Serotonin and motor activity

820

Serotonin and motor activity Barry L Jacobs* and Casimir A Fornalt The activity

of brain serotonergic

neurons

cord motoneurons

in both the

and medullary

groups

is positively

have

correlated

with the level of behavioral

arousal

and/or

behavioral

state. This, in turn, appears

on particular ion channels

pontine-mesencephalic

level of tonic antigravity gross

muscles

motor

neurons

motor

activity,

and other muscle

activity.

displays

with repetitive, Accumulating

In addition,

a further central

evidence

activity

is related

nervous

system

to be related

especially

groups

a subset

increase

pattern

as manifested

with

in association

mediated

both to the co-activation

in

associated

that this relation

and to the modulation

to the

of serotonergic

in activity

generator

indicates

the

inputs.

Addresses Program in Neuroscience, Princeton University, Princeton, New Jersey 08544-l 010, USA *e-mail: [email protected] +e-mail: [email protected] Current Opinion

in Neurobiology

1997, 7:820-825

http://biomednet.com/elecref10959438800700820 0 Current

Biology

Ltd ISSN

0959-4388

Abbreviations AHP CPG DRN S-HT

afterhyperpolarization central pattern generator nucleus raphe dorsalis 5-hydroxytryptamine; serotonin

NCS NRM

nucleus nucleus

NRO NRP

nucleus raphe obscurus nucleus raphe pallidus rapid eye movement

REM SCN TRH

and their

examined

actions

extensively.

on gross motor Much

of these

output effects

S-HT receptor subtypes and their associated and currents are reasonably well understood

(see e.g. review by Wallis animals have examined

[l]). Third, studies in behaving the relationship between the

discharge of serotonergic motor activity.

neurons

and

specific

types

of

responses. to motor

of the sympathetic

of afferent

been

centralis superior raphe magnus

nucleus suprachiasmaticus thyrotropin-releasing hormone

Introduction The role of central serotonin (5HT) in vertebrate motor function is modulatory rather than mediatory. This is true at both the cellular and behavioral levels. Thus, 5HT alone cannot cause motoneurons to fire, and gross motor output (e.g. limb movements) is essentially normal in animals whose CNS is depleted of 5HT. In this review, we examine S-HT’s role in motor function and suggest how this is related secondarily to its role in sensory information processing and autonomic regulation. 5HT’s role in motor activity can be examined at least at three levels. First, at the organismic level, it is well known that CNS depletion of S-HT leads to increased exploratory and locomotor activity in a variety of mammalian species. This is probably accounted for less by a direct effect of S-HT on motor systems than by a change in responsiveness or reactivity to environmental stimuli. Second, the effects of 5HT on brain stem and spinal

This review issues: first,

focusses on the second and third of these how 5HT alters the membrane properties

and activity gross motor

of motoneurons, and how this, in turn, affects output (e.g. locomotion and respiration); and

second, the behavioral, environmental and physiological conditions that affect the activity of brain serotonergic neurons in freely moving animals.

Anatomical

background

Simply on the basis of the anatomical distribution of their axon terminals in the CNS, it might be hypothesized that serotonergic neurons are important in motor activity. Brain stem and spinal cord a-motoneurons receive dense serotonergic inputs. For example, in the rat, there are strong inputs to motoneurons in the ventral horn, the motor nucleus of the trigeminal, and the facial motor nucleus. Interestingly, the input to brain stem motoneurons is preferentially directed toward those projecting to large muscles of the jaw, face and neck, whereas motoneurons projecting to more finely controlled muscles, such as the extraocular muscles, receive only sparse serotonergic innervation. Similarly, in the spinal cord, the serotonergic input preferentially innervates motoneurons projecting to axial rather than distal musculature [Z]. In addition to direct projections to a-motoneurons, serotonergic fibers also innervate secondary motor structures such as the substantia nigra, globus pallidus, and habenula. If these projections to various portions of the motor system were the sole targets of brain serotonergic neurons, the picture would be simple and straightforward. However, there are a number of other projections to such as the hippocampus, the dorsal nonmotor targets, column nuclei, nucleus suprachiasmaticus (SCN), and intermediolateral cell column. We hypothesize that two things account for this overall pattern of serotonergic innervation. First, when motor activity is initiated, many other systems are called into action in association with the motor demand (e.g. autonomic outflow and neuroendocrine regulation). Second, when motor activity occurs, information processing in a variety of sensory pathways is suppressed. As serotonergic neurons discharge tonically during the waking state, this would provide a continuous inhibition of sensory transmission, except under those special conditions when activity of the serotonergic system

Serotonin and motor activity Jacobs and Fornal

is

decreased,

provocative

such stimuli

as

during

orientation

to

novel

or

(see below).

