The functions of thyrotropin-releasing hormone (TRH) in the central nervous system (CNS) can be conceptualized as performed by four anatomically distinct components that together comprise a general TRH homeostatic system. These components are 1) the hypothalamic-hypophysiotropic neuroendocrine system, 2) the brainstem/midbrain/spinal cord system, 3) the limbic/cortical system, and 4) the chronobiological system. We propose that the main neurobiological function of TRH is to promote homeostasis, accomplished through neuronal mechanisms resident in these four integrated systems. This hypothesis offers a unifying basis for understanding the myriad actions of TRH and TRH-related drugs already demonstrated in animals and humans. It is consistent with the traditional role of TRH as a regulator of metabolic homeostasis. An appreciation of the global function of TRH to modulate and normalize CNS activity, along with an appreciation of the inherent limitations of TRH itself as a therapeutic agent, leads to rational expectations of therapeutic benefit from metabolically stable TRH-mimetic drugs in a remarkably broad spectrum of clinical situations, both as monotherapy and as an adjunct to other therapeutic agents. The actions of TRH are numerous and varied. This has been viewed in the past as a conceptual and practical impediment to the development of TRH analogs. Herein, we alternatively propose that these manifold actions should be considered as a rational and positive impetus to the development of TRH-based drugs with the potential for unique and widespread applicability in human illness.Thyrotropin-releasing hormone (pGlu-His-Pro-NH 2 ) was the first hypothalamic releasing factor to be identified. Soon after this seminal event, however, it was clear that the biological functions of TRH extend far beyond regulation of the thyroid axis. Greater than two-thirds of immunoreactive TRH in the CNS is detected outside the thyrotropic zone of the hypothalamus (Winokur and Utiger, 1974). Consistent with this widespread distribution, TRH has been implicated in the regulation of arousal, autonomic function, control of circadian rhythmicity, endotoxic and hemorrhagic shock, mood, pain perception, seizure activity, and spinal motor function (Nillni and Sevarino, 1999). As this new information emerged, clinical trials have proceeded to test TRH as a treatment for various disorders including depression, schizophrenia, amyotrophic lateral sclerosis (ALS), and spinocerebellar degeneration (SCD;Griffiths, 1986). Possibly reflecting the consistent use of a metabolically stable TRH analog, trials in SCD have been generally positive. In other conditions, generally employing TRH, early trials showed promise although later trials produced inconsistent results. This variability may reflect the fact that native TRH is poorly suited as a therapeutic agent. It has low bioavailability, and its half-life in plasma is about 5 min.Herein, we first review data concerning the neurobiological mechanisms of TRH systems, and we suggest a new anat...
