Motor effects of serotonin in the central nervous system

Life Sciences, Vol 27, pp Printed ~n the U S.A.

1435-1451

Pergamon Press

MINIREVIEW MOTOR EFFECTS OF SEROTONIN IN THE CENTRAL NERVOUS SYSTEM Sylvia C. Gerson and Ross J

Baldessarlnl

Departments of Psychiatry, Un~verslty of South Flor~da, Tampa, Florlda, and Harvard Medical School, and Mailman Research Center, McLean/Massachusetts General Hospital Belmont, MA, 02178 Summary Serotonerlc pathways in the CNS affect posture and movement, as well as behavloral responses to arouslng stlmull. Pharmacologlc analysls of these effects has led to an increaslngly complex and confuslng llterature. Increased avallab111ty of serotonln (5-HT) by admlnlstratlon of precursors, or by its dlrect intracranial infusion can ~nduce inhlb~tory or excitatory behavioral effects dependlng on the condltlons of the experlment, although generally motor inhlbltlon has been found Avallab111ty of 5-HT has been decreased by electrolytlc leslons of the raphe nuclel, inhlbltlon of tryptophan hydroxylase, or use of selectlve neurotoxins These treatments have generally ~ncreased motor act~vity, especlally spontaneous locomotion in a fam111ar envlronment, as well as sexual or aggressive behaviors, other behaviors, such as responses in a novel environment, presumably associated with curloslty or fear, have been paradoxically decreased after loss of 5-HT Thls dlfferentlatlon may occur to an important extent through 5-HT projections to hlppocampus and iimblc structures, notably from the median raphe. Increases or decreases of braln 5-HT, respectlvely, generally tend to decrease and increase responses to catecholamlne agon~sts such as amphetamines, and some effects of 5-HT may be mediated through catechelamlnerglc systems Increased avallablllty of 5-HT in the presence of MAO Inhlbltors, or challenge wlth 5-HT-agonlsts after selectlve 5-HT-denervatlon in the CNS has led to a behavloral syndrome marked by hyperactlvity, autonomic arousal and myoclonlc seizures The mechanlsms underlylng thls complex response may be medlated by descendlng 5-HT systems that result in motor excitation at the splnal cord level, in contrast to rostral projectlons to forebraln that may medlate many behavlorally inh~b~tory responses. There is an increaslng complexity and lack of clarlty in the llterature regardlng the contrlbutlons of 5-hydroxytryptamlne (5-HT, serotonln) to the control of motor actlvlty. Many studles suggest that 5-HT plays an inhlbltory role In the regulatlon of skeletal and vlsceral motor functlon by the central nervous system (CNS), whlle others indicate an excltatory actlon. Spontaneous locomotor behavlor has been especlally frequently evaluated after treatments deslgned to increase or decrease CNS levels of 5-HT selectlvely. Representatlve recent studles of this klnd are reviewed (see summary in Table I).

0024-3205/80/421435-17502.00/0 Copyright (c) 1980 Pergamon Press Ltd

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Increased Serotonln Many ~nvestigators have noted decreased locomotor activity in rats following systemic administratlon of the 5-HT precursor tryptophan (TP) (1,2), although some found no slgnlflcant effects either of TP injectlons (3,4,5) or of other treatments known to increase brain levels of 5-HT such as dlets rlch in this amino acid (5,6). Studles wlth 5-hydroxytryptophan (5-HTP) have also yielded results that varied with the conditions selected. Thus, in the absence of a peripheral inhibitor of aromatic amino acid decarboxylase, thls 5-HT precursor has usually decreased locomotion in rodents (1,7,8,9) The same treatment following a peripheral decarboxylase inhlbltor has been found to increase normal motor behavior (7,8,10,11), an effect not to be confused with the syndrome of CNS hyperexcltabillty and abnormal locomotion seen at higher doses of 5-HTP. A more direct approach has been the direct intracranial injection of 5-HT ~nto the cerebroventricular system to circumvent the blood-braln barrier to this polar amlne Acute intraventrlcular in3ectlon of 5-HT has been reported to produce a transient decrease in spontaneous locomotor activity in rats (12) and mice (13). More recently, both spontaneous and amphetamlne-stlmulated locomotor activity decreased in a dose-dependent manner following the continuous infuslon of 5-HT into the lateral cerebral ventricles of rats through a chroni~ally implanted cannula (14). These results taken together suggest that 5-HT can act as an inhlb~tor of locomotion ~n rodents under eondlt~ons that are not modified by a drug, but that excitatory effects can be obtained under some conditions. Decreased serotonln Experiments in which locomotor behavior has been studled following procedures that decrease 5-HT levels in the CNS have produced inconsistent results Some of the inconsistency probably reflects both the use of dlsslmllar behavioral conditlons, as well as different procedures for depletlng 5-HT The commonly used methods for reducing brain 5-HT levels are the following i) electrolytic leslons of the 5-HT contalnlng cells of the mldbraln raphe nuclei (15), 2) systemic injection of ~-chlorophenylalanlne (PCPA), an inhibitor of tryptophan hydroxylase (16), or 3) of the halogenated phenethylamine, ~-chloroamphetamlne (PCA), which is toxic to 5-HT neurons (17-20), and 4) intracerebral admlnlstration of the neurotoxlc 5-HT analogs 5,6- and 5,7dlhydroxytryptamlne (DHTs) which selectively destroy 5-HT nerve terminals in the CNS under specific conditions (21-27). Electrolytic lesions. Electrolytlc leslons of the mldbraln raphe nuclei in rats have been found consistently to produce hyperactlvity In an open fleld (28-30), in actlvlty cages (31-34) and in tilt cages (11,35) Geyer and co-workers reported that rats stereotaxlcally lesioned in the median raphe nucleus (MRN or nucleus B-8) were hyperactive when placed in a novel environment (32). The MRN-lesioned rats also had an Increased locomotor response to amphetamlne and exhibited larger startle responses to alr-puffs. Lesions of the dorsal raphe nucleus (DRN or B-7), on the other hand, did not produce any of these excitatory effects. Similar flndlngs have been reported by Jacobs et al (35,36) and by Srebro and Lorens (29) who found that rats wlth electrolytic lesions of MRN, but not DRN or lateral raphe (LRN, B-9) showed increased running wheel and open field activlty as well as enhanced reactivity to novel stlmull and envlronmental changes A recent study by Dray et al. (34) confirmed these behavloral observations, as well as the finding that the ~ lesions produced