Gross behavior and neurophysiological analyses One of the original findings in this field was that systemic administration of a variety of serotonergic drugs, including precursors, syndrome activity,

agonists, and releasers, produces a motor in rats [3]. Its most conspicuous signs are hyperhead

shakes

or ‘wet dog’ shakes,

tremor, rigidity, hindlimb abduction, head weaving, and reciprocal forepaw

hyperreactivity,

Straub treading.

tail, lateral These are

probably manifestations of the hyperactivation of the normal endogenous level of serotonergic neurotransmission at motoric sites in the CNS. Further evidence that this syndrome specifically reflects is provided by its blockade drugs and by S-HT synthesis

central serotonergic activity by serotonergic antagonist inhibition. A similar pattern

of neurologic signs is seen in a large number of other vertebrate species, including humans. It is interesting to note that in humans, these drug effects are restricted almost exclusively to motor signs (e.g. myoclonus, shivering), with few, if any, reports of significant changes

tremor, sensory

[4].

Going beyond the investigation of gross behavioral effects of systemically administered drugs, other studies have examined the effects of serotonergic drugs on specific functional systems within the CNS. For example, Barbeau and Rossignol [S] have studied the influence of monoaminergic drugs upon treadmill-induced hindlimb locomotion in spinal cats. As the serotonergic input to the spinal cord has degenerated as a result of the spinal transection in these animals, the observed effects are mediated by postsynaptic serotonergic receptors. In this preparation, S-HT’s primary action is to increase the amplitude of the motor response (i.e. increased step length and augmented contraction of hindlimb flexors and extensors). We have

examined

the

effects

of injecting

serotonergic

drugs directly into the motor nucleus of the trigeminal in behaving cats [6]. Consistent with the results described above, we observed an increase in the amplitude of both the electromyogram of the masseter muscle and of the masseteric examined

(jaw closure) at the cellular

reflex. This system has also been level by Chandler and colleagues

(see e.g. [7]). Cortical stimulation in the guinea pig elicits rhythmic, masticator-y-like

mediating

fictive

swimming

of the lamprey. When cord or to reticulospinal of the afterhyperpolarization

anesthetized jaw move-

ments. The primary excitatory drive for this response depends on glutamate. Iontophoretic application of S-HT directly facilitates digastric (jaw opener) motoneuron activity, but only in the presence of chemical (glutamate) or synaptic activation of these neurons. In addition, iontophoretic application of 5-HT facilitates and brings to threshold rhythmic digastric motoneuron discharge during subthreshold repetitive cortical stimulation. Grillner et a/. [S] have examined the influence of S-HT (and other neurotransmitters) on the neuronal mechanisms

in the

isolated

spinal

821

cord

5-HT is applied to the spinal neurons, it elicits a depression (AHP) that normally follows

the action potential. (By on the membrane resting

itself, 5-HT has no effect potential.) As the AHP is

the primary factor in determining the frequency of the neural control of locomotion, this depression produces an increase in the motoneuron discharge frequency. If S-HT is applied to the solution bathing the isolated spinal cord during fictive more intense

swimming, and longer,

motoneuronal and the burst

bursts become rate increases.

Similar effects upon fictive swimming are seen when the synaptic level of endogenously released S-HT is elevated pharmacologically. Another

system

that has attracted

a great deal of attention

is respiration, especially because of the significance of a variety of related clinical disorders such as sleep apnea and sudden infant death syndrome. Much of this research has been carried out in vitro (e.g. neonatal brain stem slices), in reduced preparations (e.g. decerebrate animals), or in anesthetized, vagotomized, paralyzed and artificially respirated animals [9,10**,1 l-131. Consistent with other evidence, these studies report that S-HT does not provide the primary drive for respiration, but modulates its activity. Probably because of the variety of receptor subtypes upon which S-HT acts, S-HT’s action on respiratory motoneurons is still not completely understood. In a medullary neonatal rat slice preparation, the frequency of respiratory burst discharge was increased when S-HT was added to the bath [12]. S-HT also caused an augmentation of tonic hypoglossal nerve discharge when applied in the bath or directly to the motoneurons. These effects were blocked by specific S-HT2 antagonists [12]. The most consistent effect of 5-HT is an augmentation of phrenic motoneuronal activity [ 111. Finally, a number vitro systems (i.e.

