The ability of endogenous neurosteroids (NSs) with pregnane skeleton modified at positions C-3 and C-5 to modulate the functional activity of inhibitory glycine receptors (GlyR) and ionotropic ɣ-aminobutyric acid receptors (GABAA R) was estimated. The glycine and GABA-induced chloride current (IGly and IGABA ) were measured in isolated pyramidal neurons of the rat hippocampus and in isolated rat cerebellar Purkinje cells, respectively. Our experiments demonstrated that pregnane NSs affected IGABA and IGly in a different manner. At low concentrations (up to 5 μM), tested pregnane NSs increased or did not change the peak amplitude of the IGABA , but reduced the IGly by decreasing the peak amplitude and/or accelerating desensitization. Namely, allopregnanolone (ALLO), epipregnanolone (EPI), pregnanolone (PA), pregnanolone sulfate (PAS) and 5β-dihydroprogesterone (5β-DHP) enhanced the IGABA in Purkinje cells. Dose-response curves plotted in the concentration range from 1 nM to 100 μM were smooth for EPI and 5β-DHP, but bell-shaped for ALLO, PA and PAS. The peak amplitude of the IGly was reduced by PA, PAS, and 5α- and 5β-DHP. In contrast, ALLO, ISO and EPI did not modulate it. Dose-response curves for the inhibition of the IGly peak amplitude were smooth for all active compounds. All NSs accelerated desensitization of the IGly . The dose-response relationship for this effect was smooth for ALLO, PA, PAS and 5β-DHP, but it was U-shaped for EPI, 5α-DHP and ISO. These results, together with our previous results on NSs with androstane skeleton, offer comprehensive overview for understanding the mechanisms of effects of NSs on IGly and IGABA .

• MeSH
• 5alfa-dihydroprogesteron farmakologie   MeSH
• chloridy farmakologie   MeSH
• GABA MeSH
• glycin farmakologie   MeSH
• krysa rodu rattus MeSH
• neurony fyziologie   MeSH
• neurosteroidy * MeSH
• potkani Wistar MeSH
• pregnanolon * farmakologie   MeSH
• pregnany farmakologie   MeSH
• receptory GABA-A fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We studied the effects of GABA receptor agonists microinjections in medullary raphé on the mechanically induced tracheobronchial cough response in anesthetized, unparalyzed, spontaneously breathing cats. The results suggest that GABA-ergic inhibition significantly contributes to the regulation of cough reflex by action of both GABA(A) and GABA(B) receptors. The data are consistent with inhomogeneous occurrence of GABA-ergic neurons in medullary raphé and their different involvement in the cough reflex control. Cells within rostral nucleus raphéobscurus with dominant role of GABA(A) receptors and neurons of rostral nucleus raphépallidus and caudal nucleus raphémagnus with dominant role of GABA(B) receptors participate in regulation of cough expiratory efforts. These cough control elements are distinct from cough gating mechanism. GABA-ergic inhibition in the raphé caudal to obex had insignificant effect on cough. Contradictory findings for GABA, muscimol and baclofen administration in medullary raphé suggest involvement of coordinated activity of GABA on multiple receptors affecting raphé neurons and/or the local neuronal circuits in the raphé modulating cough motor drive.

• MeSH
• baklofen farmakologie   terapeutické užití   MeSH
• kašel farmakoterapie   patofyziologie   MeSH
• kočky MeSH
• medulla oblongata účinky léků   fyziologie   MeSH
• muscimol farmakologie   terapeutické užití   MeSH
• nuclei raphe účinky léků   fyziologie   MeSH
• receptory GABA-A - agonisté farmakologie   terapeutické užití   MeSH
• receptory GABA-A fyziologie   MeSH
• receptory GABA-B - agonisté farmakologie   terapeutické užití   MeSH
• receptory GABA-B fyziologie   MeSH
• reflex účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• kočky MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Inhibitory circuits in the auditory brainstem undergo multiple postnatal changes that are both activity-dependent and activity-independent. We tested to see if the shift from GABA- to glycinergic transmission, which occurs in the rat medial nucleus of the trapezoid body (MNTB) around the onset of hearing, depends on sound-evoked neuronal activity. We prevented the activity by bilateral cochlear ablations in early postnatal rats and studied ionotropic GABA and glycine receptors in MNTB neurons after hearing onset. The removal of the cochlea decreased responses of GABAA and glycine receptors to exogenous agonists as well as the amplitudes of inhibitory postsynaptic currents. The reduction was accompanied by a decrease in the number of glycine receptor- or vesicular GABA transporter-immunopositive puncta. Furthermore, the ablations markedly affected the switch in presynaptic GABAA to glycine receptors. The increase in the expression of postsynaptic glycine receptors and the shift in inhibitory transmitters were not prevented. The results suggest that inhibitory transmission in the MNTB is subject to multiple developmental signals and support the idea that auditory experience plays a role in the maturation of the brainstem glycinergic circuits.

