Repeated administration of imipramine modifies GABAergic transmission in rat frontal cortex

Alterations in the functions of brain gamma-aminobutyric acid (GABA) inhibitory system and a distortion in the balance between excitatory and inhibitory synaptic transmission have been hypothesized to be possible causes of mood disorders. Experimental evidence points to modifications of GABAergic transmission as a result of prolonged treatment with antidepressant drugs, however, the influence of the tricyclic antidepressant imipramine on inhibitory synaptic transmission in the rat cerebral cortex has not yet been investigated. Therefore, in the present study the effects of single and repeated administration of imipramine were evaluated ex vivo in slices of the rat frontal cortex using electrophysiological approach. In slices prepared 2 days after the last drug administration from animals receiving imipramine for 14 days (dose 10 mg/kg p.o., twice daily) the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from layer II/III pyramidal neurons was decreased, while the mean amplitude of sIPSCs was increased. These effects were absent in slices obtained from rats which received imipramine once. Application of N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN 082), a selective mGluR7 allosteric agonist, to the slice incubation medium resulted in a decrease in the mean frequency of sIPSCs in preparations obtained from repeated imipramine-treated animals, in contrast to slices originating from control rats where no AMN 082-induced effects were observed. Repeated imipramine treatment reduced protein density levels of the three tested GABA(A) receptor subunits: α(1), β(2) and γ(2). These data indicate that repeated treatment of normal rats with imipramine results in a modification of the release mechanism of GABA from presynaptic terminals and its modulation by mGluR7 receptors as well as in an alteration in GABA(A) receptor subunit protein levels in the rat cerebral cortex

5-HT_{7} receptor modulates GABAergic transmission in the rat dorsal raphe nucleus and controls cortical release of serotonin

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 were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 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 (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (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 using 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 N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons

Nitric oxide synthase inhibitor attenuates the effects of repeated restraint stress on synaptic transmission in the paraventricular nucleus of the rat hypothalamus

Corticotropin-releasing hormone (CRH)-synthesizing parvocellular neuroendocrine cells (PNCs) of the hypothalamic paraventricular nucleus (PVN) play a key role in the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Several studies have demonstrated that synaptic inputs to these cells may undergo stress-related enhancement but, on the other hand, it has been reported that exposition to the same stressor for prolonged time periods may induce a progressive reduction in the response of the HPA axis to homotypic stressors. In the present study rats were subjected to 10 min restraint sessions, repeated twice daily for 3 or 7 days. Miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) were then recorded from PNCs in ex vivo hypothalamic slice preparations obtained 24 h after the last restraint. Restraint stress repeated over 3 days resulted in increased mean frequency and decreased rise time and decay time constant of mEPSCs, accompanied by a decrease in the excitability of PNCs, however, no such changes were evident in slices obtained from rats subjected to restraint over 7 days. There were no changes in mIPSCs after repeated restraint. Administration of the unspecific nitric oxide synthase (NOS) blocker Nω-Nitro-L-arginine (L-NNA) before each restraint, repeated over 3 days, prevented the occurrence of an increase in mEPSC frequency. However, animals receiving L-NNA and subjected to repeated restraint had similar changes in PNCs membrane excitability and mEPSC kinetics as stressed rats not receiving L-NNA. Comparison of the effects of a single 10 min restraint session followed by either an immediate or delayed (24 h) decapitation revealed an increase in the mean mEPSC frequency and a decrease in the mean mIPSC frequency in slices prepared immediately after restraint, with no apparent effects when slice preparation was delayed by 24 h. These results demonstrate that restraint, lasting 10 min and repeated twice daily for 3 days, induces a selective and long-lasting enhancement of excitatory synaptic input onto PNCs, partially by a NOS-dependent mechanism, and reduces PNC excitability, whereas prolongation of repeated stress for up to 7 days results in an adaptation

Elektrofizjologiczne badania neuronalnych mechanizmów plastyczności kory baryłkowej myszy wywołanych uczeniem się

