Albert Sattin

Effects of subconvulsive and repeated electroconvulsive shock on thyrotropin-releasing hormone in rat brain

Male Sprague-Dawley rats were given a single electroconvulsive shock (ECS) on alternate days and sacrificed 48 hrs after 1, 3, or 5 seizures. The content of TRH in hippocampus, pyriform cortex and amygdala was increased 2.5-fold, 5.4-fold and 4.3-fold respectively, 48 hrs. after 3 alternate-day electroconvulsive shocks (ECS) and remained unchanged after 2 additional shocks. Pyriform cortex exhibited a significant intermediate increase (1.7-fold) after only 1 ECS. In a second study, rats were sacrificed 48 hrs after a series of 5 alternate-day ECS vs. subconvulsive shocks (SCS). SCS had no significant effect in these same regions, but was seen to alter TRH in striatum. These results provide an interesting parallel to several aspects of clinical electroconvulsive treatment (ECT) of depression. Together with other findings, these data suggest also, that endogenous TRH may play a role in the modulation of convulsive seizures.

Effect of electroconvulsive shock on the content of thyrotropin-releasing hormone in rat brain.

Five grand-mal seizures were electrically induced in rats on alternate days. Forty-eight hours following the last seizure, TRH was quantitated in extracts of anterior cortex, hippocampus, striatum, thalamus plus midbrain, and hypothalamus. When compared to sham treated controls, TRH was found to be elevated 5-fold in the hippocampus and 2-fold in the striatum with no changes observed in the remaining regions. Since the time chosen for analysis excludes acute post-ictal effects, these results draw attention to a prolonged alteration of TRH levels in specific brain regions in an animal model of electroconvulsive treatment.

Valproate modulates TRH receptor, TRH and TRH-like peptide levels in rat brain

We have tested our hypothesis that alterations in the levels of TRH receptors, and the synthesis and release of tripeptide TRH, and other neurotropic TRH-like peptides mediate some of the mood stabilizing effects of valproate (Valp). We have directly compared the effect of 1 week of feeding two major mood stabilizers, Valp and lithium chloride (LiCl) on TRH binding in limbic and extra-limbic regions of male WKY rats. Valp increased TRH receptor levels in nucleus accumbens and frontal cortex. Li increased TRH receptor binding in amygdala, posterior cortex and cerebellum. The acute, chronic and withdrawal effects of Valp on brain levels of TRH (pGlu-His-Pro-NH2, His-TRH) and five other TRH-like peptides, Glu-TRH, Val-TRH, Tyr-TRH, Leu-TRH and Phe-TRH were measured by combined HPLC and RIA. Acute treatment increased TRH and TRH-like peptide levels within most brain regions, most strikingly in pyriform cortex. The fold increases (in parentheses) were: Val-TRH (58), Phe-TRH (54), Tyr-TRH (25), TRH (9), Glu-TRH (4) and Leu-TRH (3). We conclude that the mood stabilizing effects of Valp may be due, at least in part, to its ability to alter TRH and TRH-like peptide, and TRH receptor levels in the limbic system and other brain regions implicated in mood regulation and behavior.

Biochemical and electropharmaceutical studies with tricyclic antidepressants in rat and guinea-pig cerebral cortex.

Abstract Chopped guinea pig cerebral cortex was incubated with a series of antidepressant drugs which produced increases in the cyclic AMP content of the tissue. These effects were partially or wholly blocked by theophylline, suggesting that they were mediated by endogenous production, release and action of adenosine. A similar series of drugs was iontophoretically ejected on rat cerebral cortical neurons where augmentation of concurrently ejected adenosine was observed as slowing of the rate of cell firing. Pharmacological correlations between the two sets of data suggest a common mechanism of action.

Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs.

