Antagonism of the analeptic activity of thyrotropin-releasing hormone (TRH) by agents which enhance GABA transmission (original) (raw)
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Thyrotropin-releasing hormone (TRH) was found to antagonize pentobarbital-induced sleeping time and hypothermia. While 3 to 100 mg/kg of TRH reduced pentobarbital sleeping time when administered prior to the barbiturate, a dose-response relationship to TRH could not be established. However, doses of 10 to 100 mg/kg of TRH enhanced the lethality of pentobarbital when these compounds were administered simultaneously. Thyrotropin or L-triiodothyronine did not imitate and hypophysectomy did not reduce the effects of TRH, indicating that the pituitary is not essential for its antagonism of pentobarbital Studies of TRH analogs provided further support of this view In addition TRH reduced the sleep and hypothermia produced by thiopental amobarbital, seco-barbital and phenobarbital, and it antagonized the hypothermia and reduced motor activity produced by chloral hydrate, reserpine, chlorpromazine and diazepam Intracisternally administered TRH also reduced pentobarbital sleeping time and hypothermia but melanocyte-stimulating hormone release-inhibiting factor and somatostatin administered by this route did not While reduction of pentobarbital sleeping time by TRH could not be attributed to an affect on monoamine systems or to deamidated TRH, this action was reduced by intracisternally administered atropine suggesting that cholinergic mechanisms may contribute to the effects of TRH. Thus the results provide evidence that TRH acts on brain independent of an effect on the pituitary.
Antagonism of the analeptic activity of TRH by agents which enhance GABA transmission
Administration of 10 mg/kg TRH to mice was found to reduce the sleep and hypothermia induced by 4.7 g/kg ethanol. However, TRH did not reduce the sleep of mice that were given ?-hydroxybutyric acid (GHBA), baclophen, or aminooxyacetic acid (AOAA) in combination with 3 g/kg ethanol. TRH also failed to reverse the hypothermia induced by the combination of ethanol and baclophen or GHBA, and the characteristic neurological effects of TRH e.g. tremor, increased muscle tone, and increased respiratory rate were reduced. In addition, TRHinduced locomotor stimulation was prevented by pretreatment with small doses of the GABA-ergic agents, and while 30 mg/kg TRH reduced the hypothermia produced by large doses of the GABA-ergic drugs, it did not antagonize the locomotor retardation produced by baclophen or GHBA. A hypothesis that the analeptic effects of TRH may be mediated via an inhibition of GABA systems is discussed.
Thyrotropin-releasing hormone (TRH), administered intraperitoneally, was found to antagonize ethanol-induced sleep and hypothermia in mice without affecting brain ethanol content. This reduction of the actions of ethanol was also apparent after oral or intracisternal administration of TRH. In addition, TRH reduced ethanol-induced sleep in rats, hamsters, gerbils and guinea pigs. Evidence that the pituitary-thyroid axis is not necessary for the effects of TRH was provided by observations that hypophysectomy did not reduce TRH antagonism of ethanol narcosis and findings that neither triiodothyronine nor thyrotropin mimicked its action. Certain analogs of TRH, which have little effect on the pituitary, were also found to antagonize ethanol-induced sleep and hypothermia. Pretreatment with the antiadrenergic drugs, α-methyltyrosine, phentolamine and propranolol did pot antagonize the ability of TRH to reduce sleep induced by ethanol. However, after intracisternal administration of atropine methyl nitrate, TRH no longer caused a significant reduction of sleep, even though TRH antagonism of the ethanol-induced hypothermia was still apparent. In contrast, central administration of other anticholinergic drugs, such as d-tubocurarine and hexamethonium, reduced ethanol-induced sleep and this effect was additive with TRH. Carbachol also reduced ethanol sleeping time and this effect was also blocked by atropine methyl nitrate. The antagonism of ethanol-induced sleep by dibutyryl cyclic adenosine 3′,5′monophosphate was significantly reduced but not blocked by atropine methyl nitrate. Results provide evidence that TRH has a direct extrapituitary action on brain and that both TRH and ethanol may interact with central cholinergic systems.
Thyrotropin releasing hormone--Antagonism of pentobarbital in rodents
Thyrotropin releasing hormone (TRH) antagonises the behavioral and temperature reducing effects of pentobarbital in rodents . The hormone is effective whether given before or after the barbiturate . this antagonism by TRH of the effects of pentobarbital probably does not depend upon thyroid hormone release as L-trüodothyronine administration is ineffective .