of recent studies have employed in neonatal rat spinal cord and isolated

brain-stem/spinal-cord preparations) to study in locomotion. Bath-applied S-HT induces comotion, oscillator

suggesting component

(CPG) itself [14,15]. and S-HTz receptors Kjaerulff [16*] have

S-HT’s role fictive lo-

that it is acting directly on the of the central pattern generator S-HT also acts directly at S-HTj on motoneurons [14]. Kiehn and described the complexities of the

spatiotemporal characteristics of S-HT-induced rhythmic hindlimb activity using a neonatal rat in vitro spinal cord preparation. A number of studies have examined S-HT’s direct actions on a-motoneurons, independent of its actions on complex circuitry involved in the aforementioned types of integrative activity. Consistent with the results described in the preceding sections, S-HT alone produced little or no change in neuronal activity [17,18]. However, when S-HT was interacted with excitatory influences on motoneurons,

822

Motor systems

produced

either

by direct

application

of excitatory

amino

waking

rate

of approximately

3 spikes/s,

the

activity

of

acids or by electrical stimulation of the dorsal root or motor cortex, it produced a strong facilitation of neuronal activity.

these neurons is typically increased by approximately lo-30% in response to activating or arousing stimuli.

These effects are mediated by S-HTz* and S-HTzc receptors [19*]. Intracellular analyses indicate that this is

the cat becomes

attributable

entering

to a depolarization,

probably

decreased resting membrane Furthermore, pharmacological

mediated

by a

conductance to K+ [20,21]. analyses indicate that an

Reciprocally,

the

activity drowsy,

slow-wave

of these and

sleep.

neurons

becomes

Finally,

even this

decrease in single-unit activity culminates rapid eye movement (REM) sleep, when

declines slower

as upon

state-dependent as the cat enters neuronal activity

action at 5-I-IT2 receptors appears to mediate this effect [22]. Another way of describing this is to say that S-HT

fails virtually silent. It is worth neuronal activity during REhl

noting that an absence sleep is almost unique

shifts motoneurons from a stable hyperpolarized state, with little or no neuronal activity, to a stable depolarized

the CNS (noradrenergic neurons one of the few nuclei that share

of the locus coeruleus are this property). In general,

‘plateau’

the pattern

A recent evidence to hours)

state,

with

tonic

neuronal

activity

[23].

study has argued that much of the previous for 5-HT exerting long-lasting changes (minutes is attributable to using inappropriately high con-

centrations of S-HT are used, the effects

[24]. When are limited

nanomolar concentrations to tens of seconds.

Addressing the complexity in what would appear to be a simple issue of motoneuron excitability, Chandler and colleagues [25’] report that S-HT increases trigeminal motoneuron excitability by three mechanisms in addition to the aforementioned reduction in a K+ current: enhancement of a hyperpolarization-activated cationic current; activation of a Na+ current; and a decrease in a Caz+-dependent K+ current underlying the postspike AHP. An issue that is still unresolved is the significance in the ventral horn of S-HT’s co-localization with neuropeptides. At least 90% of these terminals contain co-localized substance P and/or thyrotropin-releasing hormone (TRH) [26]. It is assumed that the neuropeptides add excitability as they are released in a frequency-dependent this remains unproven for motoneurons physiological

conditions.

Activity of serotonergic animals Virtually neurons

manner, but examined under

neurons in behaving

all of the studies on the activity of seroronergic in behaving animals have been carried out can be grossly divided into two cat. They

in the groups: studies of the serotonergic neurons localized in the pontine-mesencephalic raphe nuclei dorsalis and centralis superior (DRN and NCS, respectively), which primarily innervate the forebrain; and studies of the serotonergic neurons localized in the medullary raphe nuclei magnus, obscurus, and pallidus (NRM, NRO, and NRP, respectively), which primarily innervate the brain stem and spinal cord.

