5-HT7 knockout mice. CONCLUSIONS: These data suggest that the observed decrease in sEPSCs and an increase in sIPSCs frequency and amplitude result from activation of 5-HT7 receptors located on GABAergic interneurons that, in turn, innervate BA projection neurons. FINANCIAL SUPPORT: Supported by grant 2016/21/B/NZ4/03618 financed by the National Science Center, Poland, and by statutory funds from Maj Institute of Pharmacology, Polish Academy of Sciences.
16

Metabotropic glutamate receptors as targets for psychotropic drugs

64%
Slawinska A., Wieronska J. M., Stachowicz K., Lason M., Gruca P., Papp M., Kusek M., Tokarski K., Doller D., Pilc A.
Acta Neurobiologiae Experimentalis
|
2013
|
tom 73
|
nr 1
Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new, efficient way to achieve antipsychotic-like effects. Such an activity was shown for mGlu2/3 and mGlu5 receptor agonists/positive modulators, as well as for ACPT-I or LSP1-2111, a non-selective mGlu group III receptors orthosteric agonists. Herein, we report the pharmacological actions of Lu AF21934 and Lu AF32615, a novel, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4receptor with proven anxiolytic, but not antidepressant-like activity, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. MK-801- and amphetamine-induced hyperactivities, as well as DOI-induced head twitches in mice were used as models for positive symptoms. Furthermore, the effect of Lu AF21934 on DOI-induced frequency of spontaneous excitatory postsynaptic currents (EPSCs) in slices from mouse brain frontal cortices was investigated. The MK-801 induced disruption of social interaction and of spatial delayed alternation in rats were used as models for negative and cognitive symptoms, respectively. Lu AF21934 (0.1, 0.5, 2 and 5 mg/kg) and Lu AF32615 (2, 5 and 10 mg/kg) dose-dependently inhibited both MK-801 and amphetamine-induced hyperactivities. Concomitantly, Lu AF 21935, an inactive enantiomer of Lu AF21934, was not effective. Moreover, the drugs antagonized DOI-induced head twitches in mice. DOI-induced increased frequency of spontaneous EPSCs was also decreased by Lu AF21395 and Lu AF32615. The MK-801-induced disruption in the social interaction test, measured as number of episodes and total time of episodes between two rats, was abolished by Lu AF21394 at a dose of 0.5 mg/kg and Lu AF32615 at a dose of 10 mg/kg. In the delayed spatial alternation test, the effective doses of Lu AF21934 were 1 and 2 mg/kg, and the AF32615 was active at a dose of 10 mg/kg. Altogether, we propose that mGlu4 receptor can be consider as promising target for the development of novel antipsychotic drugs, acting as a positive allosteric modulators of the receptor.
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