Effects of thyrotropin-releasing hormone (TRH) and a TRH analogue,MK-771, on punished responding of squirrel monkeys

The effects of thyrotropin-releasing hormone (TRH) and an enzyme-resistant analogue, MK-771, were compared on punished responding of squirrel monkeys maintained either by food presentation or stimulus-shock termination. Both TRH and MK-771 (1.0–30 mg/kg IM) produced dose-related decreases in punished responding maintained by food presentation and dose-related increases in punished responding maintained by shock termination. TRH was more potent than MK-771 in altering punished response rates maintained by either event.     

Treatment of rats with the TRH analog MK-771. Down-regulation of TRH receptors and behavioral tolerance

The regulation of receptors for thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) was studied by administering the TRH analog, MK-771 to rats by three different schedules and then measuring changes in the binding of [3H](3MeHis2) TRH and behavioral responses to a challenge with MK-771. The behavioral responses monitored were wet-dog shakes, large motor movements, small motor movements and forepaw tremor. Temperature changes were also monitored. The first schedule consisted of intracerebroventricular (i.c.v.) administration of MK-771 for seven days (5 micrograms/microliter per hr) via a mini-osmotic pump. At the end of the treatment, rats showed no shaking or large motor movements typically induced by TRH, in response to a 5 mg/kg (i.p.) challenge of MK-771. Receptors were found to be 50% of control levels in the three areas of brain examined. The second schedule consisted of the administration of MK-771 (5 micrograms/2 microliters, i.c.v., once a day and 2 mg/kg, i.p., once a day). It was found that the number of receptors decreased on about the same time course as development of tolerance to wet-dog shakes and large motor movements. The third schedule consisted of the administration of MK-771 (5 micrograms/2 microliters, i.c.v.) once every 2 hr to a total of four doses. These animals eventually developed tolerance to the wet-dog shakes produced by the subsequent challenge with MK-771 and also showed a 50% decrease in receptor binding after the fourth exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of muscarinic blockade to antagonize analepsis induced by thyrotropin-releasing hormone and MK-771 in the rat

In the rat, the antimuscarinics atropine and scopolamine amine failed to block the reduction in pentobarbital-induced sleep time produced by either thyrotropin-releasing hormone (TRH) or MK-771 (a TRH analog). Previous reports have indicated that the marked analeptic effect produced by TRH is antagonized by such agents. It is not clear at this time whether the difference between our findings and these previous studies indicates a reduced sensitivity of cholinergic receptors in the rat to muscarinic blockade, a different neurochemical mechanism of action of TRH in the rat, or other unknown factors.     

MK-771-induced electromyographic (EMG) activity in the rat: comparison with thyrotropin releasing hormone (TRH) and antagonism by neurotensin.

Administered by either intravenous (i.v.) or intracisternal (i.cis.) injections, MK-771 and TRH induced a dose-related increase in EMG activity recorded from the flexor ulnaris muscle in pentobarbital-anesthetized rats. By the i.v. route, MK-771 was 6 times more potent than TRH and with i.cis. administration MK-771 was some 30 times more active than TRH. At equieffective doses of the two peptides, MK-771 exhibited a greater (approximately 3 fold) duration of action than TRH. In unanesthetized, spinally transected rats MK-771 was also more potent than TRH in eliciting EMG activity recorded from the biceps femoris muscle. Substance P, administered by the i.cis route failed to induce EMG activity. Intracisternally administered neurotensin, which did not affect EMG activity by itself, antagonized the actions of MK-771 while somatostatin was inactive in this regard. Neurotensin did not affect the EMG activity induced by physostigmine. While these studies do not delineate the mechanism whereby TRH and MK-771 induce EMG activity, it appears reasonable to suggest that TRH and related peptides, such as MK-771, may have some influence in functional disorders of human muscle.     

Head turning induced by unilateral intracaudate thyrotropin-releasing hormone (TRH) injection in the cat

Unilateral intracaudate injection of TRH in cats (10 microgram) induced head turning responses similar to the responses produced by dopamine (DA) (10 microgram). Contralateral head turning responses were observed after injections in the central part of the caudate body, whereas, injections placed more laterally induced ipsilateral responses. While haloperidol (3 mg/kg i.m.) suppressed the DA-induced response, it appeared to potentiate the effects of TRH. Cyproheptadine (10 mg/kg i.p.) did not alter the TRH-induced responses. These results suggest that, although TRH induces DA-like effects on postural symmetry, the mediation of TRH effects bypasses striatal dopaminergic and serotonergic receptors. While intracaudate TRH and DA induced head turning, they did not alter the level of head motility as measured by the number of head movements. Haloperidol, but not cyproheptadine pretreatment, decreased the level of head motility providing evidence that postural symmetry is modulated within the striatum, whereas head motility is regulated by extrastriatal dopaminergic mechanisms.     