Lipopolysaccharide (LPS) is a proinflammatory and depressogenic agent whereas thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH2) is an endogenous antidepressant and neuroprotective peptide. LPS and TRH also have opposing effects on K+ channel conductivity. We hypothesized that LPS can modulate the expression and release of not only TRH but also TRH-like peptides with the general structure pGlu-X-Pro-NH2, where “X” can be any amino acid residue. The response might be “homeostatic,” that is, LPS might increase TRH and TRH-like peptide release, thereby moderating the cell damaging effects of this bacterial cell wall constituent. On the other hand, LPS might impair the synthesis and release of these neuropeptides, thus facilitating the induction of early response genes, cytokines, and other downstream biochemical changes that contribute to the “sickness syndrome.”Sprague-Dawley rats (300 g) received a single intraperitoneal injection of 100 µg/kg LPS. Animals were then decapitated 0, 2, 4, 8, and 24 h later. Serum cytokines and corticosterone peaked 2 h after intraperitoneal LPS along with a transient decrease in serum T3. TRH and TRH-like peptides were measured by a combination of high-performance liquid chromatography and radioimmunoassay. TRH declined in the nucleus accumbens and amygdala in a manner consistent with LPS-accelerated release and degradation. Various TRH-like peptide levels increased at 2 h in the anterior cingulate, hippocampus, striatum, entorhinal cortex, posterior cingulate, and cerebellum, indicating decreased release and clearance of these peptides. These brain regions are part of aneuroimmunomodulatory system that coordinates the behavioral, endocrine, and immune responses to the stresses of sickness, injury, and danger. A sustained rise in TRH levels in pancreatic β-cells accompanied LPS-impaired insulin secretion. TRH and Leu-TRH in prostate and TRH in epididymis remained elevated 2-24h after intraperitoneal LPS. We conclude that these endogenous neuroprotective and antidep resant-like peptides both mediate and moderate some of the behavioral and toxic effects of LPS.

Rapid modulation of TRH-like peptides in rat brain by thyroid hormones.

Recent identification of membrane receptors for T4, T3, 3,5-T2, and 3-iodothyronamine that mediate rapid physiologic effects of thyroid hormones suggested that such receptors may supplement the regulation of TRH and TRH-like peptides by nuclear T3 receptors. For this reason 200 g male Sprague-Dawley rats received daily i.p. injections of PTU or T4. Levels of TRH and TRH-like peptides were measured 0, 2 h or 1, 2, 3, or 4 days later. Rapid increases or decreases in TRH and TRH-like peptide levels were observed in response to PTU and T4 treatments in various brain regions involved in mood regulation. Significant effects were measured within 2 h of T4 injection. Nuclear T3 receptor-mediated changes in gene expression altering translation, post-translational processing and constitutive release of peptides require more than 2 h. We conclude that non-genomic mechanisms may contribute to the psychiatric effects of thyroid disease and thyroid hormone adjuvant treatment for major depression.

Escitalopram Regulates Expression of TRH and TRH-Like Peptides in Rat Brain and Peripheral Tissues

Background: Escitalopram (eCIT) is a highly selective serotonin reuptake inhibitor (SSRI) that can be an effective treatment for a number of neuropsychiatric disorders including major depression. We, and others, have previously reported that thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2) and TRH-like peptides with the general structure pGlu-X-Pro-NH2, where ‘X’ can be any amino acid residue, have neuroprotective, antidepressant, analeptic, arousal, and anti-epileptic effects that could mediate the neuropsychiatric and therapeutic effects of a variety of neurotropic agents. The present work explores the possible mediation of the therapeutic effects of eCIT by TRH and TRH-like peptides. Methods: In order to extend our understanding of the range of neurotransmitter systems that are modulated by and, in turn, influence the expression of TRH and TRH-like peptides, 16 male Sprague-Dawley rats were injected i.p. with eCIT (24 mg/kg BW) and the brain levels of TRH and TRH-like peptides in various brain regions involved in mood regulation and peripheral tissues with serotonergic innervation were measured 0, 2, 4, and 6 h later by combined HPLC and RIA. Results and Conclusion: Remarkable 3- to 25-fold increases in TRH and TRH-like peptide levels were observed 2 h after i.p. eCIT in the epididymis. This reproductive tissue has the highest level of serotonin found in most mammals. The acute (2 h) effect of eCIT in brain regions involved in mood regulation, particularly the nucleus accumbens and medulla oblongata, cerebellum, and striatum was to increase the levels of TRH-like peptides, most consistently Phe-TRH. An important exception was a decrease in the level of TRH in the nucleus accumbens. These responses, in general, were the opposite of those we have previously observed after acute restraint stress in this same rat strain. We conclude that some of the therapeutic effects of inhibition of serotonin reuptake are mediated by altered release of TRH and TRH-like peptides.

