Thyrotropin releasing hormone and CNS cholinergic neurons

Thyrotropin releasing hormone and CNS cholinergic neurons

Life Sciences, Vol. 33, pp. 111-118 Printed in the U.S.A. Pergamon Pres MINIREVIEW THYROTROPIN RELEASING HORMONE George AND CNS CHOLINERGIC N...

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Life

Sciences, Vol. 33, pp. 111-118 Printed in the U.S.A.

Pergamon Pres

MINIREVIEW THYROTROPIN

RELEASING

HORMONE

George

AND

CNS CHOLINERGIC

NEURONS

G. Yarbrough

Merck Institute for Therapeutic Research Merck Sharp & Dohme Research Laboratories West Point, PA 19486

Summary The centrally mediated pharmacological effects of thyrotropin releasing hormone (TRH), their mechanistic basis and therapeutic implications, along with the possible physiological significance of extrahypothalamic TRH, have been the subject of numerous investigations for over a decade. Despite this effort a holistic perspective on these issues and considerations does not exist. However, with continued research employing multiple and diverse experimental approaches, many interactions of TRH and related peptides with central cholinergic mechanisms have been revealed. These interactions are documented in this review and it is proposed that they can account for several of the more prominent pharmacological actions of these peptides. Additionally, it is suggested that a function of endogenous TRH, throughout the neuroaxis, may be to regulate the excitability of central cholinergic neurons. In addition to its established role in endocrine function as a hypophysiotrophic factor, thyrotropin releasing hormone (TRH; pyroglutamylhistidyl-proline amide) has been widely studied in relation to its effects on behavior, autonomic function, neuronal excitability and neurochemical parameters (see 1 for a review). In recognition of the unique pharmacological profile of this small neuronal peptide, several synthetic analogs, apparently possessing increased metabolic stability have been made and to varying degrees pharmacologically evaluated in anticipation of determining their therapeutic The justification for most of this effort can be traced to potential (2). the original (but now controversial) observations of Prange and his colleagues that TRH was efficacious in the treatment of depression (3) and the demonstration that TRH enhanced the stimulant properties of L-DOPA in mice (4). Concomitantly, a good deal of experimental work has addressed the issue of the extrahypothalmic TRH which is possible functional significance of endogenous, ubiquitously distributed in the CNS of both mammalian and non-mammalian To date, neither the basis for the unique and multiple actions of species. exogenously administered TRH or related peptides, nor the physiological role of TRH in the CNS have been posited in a universally accepted manner. However, based upon a substantial body of literature demonstrating unusual and widespread interactions of TRH with cholinergic neurons throughout the neuroproposed that some of the pharmacological actions of axis, it is presently TRH can be accounted for through interactions with central cholinergic mechanisms. Furthermore, a physiological function of endogenous TRH may be to participate in the regulation of the excitability of CNS cholinergic neurons.

0024-3205183 $3.00 + .OO Copyright (c) 1983 Pergamon Press Ltd.

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Actions

TRH and Cholinergic Neurons

on Cholinergic Soinal

Neurons

Vol. 33, No. 2, 1983

and Pathways

Motoneurons

One of the clearest examples to date of an action of TRH on cholinergic neurons was provided by Nicoll (5,6) who demonstrated a depolarizing effect of the peptide on amphibian spinal motoneurons. This action appeared largely direct in that it was only slightly reduced when synaptic transmission was blocked in the presence of tetrodotoxin (although see ref. 7) and since the depolarizations produced by the peptide rarely exceeded the neuronal firing threshold, it was suggested that TRH might exert a background facilitatory action on the excitability of these neurons. Other laboratories employing TRH (7), or structurally and pharmacologically related analogs such as MK-771 (aminoadipate-histidyl-thiazolidine amide; 8) and DN-1417 (butyrolactonecarbonyl-histidyl-proline amide; 9) have confirmed the pronounced excitatory actions of these peptides on both amphibian and mammalian spinal cord motoIt may be of some relevance that neither Yarbrough and Singh (8) neurons. nor Ono and Fukuda (9) observed any significant actions of TRH on the excitability of spinal dorsal roots. In this regard, TRH concentrations (lo), TRHlike immunoreactive fibers (11) and 3H-TRH binding sites (12) appear to be concentrated in the ventral portion of the spinal cord. It appears likely that this excitatory action on motoneurons underlies the pronounced in vivo tremorigenic effects of these peptides. Thus, TRH and MK-771 have been observed to induce a dose-related tremor in rats (13) and mice (1) and to elicit a marked, centrally-mediated activation of electromyographic (EMG) activity in cats (14) and rats (15). Moreover, these peptides have been shown to evoke flexor reflex activity in rats with acute spinal transections (16,17). Although direct information is lacking, it appears likely that the well-known respiratory stimulant effects of TRH (18) are mediated finally through an excitatory effect of the peptide on the motoneuron pool of the phrenic nerve. Altogether, the anatomical association of TRH with spinal motoneurons, the pronounced effects of TRH and related peptides on the excitability of these classical cholinergic neurons and their marked stimulatory effects on EMG and reflex activity suggest that the spinal cord is an important locus when considering the pharmacological actions and physiological functions of TRH. Septal-Hippocampal