Awersyjne warunkowanie klasyczne, polegające na skojarzeniu stymulacji dotykowej jednego z rzędów wibrys, jako bodźca warunkowego (CS), z szokiem elektrycznym w ogon, jako bodźcem bezwarunkowym (UCS), wywołuje powiększenie rozmiarów funkcjonalnych reprezentacji stym ulowanych wibrys w korze somatosensorycznej myszy, co wykazano przy zastosowaniu pomiarów aktywności metabolicznej tkanki nerwowej [13]. Efekt ten ma charakter uczenia asocjacyjnego. Dane literaturowe wskazują, źe po zakończeniu treningu, w obszarach stanowiących reprezentacje stymulowanych wibrys dochodzi do wzrostu poziomu markerów GABAergicznego przekaźnictwa synaptycznego. Jak dotąd, brak jednak danych na temat modyfikacji funkcji neuronów korowych i ich połączeń, które mogą być efektem zmian plastycznych. Celem wykonanych badań było określenie, które elementy sieci neuronalnej kory somatosensorycznej ulegają modyfikacjom w efekcie awersyjnego warunkowania klasycznego. Badania prowadzone były metodami rejestracji elektrofizjologicznej ex vivo z pojedynczych neuronów whole-cell patch-clamp w skrawkach kory somatosensorycznej myszy, poddanych wcześniej warunkowaniu awersyjnemu. W pierwszym etapie badań przeprowadzono charakterystykę elektrofizjologiczną glutaminianergicznych neuronów pobudzających i GABAergicznych neuronów hamujących. Następnie rejestrowano postsynaptyczne prądy hamujące i pobudzające, powstające spontanicznie. Uzyskane wyniki wykazały, że warunkowanie awersyjne nie spowodowało zmian podstawowych parametrów elektrofizjologicznych komórek GABAergicznych i glutaminianergicznych. w skrawkach kory pochodzących z mózgów zwierząt poddanych uprzednio procedurze warunkowania klasycznego. Wykazano, że warunkowanie klasyczne nasiliło częstotliwość spontanicznych postsynaptycznych prądów hamujących (sIPSC) rejestrowanych w komórkach glutaminianergicznych w skrawkach kory pochodzących z mózgów zwierząt poddanych procedurze warunkowania klasycznego. W przeciwieństwie do tego, nie stwierdzono istotnych zmian w częstotliwości spontanicznych postsynaptycznych prądów pobudzających (sEPSC) rejestrowanych w komórkach GABA i glutaminianergicznych. Wyniki te potwierdzają hipotezę o nasileniu przekaźnictwa synaptycznego w połączeniach pomiędzy interneuronami GABAergicznymi a neuronami pobudzającymi, powstającym w efekcie treningu. Zaobserwowane nasilenie przekaźnictwa GABAergicznego stanowi, prawdopodobnie, wyraz adaptacyjnej modyfikacji sieci neuronalnej połączeń pomiędzy neuronami baryłki, której sens polega na zapewnieniu niezbędnej równowagi pomiędzy przekaźnictwem pobudzającym a hamującym w zmienionych warunkach, związanych z awersyjnym warunkowaniem klasycznym. Mechanizm zaobserwowanych zmian nie jest znany i wymaga dalszych badań.Zadanie pt. „Digitalizacja i udostępnienie w Cyfrowym Repozytorium Uniwersytetu Łódzkiego kolekcji czasopism naukowych wydawanych przez Uniwersytet Łódzki” nr 885/P-DUN/2014 dofinansowane zostało ze środków MNiSW w ramach działalności upowszechniającej naukę

Short-term repeated corticosterone administration enhances glutamatergic but not GABAergic transmission in the rat motor cortex

It has been demonstrated that stress impairs performance of skilled reaching and walking tasks in rats due to the action of glucocorticoids involved in the stress response. Skilled reaching and walking are controlled by the primary motor cortex (M1); however, it is not known whether stress-related impairments in skilled motor tasks are related to functional and/or structural alterations within the M1. We studied the effects of single and repeated injections of corticosterone (twice daily for 7 days) on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) recorded from layer II/III pyramidal neurons in ex vivo slices of the M1, prepared 2 days after the last administration of the hormone. We also measured the density of dendritic spines on pyramidal cells and the protein levels of selected subunits of AMPA, NMDA, and GABAA receptors after repeated corticosterone administration. Repeatedly administered corticosterone induced an increase in the frequency but not in the amplitude of sEPSCs, while a single administration had no effect on the recorded excitatory currents. The frequency and amplitude of sIPSCs as well as the excitability of pyramidal cells were changed neither after single nor after repeated corticosterone administration. Treatment with corticosterone for 7 days did not modify the density of dendritic spines on pyramidal neurons. Corticosterone influenced neither the protein levels of GluA1, GluA2, GluN1, GluN2A, and GluN2B subunits of glutamate receptors nor those of α1, β2, and γ2 subunits of the GABAA receptor. The increase in sEPSCs frequency induced by repeated corticosterone administration faded out within 7 days. These data indicate that prolonged administration of exogenous corticosterone selectively and reversibly enhances glutamatergic, but not GABAergic transmission in the rat motor cortex. Our results suggest that corticosterone treatment results in an enhancement of spontaneous glutamate release from presynaptic terminals in the M1 and thereby uncovers a potential mechanism underlying stress-induced motor functions impairmen