TRH attenuates scopolamine-induced memory impairment in humans

Molchan, Susan E.; Mellow, Alan M.; Lawlor, Brian A.; Weingartner, Herbert; Cohen, Robert M.; Cohen, Martin R.; Sunderland, Trey

doi:10.1007/bf02245795

Cited by 74 publications

(36 citation statements)

References 29 publications

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“…c Comparison of the DTMS task accuracies achieved after 20 μg/kg scopolamine (Scop), with accuracies obtained after 50 μg/kg donepezil followed by scopolamine and with accuracies obtained after 100 μg/kg donepezil followed by scopolamine. Asterisk, significantly different from respective mean values in the vehicle (0 μg/kg) group, P<0.05. d The effect of donepezil in scopolamine-treated monkeys on shortdelay trial accuracies plotted as a function of donepezil dose 10 μg/kg dose range used in healthy human volunteers (Preston et al 1988;Molchan et al 1990;Ray et al 1992;Lines et al 1993;Snyder et al 2005). Scopolamine-induced impairment in task acquisition in the spatial memory task and in the proximate stages of memory formation, i.e., attention and vigilance, in the operant-conditioning tasks is also in keeping with similar effects reported in human subjects (Wesnes and Warburton 1984;Dunne and Hartley 1985;Preston et al 1989;Sunderland et al 1989;Duka et al 1996).…”

Section: Discussionsupporting

confidence: 75%

“…The scopolamine-reversal model also has been applied to clinical studies in young (Molchan et al 1990;Lines et al 1993;Reidel et al 1995) or healthy-aged subjects (Snyder et al 2005). The importance of being able to evaluate new cognition-enhancing compounds in nonimpaired human populations is derived from the difficulty in obtaining participants with AD who are not already taking regimens of cholinesterase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

et al. 2007

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Rationale The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. Objectives The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Materials and methods Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). Results The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 μg/kg in the DMTS task. Conclusions The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

et al. 2007

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“…A similar facilitation has also been seen in patients with Alzheimer's disease following TRH treatment (Mellow et al 1989(Mellow et al ,1993Molchan et al 1992) and in volunteer subjects treated with scopolamine (Molchan et al 1990(Molchan et al ,1992. However, the effectiveness of systemic neuropeptidergic treat-…”

supporting

confidence: 52%

Further Evidence for a Dissociation Between Different Forms of Mnemonic Expressions in a Mouse Model of Age-related Cognitive Decline: Effects of Tacrine and S 17092, a Novel Prolyl Endopeptidase Inhibitor

Marighetto¹,

Touzani²,

Etchamendy³

et al. 2000

Learn. Mem.

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It has been demonstrated previously on the radial maze that the emergence of an age-related mnemonic impairment is critically dependent on the form which the discrimination problems took. Hence, when the arms were presented one by one (i.e., successive go-no-go discrimination), both adult and aged mice learned to distinguish between positive (baited) and negative (unbaited) arms readily, as evidenced by their increased readiness to enter positive relative to negative arms (i.e., by a differential in arm-entry latencies). A selective impairment in the aged mice was seen when these arms were presented subsequently as pairs, such that the mice were confronted with an explicit choice (i.e., simultaneous 2-choice discrimination). When discriminative performance was measured by the differential run speed between positive and negative arms, aged mice were also impaired. This was particularly pronounced in the 2-choice discrimination condition. We examined the effects of tacrine (3mg/kg, subcutaneously) or S 17092 (10mg/kg, orally) in aged mice on the three behavioral indices of this 2-stage spatial discrimination paradigm. The results indicated that: (1) Tacrine, but not S 17092, enhanced the acquisition of go-no-go discrimination as reflected in arm-entry latencies; (2) both drugs improved choice accuracy in simultaneous discrimination, although the effect of tacrine was less striking and, in particular, far from statistical significance in the very first 2-choice responses; and (3) neither drugs significantly affected run-speed performance. We conclude further that the specific patterns of drug effects on the three indices of discriminative performance might suggest that each index is associated with a distinct form of mnemonic expression relying on separate neural systems.In humans, declarative/explicit memory appears to be more vulnerable to deterioration in senescence than procedural/ implicit memory (Poon 1985;Gabrieli 1996;Schugens et al. 1997). One cardinal characteristic of declarative memory is its flexibility as exemplified by its capacity to support inferential use of memories in novel situations (Cohen 1984). Using a two-stage paradigm of discrimination learning, Marighetto et al. (1999) have previously demonstrated that aged mice displayed impaired inferential abilities when they were required to make an explicit choice between two eventualities that were only encountered before separately, but never conjointly. In Stage 1, the mice learned to discriminate between the valence of three baited (positive) and three unbaited (negative) arms in a radial maze with each of the arms presented one at a time, i.e., successive go-no-go discrimination. Successful discrimination was indicated by the animals' increased readiness to enter positive arms relative to negative ones. In Stage 2, the animals were confronted with an explicit choice between one positive arm and one negative arm they had learned to discriminate previously. Aged mice, but not young ones, were unable to translate their preference for the positive ...

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“…Accordingly, they used high doses of i.v. TRH (0.5 mg/kg) in their studies of normal volunteers, with transient cognitive impairment produced by administration of anticholinergic agents and of patients with Alzheimer's disease (Mellow et al, 1989;Molchan et al, 1990). Modest improvements in some indices of cognitive function were observed in both groups.…”

Section: Therapeutic Implications Of Trh-mediated Homeostasismentioning

confidence: 99%

The Thyrotropin-Releasing Hormone (TRH) Hypothesis of Homeostatic Regulation: Implications for TRH-Based Therapeutics

Gary¹,

Sevarino²,

Yarbrough³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

102

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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...

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TRH attenuates scopolamine-induced memory impairment in humans

Cited by 74 publications

References 29 publications

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

Further Evidence for a Dissociation Between Different Forms of Mnemonic Expressions in a Mouse Model of Age-related Cognitive Decline: Effects of Tacrine and S 17092, a Novel Prolyl Endopeptidase Inhibitor

The Thyrotropin-Releasing Hormone (TRH) Hypothesis of Homeostatic Regulation: Implications for TRH-Based Therapeutics

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