Pathway

One of the most thoroughly studied and characterized cholinergic projections in the CNS emanates from the septum to the hippocampal formation. In an extensive series of microinjection experiments, Kalivas and Horita (19) found that the most sensitive (in terms of minimal effective dose) site for antagonizing pentobarbital narcosis in the rat was the septum. In view of the known TRH-induced biochemical changes in acetylcholine (ACh) metabolism in the hippocampus and the susceptibility of TRH analepsis to antagonism by muscarinic antagonists (see below) these investigators postulated that the analeptic actions of TRH could, in part (cf. ref. ZO), be accounted for by activation of this septo-hippocampal cholinergic pathway. Further support to suggest that this might be an important anatomical substrate for the marked analeptic actions of these peptides is derived from experiments recording hippocampal electroencephalograms (EEG) and multi-unit activity. Thus, McNaughton et al (21) found that TRH reversed the effects of amylobarbitone on septal-stimulated theta activity in the hippocampus and Kalivas et al (22) observed that the peptide produced hippocampal EEG synchrony in pentobarbital pretreated rats. These and previous findings demonstrating that TRH increased hippocampal neuronal inter-spike intervals (23) which may provide the basis for EEG synchrony clearly suggest an excitatory interaction of TRH with this

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Additional considerations which may be relevant to this cholinergic pathway. conclusion are the demonstrations of a high concentration of TRH-like immunoreactivity (24) and 3H-TRH binding sites (25) in the septal region. However, iontophoretically applied TRH failed to affect the firing of septal neurons (26) which might suggest that the apparent activation by TRH of the septalhippocampal cholinergic pathway is indirectly or transsynaptically mediated. Reticular

Activatina

and Cerebral

Cortical

Cholineraic

Interactions

The intimate association of the so-called "diffuse reticular activating system" with cholinergic mechanisms is well-known (cf. ref. 27). It is probable that the final mediator at the level of the cerebral cortex which underlies the behavioral and EEG arousal subsequent to reticular formation activaWith regard to TRH effects on brain stem reticular tion is, in fact, ACh. neuronal activity, Koranyi et al (23) observed that low doses of the peptide (30,ug/kg i.p.) resulted in a prompt reduction in neuronal inter-spike intervals while Briggs (23) reported that microiontophoretically applied TRH elicited a slow onset but prolonged excitation (similar to its effects on spinal neurons) of over 70% of the reticular neurons tested. Thus, it appears at least conceivable that some of the arousal and stimulatory effects of the peptide are secondary to an activation or a permissive facilitation of ascending and descending reticular mechanisms. In addition, it is likely that these responses are ultimately expressed through the release of ACh. This notion would be consistent with the observed effects of TRH on cortical ACh release (see below) as well as the atropine-sensitive actions of the peptide to activate the cortical EEG (29) and induce analepsis (30,31,32). With regard to the available data on the interactions of TRH or MK-771 with cholinergic excitations of cerebral cortical neurons, a consensus clearly does not exist. Several reports have now appeared documenting the presence (33,34,35) or absence (26,36,37) of a facilitory effect of microiontophoretically applied (or in one case, intravenously administered; 35) TRH on AChinduced excitations of cerebral cortical neurons. Similarly, discrepancies exist even in reports from the same laboratory as to the direct effects of TRH itself on cortical neuronal excitability (37,38). Suffice it to say, that further speculation on the possible sources of these apparent discrepancies, in the absence of new data, is not likely to prove edifying. Unfortunately, it would appear that at least in the cerebral cortex, where cholinergic projections and interneurons are known to have important functions, the effects of microiontophoretically applied TRH are not sufficiently robust as to be easily reproducible. Nonetheless, on the more positive side, a facilitatory action of TRH to enhance the effects of ACh on cortical neurons at presumed muscarinic cholinergic receptors has been observed and the compatibility of this interaction with both the suspected cholinergic desensitizing effects of anesthetic agents and the antianesthetic actions of TRH and related peptides has been discussed (1). Parasympathetic