• MeSH
• ablace * MeSH
• corpus trapezoideum fyziologie   MeSH
• inhibiční postsynaptické potenciály fyziologie   MeSH
• kochlea patofyziologie   chirurgie   MeSH
• krysa rodu rattus MeSH
• nervový přenos * MeSH
• nervový útlum účinky léků   fyziologie   MeSH
• novorozená zvířata MeSH
• receptory GABA-A - agonisté farmakologie   MeSH
• receptory GABA-A fyziologie   MeSH
• receptory glycinu agonisté   metabolismus   fyziologie   MeSH
• sluchové kmenové evokované potenciály fyziologie   MeSH
• transportéry VIAAT metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Local application of four concentrations of bicuculline methiodide (a specific antagonist of GABA(A) receptors) was used to study a sensitivity of somatosensory cortex in four age groups of immature rats with implanted electrodes. Presence and latencies of two epileptic phenomena (focal discharges and seizures) were evaluated. Focal discharges exhibited moderate tendency to a decrease of sensitivity to bicuculline methiodide with maturation. Concentration-effect relation of incidence of focal discharges was observed only in 7- and 12-day-old but not in older animals. Results with incidence and latencies of seizures did not show relations to age or concentration of bicuculline. Neither of the epileptic phenomena can be used as a reliable index of cortical maturation.

• MeSH
• bikukulin farmakologie   terapeutické užití   MeSH
• elektroencefalografie účinky léků   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• receptory GABA-A - antagonisté farmakologie   MeSH
• receptory GABA-A fyziologie   MeSH
• somatosenzorické korové centrum účinky léků   růst a vývoj   MeSH
• věkové faktory MeSH
• záchvaty farmakoterapie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The ability of pregnanolone glutamate (PA-Glu), pregnanolone hemisuccinate (PA-hSuc) and pregnanolone hemipimelate (PA-hPim), neuroactive steroids with a negative modulatory effect on excitatory N-methyl-d-aspartate receptors, to influence the functional activity of inhibitory γ-aminobutyric acid and glycine receptors was estimated. The GABA- and glycine-induced chloride currents (IGABA and IGly) were measured in isolated pyramidal neurons of the rat hippocampus using the patch-clamp technique. Compound PA-Glu was found to potentiate IGABA and to inhibit IGly, while PA-hSuc and PA-hPim inhibited both IGABA and IGly. Moreover, PA-Glu, PA-hSuc, and PA-hPim had a greater effect on desensitization than on the peak amplitude of IGly. At a high concentration of glycine (500 μM), the effect of neurosteroids on the peak amplitude of IGly disappeared, and the acceleration of desensitization remained. The conversion of PA-Glu into androstane glutamate (AND-Glu), an analogue that lacks the C-17 acetyl moiety, completely eliminated the effects on these receptors. Our results indicate that the C-17 acetyl moiety is crucial for the action on IGABA and IGly. Our results indicate that the pregnanolone derivatives, in contrast to the androstane analogues, modulate IGABA and IGly at low micromolar concentrations and this family of neurosteroids can be useful for future structure-activity relationship studies of the steroid modulation of other receptor types.