Antagonism of the analeptic activity of thyrotropin-releasing hormone (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, TRH-induced 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.     

Lack of effect of chronically administered thyrotropin-releasing hormone (TRH) on regional rat brain tyrosine hydroxylase activity.

Chronic treatment of adult male rats with TRH (1 or 10 mg/kg IP) for 5 or 9 days failed to alter the activity of tyrosine hydroxylase (TH), the enzyme regulating the rate-limiting step in catecholamine biosynthesis. In contrast, as previously described, chronic reserpine administration (0.5 mg/kg IP: 9 days) resulted in a significant rise in TH activity in midbrain, hypothalamus, pons-medulla and forebrain. These results suggest that the enhanced brain norepinephrine turnover reported to occur after treatment with TRH is not due to synthesis of new TH enzyme protein.     

Absence of acute stimulant effects after intravenous thyrotropin-releasing hormone (TRH) in man: Comparison to d-amphetamine

Thyrotropin-releasing hormone (TRH) has been reported to have behavioural effects in man. The current study compared TRH to d-amphetamine and placebo in normal humans. While a number of d-Amp effects were noted, TRH was not significantly different from placebo.     

Effects of MK-771, a novel TRH analog,on brain dopaminergic and serotonergic systems

The effect of acute treatment with MK-771, a thyrotropin-releasing hormone analog, has been investigated on the synthesis and release of dopamine and 5-hydroxytryptamine in rat brain. Single injection of MK-771 in doses of 10 and 15 mg/kg produced a rise in tyrosine hydroxylase activity as well as homovanillic acid level in striatum (a site of nigrostriatal dopamine system) and olfactory tubercles (a site of mesolimbic dopamine system). The dopamine levels remained unchanged (olfactory tubercles, hippocampus) or decreased (striatum, hypothalamus, pons-medulla) after MK-771 treatment. Acute MK-771 injection at the dose of 15 mg/kg increased mid-brain tryptophan hydroxylase activity and tryptophan levels by 26% and 55%, respectively. A consistent increase in the levels of 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid was reported in several brain areas. These data suggest that MK-771 elicits a marked increase in the synthesis and turnover of brain dopamine and 5-hydroxytryptamine.     

Effects of thyrotropin-releasing hormone (TRH) on the isolated small intestine and taenia coli of the guinea pig

Thyrotropin-releasing hormone (TRH) produced a contraction in the isolated segment of duodenum and taenia coli of the guinea-pig (pA2, 8.0 and 8.9). TRH induced a contraction, a relaxation, or a contraction followed by relaxation in the jejunum and ileum. All the responses to TRH of the small intestine and the taenia coli were abolished in the presence of tetrodotoxin but not affected by hexamethonium. The contractile response to TRH of the small intestine was abolished and replaced by a relaxation in the presence of hyoscine. This relaxant response was not affected by guanethidine. The taenial response to TRH was partially inhibited by either hyoscine or methysergide and markedly diminished by the two together. These findings indicate that TRH acts on the myenteric neurons of the small intestine and taenia coli of the guinea pig. The contractile response of small intestine is likely to be induced through cholinergic nerves while cholinergic, serotonergic and unidentified excitatory neurons seem to be involved in the taenial response. These neurogenic actions of TRH on the guinea-pig intestine are in contrast with the myogenic natur of the response to TRH in the duodenum of the rat.     

Antagonism of isolation-induced aggression in mice by thyrotropin-releasing hormone (TRH)

TRH was shown to be an extremely potent (ED50 = 0.04 mg/kg, IP) antagonist of isolation-induced aggression in male mice. The antifighting activity of TRH was selective in that it did not produce concurrent neurological impairment or significant alterations in spontaneous locomotor activity at antiaggressive doses. This activity of TRH appeared to be a direct affect on CNS structures since neither triiodothyronine nor any of the constituent amino acids of TRH antagonized aggression in isolated mice. The results are discussed in terms of the recent clinical effectiveness of TRH in some cases of mental illness (e.g., depression and schizophrenia).     