The activity of brain serotonergic neurons varies dramatically across the sleep-wake-arousal cycle. During the quiet waking state, the activity of DRN neurons, the largest cluster of brain serotonergic cells, is slow and highly regular or clock-like [27]. From a quiet

of activity

in DRN serotonergic serotonergic neurons NCS,

NRO/NRP,

across

the sleep-wake-arousal

of in

cycle

neurons is closely paralleled by in the other major groups: namely,

and NRM

[28].

In an attempt to understand the functional role of brain serotonergic neurons, we began a series of studies in which we exposed animals to various stressors and challenges while recording the activity of DRN neurons, including a heated environment or administration of a pyrogen, drug-induced increases or decreases in arterial blood pressure, insulin-induced hypoglycemia, loud noise, physical restraint, or a natural enemy (dog) [29-321. Despite the fact that all of these conditions evoked strong behavioral responses and/or physiological changes indicative of sympathetic activation, none of them significantly activated serotonergic neuronal activity beyond the level normally seen during an undisturbed active waking state. To what might the activity of these neurons be related? Because the activity of serotonergic neurons is almost totally suppressed during REM sleep, a period characterized by profound muscle inhibition, we examined the possibility that there might be a relationship between these two phenomena. Lesions of the dorsomedial pons in cats produce a state that, according to all criteria, appears to be REM sleep, except that antigravity muscle tone is present; thus, the animals are capable of movement and even coordinated locomotion. In both waking and slow-wave sleep, the activity of DRN serotonergic neurons in these pontine-lesioned cats was similar to that of normal animals [33]. However, when these animals entered REhI sleep, neuronal activity increased instead of displaying the decrease typical of this state. Those animals displaying the greatest amount of restored muscle tone and overt behavior during REhl sleep showed the highest levels of neuronal activity, with some of their serotonergic neurons discharging at a level approximating that of the waking state. Microinjection of carbachol, a cholinomimetic agent, into this same pontine area produces a condition somewhat reciprocal to non-atonia REM sleep. These animals are awake, as demonstrated by their ability to track visual stimuli, but are otherwise paralyzed. However, unlike the normal waking state, during which serotonergic neurons

Serotonin and motor activity Jacobs and Fornal

are tonically active, DRN serotonergic in these paralyzed animals [34].

neurons

are inactive

These data suggested that a strong positive relationship exists between the tonic level of motor activity (muscle tone) and the firing rate of DRN serotonergic neurons. Recently, we have observed much more specific relationships between serotonergic neuronal activity and motor function. When cats engage in a variety of CPG-mediated oral-buccal activities, such as chewing/biting, licking, or grooming, approximately one-fourth of the DRN serotonergic neurons increase their activity by as much as two to fivefold [35**]. In contrast, the rest of the serotonergic neurons in this nucleus maintain their slow and rhythmic activity. These increases in neuronal activity invariably terminate coincident with the end of the behavioral sequence. Equally impressive is the fact that even brief (1-5 s) spontaneous pauses in these behaviors are accompanied by an immediate decrease in neuronal activity to baseline levels, or below. The increased neuronal activity during these CPG-mediated behaviors is typically tonic, but is occasionally modulated in phase with a particular aspect of the repetitive behavior. During a variety of other nonrhythmic episodic or purposive movements, even those involving oral-buccal responses, such as yawning, no increase, or even a decrease in neuronal activity is seen. Reciprocally, during attentional shifts, such as those occurring during orienting movements in response to novel or imperative stimuli, the activity of DRN serotonergic neurons may fall silent for several seconds. Somewhat surprisingly, most of these DRN neurons can also be activated by somatosensory stimuli applied to the head and neck region, whereas the same stimuli applied to the rest of the body surface are typically ineffective. As discussed above, serotonergic neurons in the rostra1 pons (DRN and NCS) provide almost the entire serotonergic innervation of the forebrain, whereas those in the caudal medulla (NRO and NRP) are the source of much of the serotonergic innervation of the spinal cord. Therefore, it is interesting to compare the response properties of neurons in these two separate groups. Contrary to pontine serotonergic neurons, where only a subgroup of neurons is activated during CPG-mediated behaviors, virtually all medullary serotonergic neurons are activated under at least some of these conditions [36”]. The degree of activation, however, is much less impressive (i.e. SO-100% above baseline versus 100-400% above baseline for the DRN). In this context, it may be important to note that the basal, quiet waking discharge rate of the medullary serotonergic neurons is approximately twice that of the pontine serotonergic neurons - 5-6 spikes/s versus 2-3 spikes/s. There also appears to be at least some degree of response specificity for these neurons. Thus, virtually all medullary serotonergic neurons are activated during treadmill-induced locomotion, but only subgroups are activated during hyperpnea (induced by exposure