TRH and TRH-like peptide expression in rat following episodic or continuous corticosterone

Sustained abnormalities of glucocorticoid levels have been associated with neuropsychiatric illnesses such as major depression, posttraumatic stress disorder (PTSD), panic disorder, and obsessive compulsive disorder. The pathophysiological effects of glucocorticoids may depend not only on the amount of glucocorticoid exposure but also on its temporal pattern, since it is well established that hormone receptors are down-regulated by continuously elevated cognate hormones. We have previously reported that TRH (pGlu-His-Pro-NH2) and TRH-like peptides (pGlu-X-Pro-NH2) have endogenous antidepressant-like properties and mediate or modulate the acute effects of a single i.p. injection of high dose corticosterone (CORT) in rats. For these reasons, two accepted methods for inducing chronic hyperglucocorticoidemia have been compared for their effects on brain and peripheral tissue levels of TRH and TRH-like peptides in male, 250 g, Sprague-Dawley rats: (1) the dosing effect of CORT hemisuccinate in drinking water, and (2) s.c. slow-release pellets. Overall, there were 93% more significant changes in TRH and TRH-like peptide levels in brain and 111% more in peripheral tissues of those rats ingesting various doses of CORT in drinking water compared to those with 1-3 s.c. pellets. We conclude that providing rats with CORT in drinking water is a convenient model for the pathophysiological effects of hyperglucocorticoidemia in rodents.

Some regional anatomical relationships of TRH to 5-HT in rat limbic forebrain.

It is now a recognized principle that various neuropeptides are neuronally co-localized with biogenic amine or aminoacid neurotransmitters. In the rat CNS it has previously been shown that TRH is co-localized with 5-HT (and also with substance P) in cell bodies of the posterior raphe that project to the spinal cord. Although TRH cell bodies are known to be widely distributed throughout the forebrain there is no other known co-localization with 5-HT. In this study we further specify the anatomical relationship of TRH with 5-HT by use of surgical and neurotoxic lesioning with reference to limbic forebrain regions wherein TRH is greatly increased following seizures. In groups of rats, the fimbria-fornix was lesioned alone, or combined with a lesion of the dorsal perforant path or the ventral perforant path. There was a sham lesioned control group. Additional groups were lesioned with 5, 7 dihydroxytryptamine, 100 μg i.v.t., 45 min. after i.p. desipramine, 25 mg/kg. All rats were sacrificed three weeks after lesions. Indoleamines were determined by HPLC in left anterior cortex, left pyriform/olfactory cortex, left dorsal hippocampus and left ventral hippocampus. TRH was determined by specific RIA in the corresponding right brain regions. The modal n was 7 rats. The surgical lesions reduced 5-HT to below the detection limit in dorsal hippocampus in all three groups, and to 31–52% of control in all the ventral hippocampus groups. 5-HIAA was reduced to 19–37% of control in dorsal and to 30–51% of control in ventral hippocampus. TRH was reduced to 44–61% of control in dorsal hippocampus and to 48–53% of control in ventral hippocampus. As was repeatedly observed in our previous reports all TRH levels in ventral hippocampus were higher than in dorsal hippocampus. The 5, 7 dihydroxytryptamine treatment nearly eliminated the indoleamines from all the forebrain regions examined while TRH levels were unchanged. These results can be explained by our previous data showing that immunoreactive TRH is intrinsic and localized to the vicinity of both CA and dentate granule cells of the hippocampus, but about half of hippocampal TRH enters via fibers of the fimbria-fornix. The perforant path appears to contribute no TRH to hippocampus, but, results with the combined lesion groups showed some reduction of 5-HIAA in ventral hippocampus as is expected from the known perforant path contribution of 5-HT. Since the neurotoxic lesion had no effect on TRH, the 5-HT pathway through the fimbria-fornix is probably anatomically separate from a parallel TRH pathway there. This study shows that co-localization of TRH with 5-HT is very unlikely in four specific limbic forebrain regions.

A Possible Role for Thyrotropin Releasing Hormone (TRH) in Antidepressant Treatment

TRH is a tripeptide which was discovered in the context of hypothalamic-thyroid function but which is now known to be widely distributed throughout the CNS (Jackson, 1982). The majority of TRH in the CNS is extrahypothalamic and its regional concentrations are highly variant (Kubek et al., 1977).