A TRH analog (DN-1417): Motor stimulation with rearing related to catecholaminergic mechanisms in rats

The effect of an analog of TRH, γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2–20 $\text{mg}\text{kg}$, i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 $\text{mg}\text{kg}$, i.p.), haloperidol (0.1, 0.5 $\text{mg}\text{kg}$, i.p.), pimozide (1 $\text{mg}\text{kg}$, i.p.) or α-methyltyrosine (250 $\text{mg}\text{kg}$, i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 $\text{mg}\text{kg}$, i.p.) or FLA-63 (25 $\text{mg}\text{kg}$, i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 $\text{mg}\text{kg}$, i.p.) and methysergide (10 $\text{mg}\text{kg}$, i.p.) had no effect, atropine (10 $\text{mg}\text{kg}$, i.p.) and mecamylamine (10$\text{mg}\text{kg}$, i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 × 10^?5 M) significantly enhanced the spontaneous release of [³H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.     

Comparative effects of thyrotropin releasing hormone,MK-771 and DN-1417 on morphine abstinence syndrome

The effect of thyrotropin releasing hormone (TRH) were compared with two of its analogs, l-N-(2-oxopiperidin-6-yl-carbonyl)-l-histidyl-l-thiazolidine-4-carboxamide (MK-771) and -butyrolactone-4-carboxyl-histidylprolineamide (DN-1417) on the abrupt and naloxone-precipitated abstinence symptoms in morphine-dependent male Swiss-Wester mice. Mice were made physically dependent on morphine by subcutaneous implantation for 3 days of a pellet containing 75 mg morphine free base. Control mice were implanted with placebo pellets. Intracerebral administration of TRH (10 ng-10 g per mouse) immediately after removal of placebo pellets had no effect on the basal temperature of mice. Mice implanted with morphine pellets exhibited a characteristic hypothermic response following the removal of the pellets. TRH at all doses employed prevented the hypothermia observed during abrupt withdrawal of morphine (pellet removal). DN-1417 and MK-771 (10 ng-10 g per mouse) on the other hand produced a short lived hyperthermic response in mice from which placebo pellets had been removed. However, both TRH analogs produced long-lasting antagonism of withdrawal hypothermia in mice from which morphine pellets had been removed. TRH and its analogs had no effect on the body weight loss observed during abrupt withdrawal of morphine. Intracerebral administration of 10 g TRH and its analogs inhibited the naloxone-induced jumping response as evidenced by increases in naloxone ED₅₀ values to elicit this response. It is concluded that TRH and its analogs may be useful in combating some of the withdrawal symptoms in opiate-dependent subjects.     

Influence of thyrotropin releasing hormone (TRH) on drug-induced narcosis and hypothermia in rabbits

Thyrotropin releasing homone (TRH) administered via the intracerebroventricular (icv) route in doses ranging between 0.1 and 100 g decreased the duration of pentobarbital-induced narcosis in rabbits. Antagonism of narcosis occurred whether TRH was administered before or after the barbiturate. TRH doses above 10 g produced, in addition, behavioral excitation and hyperthermia. The antagonism of phenobarbital-induced narcosis was not as profound; animals were aroused only for a short period of time, after which the narcotized state returned. However, TRH exerted a prolonged antagonism or reversal of the phenobarbital-induced hypothermia. The central nervous system depression and analgesia produced by morphine were unaffected by TRH, but hypothermia and respiratory depression were reversed. TRH may represent an arousal factor in mammalian brain.     

促甲状腺激素释放激素对兔创伤性休克的影响

ＴＲＨ０．２２～２ｍｇ·ｋｇ－１ｉｖ使创伤性休克兔血压迅速回升，持续２０ｍｉｎ基本稳定不变。首次ｉｖＴＲＨ和以０．６７ｍｇ·ｋｇ－１·ｈ－１连续静脉输入使休克兔血压在５ｈ内维持在较高水平，同时提高５ｈ存活率。ＴＲＨ亦能对抗休克时的心率减慢及脉压缩小。但快速ｉｖＴＲＨ明显加速休克兔的死亡。     

促甲状腺激素释放激素对大鼠内毒素性休克的影响

研究了不同剂量TRH(促甲状腺激素释放激素)对大鼠大肠杆菌内毒素性休克的影响,并与纳洛酮进行比较.发现低(0.22mg·kg~(-1),iv)、中(0.67mg·kg~(-1),iv)、高(2mg·kg~(-1),iv)剂量的TRH均能迅速纠正内毒素性低血压,且明显提高大鼠24h存活率.2mg·kg~(-1)纳洛酮的升压效应与低剂量TRH相当,但前者在较低血压水平上提高大鼠存活率的作用更强,此点与TRH不同.     