• MeSH
• hipokampus účinky léků   fyziologie   MeSH
• krysa rodu rattus MeSH
• neurony účinky léků   fyziologie   MeSH
• neurotransmiterové látky chemie   farmakologie   MeSH
• orgánové kultury - kultivační techniky MeSH
• potkani Wistar MeSH
• pregnanolon chemie   farmakologie   MeSH
• pyramidové buňky MeSH
• receptory GABA-A fyziologie   MeSH
• receptory glycinu fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cíl studie: Cílem studie bylo zjištění vztahů mezi manifestací tinnitu, nálezem na sluchových evokovaných potenciálech a genetickým pozadím u receptoru pro gamaaminomáselnou kyselinu typu A (GABA(A) receptor), podporující desinhibiční hypotézu vzniku tinnitu. Soubor a metodika: Bylo vyšetřeno 131 pacientů z hlediska sluchové ztráty, provedena kvantifikace tinnitu, sluchové evokované potenciály střední latence (MLR) a kmenové sluchové evokované potenciály (BAEP) a dále stanovení genotypu (CA)n repetitivní sekvence pro beta‑3 podjednotku GABA(A) receptoru. Následně byly hledány vztahy mezi jednotlivými výsledky a manifestací tinnitu. Výsledky: Byla nalezena korelace tinnitus skóre s amplitudovým poměrem vln V/III v BAEP (R = 0,22, p < 0,001) a s průměrným sluchovým prahem (R = 0,22, p = 0,17). Rovněž byla nalezena korelace tinnitus skóre s amplitudou vlny PA v MLR (R = 0,31–0,37; p < 0,001). Výsledky MLR neukázaly žádný vztah k průměrnému sluchovému prahu. U skupiny s kratší anamnézou tinnitu (méně než devět měsíců) byl prokázán rozdíl v manifestaci tinnitu na genotypu pro (CA)n repetitivní sekvenci genu pro beta‑3 podjednotku GABA(A) receptoru (p = 0,002). Tento výsledek byl rovněž konzistentní s rozložením amplitudy vlny PA v dané subpopulaci. Závěr: Tyto výsledky svědčí o existenci dvou hlavních regulačních mechanizmů vzniku tinnitu: první, který je závislý na velikosti sluchové ztráty, je na úrovni mozkového kmene, zatímco druhý je na úrovni korové s možnou souvislostí s genotypem (CA)n repetitivní sekvence pro beta‑3 podjednotku GABA(A) receptoru.

Study aim:Study objective was to explore associations between manifestation of tinnitus, auditory evoked potentials and genetic background of gamma‑aminobutyric acid type A (GABA(A) receptors) to support the disinhibited feedback hypothesis of tinnitus generation. Materials and methods: A population of 131 patients was assessed for severity of hearing loss, quantification of tinnitus, mid‑latency responses (MLR) and brainstem auditory evoked potentials (BAEP), and (CA)n tandem repeat polymorphism in GABA(A) Beta‑3 subunit gene to establish any correlation with manifestation of tinnitus. Results: It was observed that tinnitus score correlates with V/III amplitude ratio in BAEP (R = 0.22, p < 0.001) and with mean pure tone audiometry (PTA) threshold (R = 0.22, p = 0.017). Analysis of the MLR results showed a significant correlation between the PA wave amplitude and the tinnitus score (R = 0.31–0.37; p < 0.001). MLR result analysis showed no statistically significant correlation between the wave amplitudes and the mean auditory threshold. An analysis of a subgroup with shorter clinical history (less than nine months) revealed a statistically significant difference in the tinnitus score in relation to the genotype of (CA)n tandem repeat of the GABRß3 receptor subunit gene (p = 0.002). This result was also consistent with the distribution of the PA wave amplitude in the given subpopulation. Conclusion: Our findings indicate existence of two main regulatory mechanisms of tinnitus generation: first, the brainstem mechanism is dependent on the severity of the hearing loss; second, the cortical mechanism is likely to be dependent on the genotype of (CA)n tandem repeat in GABA(A) beta‑3 subunit gene.

• MeSH
• akustická stimulace metody   MeSH
• audiometrie čistými tóny * využití   MeSH
• dospělí MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• koncové repetice genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozkový kmen fyziologie   MeSH
• receptory GABA-A * fyziologie   genetika   MeSH
• senioři MeSH
• sluchová dráha fyziologie   MeSH
• sluchové evokované potenciály * fyziologie   genetika   MeSH
• sluchový práh * fyziologie   MeSH
• tinnitus * diagnóza   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

