The effect of TRH on 5-HT1 receptors in the rat brain was investigated. A crude membrane preparation was incubated at 37 degrees C for 15 min with or without TRH prior to [3H]5-HT binding assay. TRH at 100 nM increased the number of 5-HT1 receptors significantly (approximately 20%) in the limbic forebrain and the hippocampus without altering their affinity. As this concentration of TRH is close to its dissociation constant (2 nM and 51 nM in the limbic forebrain, 11 nM in the hippocampus), this effect is probably of physiological relevance. This finding seems to support a pharmacological finding of others that the anti-convulsion effect of TRH may be related to increased serotonergic transmission.

Amygdala↗

PubMedDate not supplied

Modulation of dopamine receptors by thyrotropin-releasing hormone in the rat brain.

Nanomolar concentration of thyrotropin-releasing hormone (TRH) in vitro caused a significant reduction of [3H]apomorphine binding sites (70% of the control) in the rat striatum and the limbic forebrain. [3H]Spiperone binding was not affected by TRH. On the other hand, dopamine and apomorphine displaced [3H]TRH binding partially, suggesting the presence of a TRH receptor subpopulation that has a high affinity for dopamine agonist. Most of the neuroleptics displaced [3H]TRH binding dose-dependently in the micromolar range. (-)-Sulpiride had no affinity to TRH receptors. These findings suggest that one of the important roles of TRH as a neuromodulator is to modulate receptors for classical neurotransmitters, and this receptor-receptor interaction may be of importance in explaining the well known stimulating effects of TRH on the dopaminergic system.

Animals↗

PubMedDate not supplied

Effect of TRH analog (DN-1417) on tyrosine hydroxylase activity in mesocortical, mesolimbic and nigrostriatal dopaminergic neurons of rat brain.

Tyrosine hydroxylase (TH) was assayed in eight regions of rat brain following repeated treatment with a TRH analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-histidyl-prolinamide). Repeated DN-1417 treatment (20 mg/kg/day, IP) for 7 days increased TH activity in the ventral tegmental area and decreased in the prefrontal cortex polar, medial and lateral fields and olfactory tubercles. No significant change in TH activity was found in the nucleus accumbens, striatum and substantia nigra. Kinetic analysis showed that the increased TH activity in the ventral tegmental area was due to an increase in Vmax, but not a change in the apparent Km of TH for a cofactor, 6-methyl-tetrahydropteridine. When TH was assayed at a suboptimal pH and in the presence of a subsaturating cofactor, the striatal TH was activated significantly after DN-1417. In the prefrontal cortex medial field, nucleus accumbens and olfactory tubercles, TH activity assayed under the suboptimal condition was not modified by DN-1417 treatment. These results suggest an intimate involvement of central dopaminergic systems in the actions of DN-1417.

Animals↗

PubMedDate not supplied

Clinical study of oral administration of DN-1417, a TRH analog, in patients with intractable epilepsy.

An open dose-finding trial of orally administered DN-1417 was undertaken to investigate dose, efficacy, and adverse reactions. One hundred ninety patients, with epilepsy resistant to conventional drug treatment, were randomly allocated to two treatment groups of low dose (20 mg/day for adult) and high dose (80 mg/day for adult). Medication was given while fasting, once a day, for 8 weeks. If at the end of the first 4-week treatment period the patient had a satisfactory response, the dose was doubled. Patient response was assessed by global improvement rating (GIR) based on changes in seizure frequency, EEG findings, and nonparoxysmal clinical manifestations. The responses assessed by GIR was "slightly to markedly improved" in 48% of the patients with low-dose treatment and 55% with high-dose treatment. There was no clear dose-related difference between the two treatments. In patients with Lennox-Gastaut syndrome having no history of West syndrome, the rate of response assessed by GIR was found to be slightly dose-related (low dose, 61%; high dose, 73%).

Administration, Oral↗