Studies on the transport of thyrotropin-releasing hormone (TRH) analogues in Caco-2 cell monolayers

The transport mechanisms of thyrotropin-releasing hormone (TRH) and its pharmacologically active analogues ((3-methyl-His(2))TRH (MeTRH), taltirelin, montirelin, azetirelin) across Caco-2 cell monolayers were characterized. The results of kinetic analysis showed a linear relationship between the concentration (over the range 0.5-10 mM) and apical-to-basolateral transport rate of these agents. The permeability coefficients (P(app)) of these agents were not substantially different from each other, and their P(app) ratios of the basolateral-to-apical over the apical-to-basolateral transport were close to one (0.73-1.23). The cellular transport of [(3)H]MeTRH at low concentrations (3-15 nM) showed a linear relationship between the concentration and transport rate. The transport of [(3)H]MeTRH in Caco-2 cell monolayers was neither affected by TRH nor TRH analogues, and there was little difference in P(app) values between [(3)H]MeTRH and [(14)C]mannitol. The cell-per-medium ratio of [(3)H]MeTRH in the cellular uptake experiment was similar to the value of [14C]mannitol. A large excess of TRH and MeTRH did not significantly influence cell-per-medium ratios of [(3)H]MeTRH in Caco-2 cell monolayers. The k'(IAM) value, which represents lipophilicity, was decreased in the following order: montirelin > taltirelin > TRH > azetirelin, and the values varied from 0.234 to 1.028. These results indicate that a paracellular passive diffusion may be the major route for the transport of TRH and its analogues in Caco-2 cell monolayers.     

Inhibition of the binding and the behavioral effects of thyrotropin-releasing hormone (TRH) by the triazolobenzodiazepines

The abilities of 4 triazolobenzodiazepines, adinazolam, alprazolam, estazolam and triazolam, to inhibit thyrotropin-releasing hormone (TRH) receptor binding and to antagonize the narcoleptic effects of TRH were examined. The IC50 values for inhibition of 3H-3-methyl-His-2-TRH (MeTRH) binding ranged from 19 microM to 477 microM, and the Hill coefficient from 0.53 to 0.98. Similar ranges of values were obtained from benzodiazepines of other structural classes. Thus, the inhibition of TRH receptor binding by the triazolobenzodiazepines is similar to that produced by other types of benzodiazepines. Furthermore, the triazolobenzodiazepine, alprazolam, antagonized the narcoleptic effect of TRH. However, this action is not necessarily linked to its inhibition of TRH receptor binding since alprazolam also inhibited the narcoleptic effect of amphetamine.     

The effect of repeated treatment with antidepressant drugs on the thyrotropin-releasing hormone (TRH)-induced hyperthermia in mice

The effect of acute (single dose) or repeated (twice daily, for 14 days) administration of 10 mg kg-1 p.o. of imipramine, amitriptyline, citalopram or mianserin has been examined on the hyperthermia induced by thyrotropin-releasing hormone (TRH) (40 mg kg-1 i.p., 2, or 2 and 72 h after single or last dose of antidepressants, respectively) in mice. Both imipramine and amitriptyline, given repeatedly, potentiated the TRH response, though the effect was observed 2 but not 72 h after the last dose of those drugs. Potentiation was also found after the single dose of imipramine or amitriptyline. On the other hand, citalopram and mianserin, administered either acutely or repeatedly, did not affect the TRH-induced hyperthermia.     

Mesolimbic involvement in the locomotor stimulant action of thyrotropin-releasing hormone (TRH) in rats.

Thyrotropin-releasing hormone (TRH) injected i.p. in doses of 5 mg/kg and higher had a strong locomotor stimulant action with development of frequent rearing, mild sniffing, grooming, preening and other excitatory behaviours. The locomotor stimulation was also produced by bilateral injection of TRH and dopamine (DA) into the nucleus accumbens but not by bilateral injection of these substances into the caudate nucleus. Unilateral intracaudate injection of TRH provoked no behavioural changes in contrast to a distinct circling response to similarly injected DA. Either i.p. or bilateral intra-accumbens injection of haloperidol or pimozide on low doses effectively blocked the locomotor stimulant action of TRH. These results indicate that the DA system in the nucleus accumbens may be of importance in mediation of the locomotor stimulant action of TRH. Differential affinity of TRH to the two DA systems, the mesolimbic and nigrostriatal DA systems is also suggested.