823

to carbon dioxide), or during chewing/licking. Many of these individual neurons are activated in association with more than one of these motor activities. In most cases, there is a strong positive correlation between the magnitude of neuronal activation and the speed of locomotion and/or depth of respiration. As with pontine serotonergic neurons, the increased activity of medullary serotonergic neurons is sometimes phase-locked to the behavior (e.g. in association with the step cycle) and typically is tightly coupled to the onset and offset of the behavior. Recently, we have found that approximately half of the serotonergic NRO/NRP neurons tested are activated during exposure to a low ambient temperature (SC), which induces bursts of shivering but no appreciable changes in core temperature (FJ Martin eta/., Sot Neurosci Ah- 1997, 23:485.12). The remaining cells are unaffected by this manipulation. Finally, when DRN neurons are examined under identical conditions, none are activated during treadmill-induced locomotion or cold exposure, but some are activated during carbon dioxide-induced hyperpnea ([37]: FJ hlartm et al., Sot Neurosci Abstr 1997, 23:485.12). Almost all of the manipulations studied to date that activate medullary serotonergic neurons increase both motor and sympathetic activities (e.g. treadmill locomotion, hypercarbic vencilatory challenge and cold exposure). It is well known that serotonergic neurons in the NRO and NRP have extensive projections to the intermediolateral cell column of the spinal cord, where they make monosynaptic connections with sympathetic preganglionic neurons, including those that innervate the adrenal gland [38]. The serotonergic cells in these raphe nuclei, in turn, receive monosynaptic inputs from axons originating in the rostra1 ventrolateral medulla, the primary source of sympathetic activity. A number of studies have shown that medullary serotonergic neurons exert, predominantly, an excitatory influence on sympathetic outflow and, therefore, may serve to elevate arterial blood pressure and heart rate [39,40]. Whether these neurons can modulate sympathetic outflow independent of somatic motor activity remains to be determined. To address this question, we have recently examined the responses of serotonergic NRO/NRP neurons to manipulations that elicit sympathetic activation but produce no change or even a decrease in motor output. In one experiment, insulin-induced hypoglycemia was used to preferentially activate the sympathoadrenal system (BL Jacobs, FJ Martin, CA Fornal, CW Metzler, Sot Neurosci Abstr 1997, 23:485.13). Following insulin administration, blood glucose decreased to approximately 50% of baseline levels. This was accompanied by significant increases in plasma catecholamines. Surprisingly, the discharge rate of serotonergic NRO/NRP neurons was markedly reduced (-50%) after insulin, and was temporally correlated with the decrease in blood glucose levels. The subsequent administration of glucose, at doses sufficient

824

Motor systems

to reverse hypoglycemia, promptly restored neuronal activity and plasma catecholamines to baseline levels. The observation that serotonergic NRO/NRP neuronal activity is depressed, rather than enhanced, during the period of increased sympathetic activity following insulin administration does not support a primary role for these neurons in sympathetic activation. Instead, the depression of serotonergic NRO/NRP neuronal activity may be directly related to the diminished skeletal muscle tone and behavioral suppression associated with insulin-induced hypoglycemia. Recently, we have examined the responses of serotonergic NRO/NRP neurons to systemic administration of vasoactive compounds (FJ hlartln, BL Jacobs, CA Fornal, unpublished data). Hydralazine, a direct long-acting vasodilator, was used to produce prolonged reflex activation of the sympathetic nervous system. The dose of hydralazine employed in these experiments produces a sustained elevation of heart rate and plasma norepinephrine levels. However, no significant changes in neuronal activity were observed after hydralazine administration. Furthermore, the activity of these neurons was unaffected by transient decreases in arterial blood pressure produced by sodium nitroprusside administration. These results are consistent with those of a previous study [41] conducted in anesthetized rats, which showed that the discharge of medullary serotonergic neurons was unrelated to the cardiac cycle and was unaffected by baroreceptor reflex activation.

regarding repetitive motor activity (running) afferents deriving from serotonergic neurons.