Peptides, 1984
chlordiazepoxide and ethanol were studied alone and in combination with thyrotropin-releasing hormone (TRH), IM, on punished behavior. Key-peck responses of pigeons were maintained by food presentation under a fixed-interval 3-rain schedule in which every 30th response produced shock. Moderate doses of pentob~,rbitai, chlordiazepuxide and ethanol increased punished responding to 150-200% of control values while the higher doses of these drugs almost completely eliminated responding. TRH (0.01-1 mg/kg) bad little effect on punished responding and 3 mg/kg produced 50% decreases. Although the lower doses of TRH were without effect when given alone, doses of 0.03 mg/kg and greater markedly potentiated the rate-increasing effects of pentobarbiud, chlordiazepoxide and ethanol. Increases in punished responding of 350% were obtained with combinations of TRH and these drugs. The rate-decreasing effects of the sedative-hypnotic and anxiolytic compounds were not reversed by TRH. Potentiation of the beimviorai effects of sedative-hypnotic and anxiolytic drugs by TRH suggests that TRH may play an important role in modulating the behavioral effects of these compounds and that combinations of neuroactive peptides with certain psychotherapeutic agents may be of some therapeutic value. Thyrotropin-releasing hormone (TRH) Drug interactions Pigeons
Effects of Thyrotropin-releasing Hormone on GABAergic Synaptic Transmission of the Rat Hippocampus
European Journal of Neuroscience, 1996
The effect of thyrotropin-releasing hormone (TRH), a neuropeptide physiologically present in the mammalian hippocampus, on spontaneous, miniature and evoked GABAergic postsynaptic currents was investigated using whole-cell patch-clamp recording from pyramidal cells and interneurons of the rat hippocampal thin slice preparation. Bath application of 10 pM TRH induced an increase in the frequency of spontaneous postsynaptic currents from 1.07 2 0.68 to 3.16 ? 0.73 Hz in pyramidal neurons and interneurons of the stratum lacunosummoleculare (SL-M). In tetrodotoxin solution TRH did not change miniature postsynaptic currents. Application of TRH to minislices containing only the CA1 region still produced an increase in the spontaneous postsynaptic current frequency, indicative of an action by TRH upon a local GABAergic circuitry. Paired recordings from one pyramidal cell and one stratum lacunosum moleculare interneuron displayed synchronous events whose frequency rose after TRH application, suggestive of a common, TRH-sensitive input. In a small subset of cells TRH induced the appearance of highly rhythmic large postsynaptic currents at a frequency of -2 Hz, as confirmed by autocorrelation analysis. Postsynaptic currents electrically evoked by focal stimulation of stratum lacunosum-moleculare were depressed from 90 ? 27 to 44 5 15 pA after application of TRH. This phenomenon was solely due to an increase in the number of synaptic failures. It is proposed that the effect of TRH on the GABAergic system was primarily exerted on a subset of interneurons controlling the activity of pyramidal cells as well as stratum lacunosum-moleculare interneurons.
Thyrotropin-releasing hormone increases GABA release in rat hippocampus
The Journal of Physiology, 2006
Thyrotropin-releasing hormone (TRH) is a tripeptide that is widely distributed in the brain including the hippocampus where TRH receptors are also expressed. TRH has anti-epileptic effects and regulates arousal, sleep, cognition, locomotion and mood. However, the cellular mechanisms underlying such effects remain to be determined. We examined the effects of TRH on GABAergic transmission in the hippocampus and found that TRH increased the frequency of GABA A receptor-mediated spontaneous IPSCs in each region of the hippocampus but had no effects on miniature IPSCs or evoked IPSCs. TRH increased the action potential firing frequency recorded from GABAergic interneurons in CA1 stratum radiatum and induced membrane depolarization suggesting that TRH increases the excitability of interneurons to facilitate GABA release. TRH-induced inward current had a reversal potential close to the K + reversal potential suggesting that TRH inhibits resting K + channels. The involved K + channels were sensitive to Ba 2+ but resistant to other classical K + channel blockers, suggesting that TRH inhibits the two-pore domain K + channels. Because the effects of TRH were mediated via Gα q/11 , but were independent of its known downstream effectors, a direct coupling may exist between Gα q/11 and K + channels. Inhibition of the function of dynamin slowed the desensitization of TRH responses. TRH inhibited seizure activity induced by Mg 2+ deprivation, but not that generated by picrotoxin, suggesting that TRH-mediated increase in GABA release contributes to its anti-epileptic effects. Our results demonstrate a novel mechanism to explain some of the hippocampal actions of TRH.
Neurochemistry International, 2018
3-iodothyroacetic acid (TA 1) is among the by-products of thyroid hormone metabolism suspected to mediate the non-genomic effects of the hormone (T3). We aim to investigate whether TA 1 systemically administered to mice stimulated mice wakefulness, an effect already described for T3 and for another T3 metabolite (i.e. 3-iodothryonamine; T1AM), and whether TA 1 interacted at GABA-A receptors (GABA-AR). Mice were pre-treated with either saline (vehicle) or TA 1 (1.32, 4 and 11 mg/kg) and, after 10 min, they received ethanol (3.5 g/kg, i.p.). In another set of experiments, TA 1 was administered 5 min after ethanol. The latency of sleep onset and the time of sleep duration were recorded. Voltage-clamp experiments to evaluate the effect of 1 mM TA 1 on bicuculline-sensitive currents in acute rat hippocampal slice neurons and binding experiments evaluating the capacity of 1, 10, 100 mM TA 1 to displace [ 3 H]flumazenil from mice brain membranes were also performed. 4 mg/kg TA 1 increases the latency of onset and at 1.32 and 4 mg/kg it reduces the duration of ethanolinduced sleep only if administered before ethanol. TA 1 does not functionally interact at GABA-AR. Overall these results indicate a further similarity between the pharmacological profile of TA 1 and that of T 1 AM.