Innervation

of Various

Organs

Vagal innervation of the thyroid gland: The activity of the thyroid of vagal cholinergic nerves (39). Tonoue is, in part, under the influence and Nomoto (40) demonstrated that intracerebroventricular (i.c.v.) administration of TRH increased the microcirculation within the thyroid gland, an effect which was abolished by vagotomy. Pursuant to these observations, Tonoue (41) demonstrated, by direct monitoring of the activity of the superior laryngeal nerve, that i.c.v. TRH in urethane anesthetized rats caused a doserelated increase in vagal outflow to the thyroid. These studies suggest an alternate and novel pathway for the regulation of thyroid function by TRH. Of even more interest is the recent report from the same author (42) that

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2,

1985

of rabbit antiserum to TRH reduced the basal spontanei.c.v. administration ous activity of the superior laryngeal nerve which allows for the speculation that the tonic activity of vagal afferents to the thyroid gland (and elseIn relation to this where; see below) may be regulated by endogenous TRH. a modest density of TRH-like immunoreactive fibers has been hypothesis, observed around the caudal parts of the vagal nuclei in rats (43). Parasympathetic innervation of the pupil: As assessed by both indirect and direct means, TRH and MK-7/l have been shown to activate the efferent cholinergic projection from the Edinger-Westfall nucleus to the pupil of the Thus, it has been demonstrated that these peptides (a) eye in cats (44,45). antagonize clonidine-induced pupillary dilatation in both normal and phenoxy(b) antagonize the pupillary dilatation benzamine pretreated preparations, but not the contracture of the nictitating membrane caused by stimulation of of ciliary nerve activthe superior cervical nerve, (c) in direct recordings ity reverse the depressant effects of clonidlne and (d) stimulate ciliary nerve activity in normal cats and in cats with transections of the sympathetic These obsernerves to the eye, spinal cord or spinal cord plus optic tracts. vations clearly indicate that these peptides exert a facilitatory effect on the cranial occulomotor nucleus to increase parasympathetic outflow to the iris. Vagal innervation of the gastrointestinal tract: The actions of TRH on the sastrointestinal tract have been extensively studied and it appears that in a manner quite analogous to that previously discussed for the the peptide, thyroid and eye, elicits centrally-mediated, vagal-dependent stimulations of Reports from Horita's laboratory (46,47) have clearly shown gut motility. that in rabbits, i.c.v. (but not peripheral) administration of TRH caused a stimulation of colonic muscular activity. This stimulatory effect was abolished or reduced by atropine (given either directly into the brain or More intravenously), ganglionic blocking agents or bilateral vagotomy. recently, a serotonergic component in the TRH vagally mediated stimulation of colonic transit and diarrhea has been invoked (48). In rats, the i.c.v. administration of TRH caused a marked increase in the electroenteromyographic activity of the proximal duodenum which was blocked by atropine or vagotomy (49). While TRH may also exert peripheral neurogenic and myogenic effects on intestinal muscle (cf. 50,51), these findings suggest that the peptide has a central facilitatory effect on vagal efferent nerves which regulate the conSimilarly, intracisternal tractility of portions of the intestinal tract. administration of TRH to rats has recently been shown to elicit an atropinesensitive increase in secretion of gastric acid (52). However, in dogs, the effects of TRH on basal gastric secretion appear predominantly inhibitory in nature (53,54,55) while in cats TRH reduced insulin-evoked elevations in gastric acid without affecting basal gastric acid secretion (56). Since the expression of insulin-induced elevations of gastric acid is mediated centrally through the vagus, these data may suggest that TRH exerts an inhibitory influence on brain centers which regulate the activity of vagal nerves. Actions

on Biochemical

Parameters

of Cholinergic

Neuronal

Activity

The high affinity, Nat-dependent synaptosomal uptake of choline is thought to be an index of in vivo cholinergic neuronal activity (57). While not affecting regional bra= levels of ACh or choline uptake in normal rats, intraperitoneally administered TRH was found to antagonize barbiturate-induced decreases in high affinity choline uptake in the cerebral cortex, hippocampus and midbrain (58,59). Similarly, MK-771, administered i.c.v., antagonized barbiturate-induced decreases in choline uptake in the same brain areas (60). The direct inference from these data is that these peptides can antagonize barbiturate-induced decreases in cholinergic neuronal activity. Confirmatory

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to this conclusion is the recent demonstration that intraseptal infusion of TRH reversed pentobarbital-induced decreases in ACh turnover in the hippoAdditionally, Malthe-Sorenssen et al (62) have shown that TRH campus (61). stimulated the turnover rate of ACh in the parietal cortex of unanesthetized It has also been reported that MK-771 enhanced the incorporation of rats. 3H-choline into 3H-ACh in the whole brains of pentobarbital-treated mice The most direct demonstration to date of an effect of TRH and MK-771 (59). on ACh biochemical dynamics resides in the demonstration of a marked, apparstimulation of the release of ACh from the cerebral cortiently dose-related, cal surface of anesthetized rabbits following i.v. administration of the In vitro, TRH does not influence acetylcholinesterase (G. B. peptides (63). Koelle, personal communication) or the uptake or K+-evoked release of choline Thus, the presently available biochemical data from brain synaptosomes (37). indicate that these peptides can stimulate the activity of central cholinergic neurons in vivo through a mechanism which is more readily apparent when neuronal actlvlty has been depressed (as for example, by barbiturate drugs). Behavioral