We have incorporated these data into a general theory of 5HT function wherein we hypothesize that activation of brain serotonergic neurons facilitates motor output and, simultaneously, suppresses sensory information processing [43,44]. In addition, we hypothesize that serotonergic neurons play an auxiliary role in coordinating appropriate autonomic and neuroendocrine outputs to the ongoing tonic or repetitive motor activity. This is consistent with a recent report that showed that the activity of NRO/NRP presumed serotonergic neurons in decerebrated, paralyzed, vagotomized and artificially ventilated cats is decreased during carbachol-induced atonia, along with decreases in hypoglossal, phrenic and postural nerve activity [lo”]. In addition, antidromic stimulation showed that at least some of these neurons had direct projections to both motor (hypoglossal nucleus) and autonomic (the dorsal motor nucleus of the vagus and/or the nucleus of the solitary tract) centers. Finally, when serotonergic neuronal activity is suppressed, such as during orientation, the functions are reversed, with motor output disfacilitated and sensory processing disinhibited, permitting more focussed information processing to occur.

Acknowledgements Christine hlcrzlcr, Luis Eduardo Kibciro-do-valle, \i-asey, and Francisco I\lartin-Cora made important to the

authors

supported

by

research

References

in this

review

scientific

The

authors’

contributions research

was

of Scientific

Research.

and recommended

reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

. ..

of special interest of outstanding interest

1.

Wallis DI: 5-HT receptors involved in initiation or modulation of motor patterns: opportunities for drug development Trends Pharmacol Sci 1994, 15:288-292.

2.

Steinbusch HWM: Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 1981, 4:557-618.

3.

Jacobs BL: An animal behavior model for studying central serotonergic synapses. Life Sci 1976, 19:777-786.

4.

Sternbach H: The serotonin syndrome. 148:705-713.

5.

Barbeau H, Rossignol S: Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs. Braain Res 1991, 546:250-260.

6.

Ribeiro-do-Valle LE, Metzler CW, Jacobs BL: Facilitation of masseter EMG and masseteric (jaw closure) reflex by serotonin in behaving cats. Brain Res 1991, 550:197-204.

Conclusions The activity of brain serotonergic neurons, regardless of the nuclei in which they are found, changes dramatically across the sleep-wake-arousal cycle. At least in part, this appears to be correlated with changes in the level of tonic motor activity that accompany these alterations in behavioral state. Somewhat surprisingly, serotonergic neurons are only minimally responsive to any of a broad range of environmental or physiological challenges/stressors. Beyond the level of neuronal activity attained during waking, many serotonergic neurons display a further, often dramatic, elevation of neuronal activity during the expression of repetitive, CPG-mediated motor outputs. A recent report provides one example of the functional significance of this relationship. Mice with destruction of the serotonergic input to their circadian pacemaker in the SCN are unable to synchronize to a regularly scheduled running-wheel paradigm used to entrain control animals [42’]. Thus, the signal to the SCN

described

France hlarrosu, Slgrid

grants from the National Institurc of hlental Health and the

Air Force Office

Overall, these results suggest that the discharge of serotonergic NRO/NRP neurons is related more closely to changes in motor output than to changes in sympathetic outflow. These neurons may influence sympathetic activity, but only in relation to increased motor output, as this appears to be the primary determinant of serotonergic neuronal activity in the behaving animal.

is carried by

Am J Psychiatry 1991,

Katakura N, Chandler St+ An iontophoretic analysis of the pharmacologic mechanisms responsible for trigeminal motoneuronal discharge during masticatory-like activity in the guinea pig. J Neurophysiol 1990, 63:356-369. Grillner S, Wallen P, Brodin L, Lansner A: Neuronal network generating locomotor behavior in lamprey: circuitry, transmitters, membrane properties, and simulation. Annu Rev Neurosci 1991, 4:169-l 99.

Serotonin and motor activity Jacobs and Fornal

825

27.

Trulson ME, Jacobs BL: Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res 1979, 163:135-150.