• MeSH
• alosterická regulace * MeSH
• alosterické místo * MeSH
• benzodiazepiny farmakokinetika   farmakologie   MeSH
• chemie farmaceutická MeSH
• farmakokinetika MeSH
• kalcimimetika farmakokinetika   farmakologie   MeSH
• lidé MeSH
• neurotransmiterové látky farmakokinetika   farmakologie   MeSH
• racionální návrh léčiv MeSH
• receptory GABA-A * fyziologie   MeSH
• receptory spřažené s G-proteiny fyziologie   MeSH
• sirtuin 1 farmakokinetika   farmakologie   MeSH
• systémy cílené aplikace léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

The role of inhibitory γ-aminobutyric acid-A (GABA-A) system in the cortical epileptic afterdischarges (ADs) was studied at three different developmental stages of rats. Animals 12, 18 and 25days old with implanted epidural electrodes were pretreated with bicuculline (1 and 2mg/kgi.p.) and 15min later repeatedly stimulated with low frequency trains with stepwise increasing current intensity. Bicuculline only exceptionally decreased threshold current intensities necessary for elicitation of movements directly bound to stimulation, spike-and wave ADs, clonic seizures and transition into a limbic type of ADs. Duration of ADs was not systematically affected by either dose of bicuculline. In contrast, transcallosal evoked potentials exhibited under the influence of bicuculline steeper curve expressing relation between intensity of stimuli and amplitude of responses. In contrast to GABA-B receptors, GABA-A receptors do not play an important role in generation and arrest of cortical epileptic ADs in immature rats.

• MeSH
• bikukulin farmakologie   MeSH
• elektrická stimulace MeSH
• evokované potenciály účinky léků   fyziologie   MeSH
• GABA antagonisté farmakologie   MeSH
• implantované elektrody MeSH
• krysa rodu rattus MeSH
• mozková kůra účinky léků   patofyziologie   MeSH
• potkani Wistar MeSH
• receptory GABA-A fyziologie   MeSH
• záchvaty patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Whole cell patch-clamp recordings from GABAergic cells of thalamic reticular nucleus (RTN) in thalamocortical slices made from postnatal day 6 (P6) to 10 (P10) were used to investigate the pattern of rebound bursts (RBs) triggered by an injection of hyperpolarizing current into RTN cells. The number of RBs in the RTN and the overlying Na+/K+ spikes changed in an agedependent manner. The generation of RBs depended largely on the amplitude of the after-hyperpolarizations (AHPs). RB patterns in response to hyperpolarizing current injection into relay cells were markedly different from RB patterns in RTN cells with an after-depolarization. GABAA receptor antagonist bicuculline methiodide (BMI) changed burst firing patterns, increasing the duration of RB and decreasing the amplitude of AHP in RTN cells. Furthermore, local puffs of NMDA in the presence of BMI induced RBs. K+ channel blocker 4-aminopyridine partially mimicked the effect of BMI on AHPs. The shapes of RBs were altered by a selective CaMKII inhibitor KN-62, but not by an inactive analog KN-04.

• MeSH
• 1-(5-isochinolinsulfonyl)-2-methylpiperazin analogy a deriváty   farmakologie   MeSH
• 4-aminopyridin farmakologie   MeSH
• akční potenciály fyziologie   účinky léků   MeSH
• bikukulin analogy a deriváty   farmakologie   MeSH
• blokátory draslíkových kanálů farmakologie   MeSH
• financování organizované MeSH
• GABA antagonisté farmakologie   MeSH
• GABA fyziologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• jádra thalamu cytologie   fyziologie   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• nervový útlum fyziologie   účinky léků   MeSH
• neurony fyziologie   MeSH
• novorozená zvířata MeSH
• orgánové kultury - kultivační techniky MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 2 antagonisté a inhibitory   metabolismus   MeSH
• receptory GABA-A - antagonisté MeSH
• receptory GABA-A fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

• MeSH
• anestetika farmakologie   škodlivé účinky   MeSH
• anestezie MeSH
• celková anestezie škodlivé účinky   trendy   MeSH
• farmakologické účinky MeSH
• lidé MeSH
• mícha fyziologie   účinky léků   MeSH
• mozek fyziologie   účinky léků   MeSH
• neurotransmiterové látky MeSH
• receptory GABA-A fyziologie   účinky léků   MeSH
• signální transdukce MeSH
• výzkum MeSH
• Check Tag
• lidé MeSH