Findings

and Other

Relevant

Considerations

The analeptic (i.e., antagonism of the depressant or sedating effects of drugs) action of TRH and related analogs is the most remarkable pharmacological property of this class of compounds and it was the initial observations of Breese and coworkers (30), studying this phenomenon, that led to the original suggestion of an interaction of TRH with central cholinergic mechanisms. These investigators observed that intracisternally administered atropine antagonized the ability of TRH to reduce pentobarbital sleeping time in mice. Similar findings that muscarinic antagonists could prevent or reduce the barbiturate sleep shortening action of TRH or DN-1417 have been documented in rabbits (31) and rats (32,64). In addition, in the elegant study by Nagai et al (32) it was observed that TRH partially reversed pentobarbital-induced decreases in cerebral glucose utilization and that this effect of TRH was also abolished by atropine. However, Santori et al (65) have recently reported that anticholinergic drugs failed to antagonize TRH or MK-771 analepsis in rats. No obvious explanation for these latter negative findings is apparent. Moreover, Kalivas and Horita (66) have observed that in the the analeptic actions of intraseptally administered rat, atropine antagonized TRH but not when the peptide was given i.c.v. suggesting the involvement of other noncholinergic systems in TRH analepsis in this species. It has recently been found that MK-771 antagonized apomorphine-induced stereotypic behaviors in rats chronically treated with haloperidol (67). As discussed by these authors, this action of the peptide is similar to previously reported observations with choline and physostigmine and may reflect the cholinergic stimulatory properties of the TRH analog in this animal model of tardive dyskinesia. It should be pointed out that neither TRH nor any of the analogs under consideration appear to possess any intrinsic cholinomimetic or ganglionic Their major action with regard to cholinergic systems stimulatory activity. appears to be a stimulation of cholinergic neuronal activity resulting in a functional elevation of cholinergic tone. Additionally, there is evidence to suggest that they may sensitize post-synaptic cholinergic receptors to the antagonism by Thus, in the cases where it has been observed, effects of ACh. anticholinergic drugs of the effects of TRH would be considered a secondary event to those actions of the peptide on cholinergic nerves effecting a release of ACh and should not be considered as reflecting a direct action of Further support for this idea can be taken from TRH at muscarinic receptors. the data indicating that the direct excitatory effects of TRH, as for example in depolarizing spinal cord ventral roots (9), exciting brain stem reticular

TRH and Cholinergic

116

neurons (28) or elevating antimuscarinic agents.

ciliary

Neurons

nerve

activity

Vol.

(45) are not

33. No.

antagonized

2, 1983

by

Conclusions TKH has been shown to interact with CNS cholinergic neurons at many A schematic representation of these loci is sites throughout the neuroaxis. It is conceivable that certain populations of cholinergic provided in Fig. 1. neuronal cell bodies possess specific TRH receptive sites and that a function of endogenous TRH, which appears to be anatomically associated with these is to modulate the level of excitability of these neurons. If perikarya, this is true, then certain CNS disorders which are thought to result from a in TKH state of cholinergic hypofunction may, in fact, reflect aberrations There is presently little direct dynamics affecting these neuronal systems. information to support or refute this hypothesis, although the potential therapeutic implications of this concept have been previously discussed (2,63). It is possible to be somewhat more definitive with regard to the pharmacological effects of exogenously administered TRH where a unique facilitatory While or excitatory action on some central cholinergic neurons is evident. numerous interactions with other neurotransmitter systems in the CNS have it would appear that at least some of the pharmacological been documented, actions of these interesting peptides can be satisfactorily accounted for through their interaction with central cholinergic pathways.

SPINAL

Q

MIDBRAIN

CORD

CNS -PNS

.--

---

I ACh

.a PI X

MN

- ----

--

ACh

--_---_

ACh

FIG.

1

TRH interactions with CNS cholinergic sites. In this schematic representation, the loci where TRH and related peptides have been shown to interact with central cholinergic pathways are depicted.

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See text for details. Abbreviations used: PNS-peripheral nervous system; MN - motoneuron; X- vagal nuclei; m - occulomotor nuclei; BSRF - brainstem reticular formation; Sept. - septum; Hipp - hippocampus. Adapted from ref. 63. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. ;:: 30. 31. 32. 33. 34.

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