Woch G, Davies RO, Pack Al, Kubin L: Behaviour of raphe cells projecting to the dorsomedial medulla during carbacholinduced atonia in the cat / Pbysiol 1996, 490:745-758. This study demonstrates that medullaty serotonergic neurons, whose activity is suppressed during carbachol-induced atonia, may project to both motoneurons and autonomic centers. The authors suggest that such neurons may be important in respiratory control, especially of the upper airway.

28.

Jacobs BL, Fornal CA: Activity of brain serotonergic neurons in the behaving animal. Pharmacol Rev 1991, 43:563-578.

29.

Fornal CA, Litto WJ, Morilak DA, Jacobs BL: Single-unit responses of serotonergic neurons to glucose and insulin administration in behaving cats. Am J Physiol 1989, 257:R1345RI 353.

11.

Bonham AC: Neurotransmitters in the CNS - control of breathing. Respir fhysiol 1995, 101:21 g-230.

30.

12.

Al-Zubaidy ZA, Erickson RL, Greer JJ: Serotonergic and noradrenergic effects on respiratory neural discharge in the medullary slice preparation of neonatal rats. fur J Physiol 1996, 431:942-949.

Fornal CA, Litto WJ. Morilak DA, Jacobs BL: Single-unit responses of serotonergic dorsal raphe nucleus neurons to environmental heating and pyrogen administration in freely moving cats. fip Neural 1987, 98:388-403.

31.

Fornal CA, Litto WJ, Morilak DA, Jacobs BL: Single-unit responses of serotonergic dorsal raphe neurons to vasoactive drug administration in freely moving cats. Am J Physiol 1990, 259:R963-R972.

9.

Morin D, Monteau R, Hilaire G: +Hydroxytryptamine modulates central respiratory activity in the newborn rat: an in vitro study. Eur J Pharmacol 199 1, 192:89-95.

10. ..

13.

Richmond CR, Hudgel DW: Hypoglossal motoneuron responses to serotonergic Respir Physiol 1996, 106:153-l 60.

and phrenic active agents in rats. 32.

14.

Cazalets JR, Sqalli-Houssaini Y, Clarac F: Activation of the central pattern generators for locomotion by serotonin and excitatory amino acids in neonatal rat J Physiol 1992, 455:187-‘204.

Wilkinson LO, Jacobs BL: Lack of response of serotonergic neurons in the dorsal raphe nucleus of freely moving cats to stressful stimuli. Exp Neural 1988, 101:445-457.

33.

15.

Cowley KC, Schmidt BJ: A comparison of motor patterns induced by N-methyl-D-aspartate. acetylcholine and serotonin in the in vitro neonatal rat spinal cord. Neurosci Lett 1994, 171:147-150.

Trulson ME, Jacobs BL, Morrison AR: Raphe unit activity during REM sleep in normal cats and in pontine lesioned cats displaying REM sleep without atonia. Brain Res 1981, 226:7591.

34.

Steinfels GF, Heym J, Strecker RE, Jacobs BL: Raphe unit activity in freely moving cats is altered by manipulations of central but not peripheral motor systems. Brain Res 1983, 279:77-84.

16. .

Kiehn 0, Kjaerulff 0: Spatiotemporal characteristics of 5-HT and dopamine-induced rhythmic hindlimb activity in the in vitro neonatal rat J Neurophysiol 1996, 75:1472-l 482. This study recording EMGs provides a detailed spatiotemporal analysis of the multiplicity of 5-HT’s actions upon hindlimb muscles associated with locomotion. The authors show that 5-HT and dopamine induce complex and different rhythmic patterns and control different ranges of cycle frequencies in the neonatal rat. 1 7.

McCall RB, Aghajanian GK: Serotonergic facilitation of facial motoneuron excitation. Brain Res 1979, 169:l l-27.

18.

White SR, Neuman RS: Facilitation of spinal motoneuron excitability by 5-hydroxytryptamine and noradrenaline. Brain Res 1980, 188:l 19-127.

19. .

White SR, Fung SJ, Jackson DA, lmel KM: Serotonin, norepinephrine and associated neuropeptides: effects on somatic motoneuron excitability. frog Braain Res 1996, 107:183199. This is a fine review of the neurophysiological effects of 5-HT, norep,nephrine, and associated neuropeptides (especially substance P and TRH) on mammalian brain stem and spinal cord a-motoneurons. 20.

VanderMaelen CP, Aghajanian GK: Serotonin-induced depolarization of rat facial motoneurons in viva: comparison with amino acid transmitters. Brain Res 1982, 239:139-l 52.

21.

White SR, Fung SJ: Serotonin depolarizes cat spinal motoneurons in situ and decreases motoneuron after hyperpolarizing potentials. Brain Res 1989, 502:205-2 13.

22.

White SR, Neuman facilitatory but not norepinephrine on Neuropharmacology

RS: Pharmacological antagonism of inhibitory effects of serotonin and excitability of spinal motoneurons. 1983, 22:489-494.

Fomal CA, Metzler CW, Marrosu F, Riblero-do-Valle LE, Jacobs BL: A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements. Brain Res 1996, 716:123-l 33. The first study to show that the discharge of serotonergic neurons in the dorsal raphe nucleus is related to rhythmic motor activity. Prior to this study, the activity of these neurons was thought to vary only in association with behavioral state and/or tonic muscle tone. 35. ..

36. ..

Veasey SC, Fornal CA, Metzler CW, Jacobs BL: Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats. J Neurosci 1995, 155346-5359. The first study to examine the relationship between the discharge of medullary serotonergic neurons and motor activity in the behaving animal. This study showed that a large percentage of serotonergic neurons in the raphe nuclei obscurus and pallidus are activated during specific motor challenges. 37.

Veasey SC, Fornal CA, Metzler CW, Jacobs BL: Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats. Neuroscience 1997, 79:161-169.

38.

Bacon SJ, Zagon A, Smith AD: Electron microscopic evidence of a monosynaptic pathway between cells in the caudal raphe nuclei and sympathetic preganglionic neurons in the rat spinal cord. Exp Brain Res 1990, 79:589-602.

39.

McCall RB: Evidence for a serotonergically mediated sympathoexcitatory response to stimulation of medullary raphe nuclei. Brain Res 1984, 311 :13 l-1 39.

23.

Hounsgaard J, Hulrborn H, Jesperson B, Kiehn 0: Bistability of alpha-motoneurones in the decerebrate cat and in the acute spinal cat after intravenous 5-hydroxytryptophan. J Physiol 1988, 405:345-367,

40.

Huangfu D, Hwang L-J, Riley TA, Guyenet PG: Role of serotonin and catecholamines in sympathetic responses evoked by stimulation of rostra1 medulla. Am J Physiol 1994, 266:R338R352.

24.

Douse MA, White DP: Serotonergic effects on hypoglossal neural activity and reflex responses. Brain Res 1996, 726:213222.

41.

McCall RB, Clement ME: Identification of serotonergic and sympathetic neurons in medullary raphe nuclei. Brain Res 1989, 477:172-l 82.

25. .

Hsiao CF, Trueblood PR, Levine MS, Chandler SH: Multiple effects of serotonin on membrane properties of trigeminal motoneurons in vitro. J Neurophysiol 1997, 77:291 O-2924. This study provides a detailed analysis of the multiplicity of actions on the membrane properties of guinea pig trigeminal motoneurons examined in vitro. Most of the conductance changes were mediated by actions at 5-HT, receptors. 26.

Arvidsson U, Cullheim S, Ulfhake B, Bennett GW, Fone KCF, Cuello AC, Verhofstad AAJ, Visser TJ, Hokfelt T: 5_hydroxytryptamine, substance P, and thyrotropinreleasing hormone in the adult cat spinal cord segment L7: immunohistochemical and chemical studies. Synapse 1990, 6:237-270.

42. .

Edgar DM, Reid MS, Dement WC: Serotonergic afferents mediate activity-dependent entrainment of the mouse circadian clock Am J Physiol 1997, 273:R265-R269. This study demonstrates that, under ‘free-running’ conditions, the ability of mice to entrain to a two hour running-wheel paradigm was dependent on an intact serotonergic input to the circadian pacemaker in the suprachiasmatic nucleus. 43.

Prochazka A: Sensorimotor gain control: a basic strategy of motor systems? Prog Neurobiol 1989, 33:281-307.

44.

Nelson RJ: interactions between motor commands and somatic perception in sensorimotor cortex. Curr Opin Neurobiol 1996, 6:801-810.