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selective decreases of 5-HT in the hlppocampus and llmblc structures, whereas DRN lesions dld not (32) This anatomic selectivity of behavioral effects may reflect the selectivity of median raphe (B-8) projections to hlppocampal and septal (as well as hypothalamlc and cortical) regions vs a preferential strlatal, thalamic and cortical projection from the dorsal raphe (B-7) and more diffuse projections from the lateral raphe (B-9) (36-39) Jacobs et al (35) provided further support for this vlew in observing that tilt cage hyperactivity seen after MRN lesions or PCPA treatment may also be mediated by 5-HT depletlon in the hlppocampus selectively, since aspiration of the hlppocampus prlor to electrolytic leslons or systemic injection of PCPA abolished the ability of both treatments to produce locomotor hyperactivity These observatlons all suggest an Important iocomotlon-alterlng role of 5-HT in the hlppocampus. To complicate the interpretation of these findings, in experiments comparing the effects of midbraln raphe electrolytic lesions and neurochemlcal lesions with intra-raphe injections of 5,7-DHT, Lorens and co-workers (30) found that, although both methods produced similar depletions of 5-HT in all brain regions (including hippocampus), rats wlth electrolytlc lesions were hyperactlve in the open field but 5,7-DHT-treated anlmals were not. Thls suggests that the behavioral effects of electrolytic lesions may not be due prlmarily to a decrease in brain 5-HT resulting from a disruption of ascending 5-HT pathways, but may involve damage to non-serotonergle pathways. Simllarly, K~hler and Lorenz compared the effects of PCPA and electrolytlc leslons of raphe nuclel on open-fleld activity in ratsonly the raphe-lesloned animals showed an Increase in locomotion, even though the reduction in forebrain 5-HT by PCPA (85%) was even greater than after leslonlng (55%) (28) Thus, there does not appear to be a simple relationshlp between 5-HT levels in speclfic brain regions and locomotor activity Some investigators have suggested that other transmitter systems are involved as well. For example, Yamamoto and Ueki (33) reported that motor hyperactivity in raphe-lesloned rats was significantly suppressed by catecholamine (CA) depleting agents (e g., ~-methyl-~-tyroslne) or antagonists (e.g., chlorpromazlne, haloperldol) and hypotheslzed that raphe lesions may activate catecholamlnergic systems normally suppressed by 5-HT projections to forebrain. It is also possible that forebraln 5-HT and CA projections exert opposite and more or less interdependent behavioral effects (32), thls view would be compatlble with Brodie and Shore's (40) early hypothesis that behavioral arousal is a joint function of serotonerglc inhibition and catecholaminerglc excltatlon p-Chlor0Phenylalan!ne

(PCPA)

Experiments in which 5-HT depletlon was induced by t r e a t m e n t with PCPA, a relatively specific inhibitor of the synthesis of 5-HT, have produced increases of activity under some conditions (35,41,42) or a mixture of increases and decreases (3,43,44), dependlng on the conditions. A few studies, inexplicably, have reported little or no effect of PCPA on locomotion (28,45-47) Repeated PCPA can lead to a small decrease of locomotor activity, suggestlng that adaptation occurs (probably including systems other than 5-HT neurons) after prolonged depletion of 5-HT (47) The complexity of the behavioral actlons of PCPA may reflect its imperfect specificity as an inhlbitor of tryptophan hydroxylase, for example, it can deplete eateeholamlnes in brain to some extent as well (48,49) Observations of increases and decreases of motor activity with different conditions in the same experiment require further clarification For example,

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Matte and Tornow found that whlle flne motor act~vlty measured in mlce by an actlvlty monitor was somewhat reduced after treatment w~th PCPA, coarse movements closely correlated wlth aggressive behavior were Increased (43) Marsden and Curzon also reported ~ncreases ~n aggresslve behavior ~n rats after an in3ectlon of PCPA as well as increased locomotor actlvlty in the home cage wlth llghts on (3,41) In contrast, actlvlty in the novel envlronment of an open fleld was markedly dlminlshed (3) It Is temptlng to speculate that 5-HT may exert effects on motor behavior in dlssimilar ways depending on the presumed "affectlve" aspect of the behavlor under observation Thus, dlmln~shed ava~lab~l~ty of forebra~n 5-HT may selectively ~ncrease some agon~st~c (especlally aggressive and sexual) behaviors, while behaviors that may reflect "curiosity" or "fear" (e g , novel open field) may be reduced A further complicatlon is introduced by conslderlng the effects of altered 5-HT levels and the dlurnal pattern of motor actlvity. Several reports ~ndlcate that the pattern and rhythm of actlvlty in rodents are markedly altered by PCPA (3,44,50). Increased actlvlty IS especially llkely in the light phase over several days (3,44), and seems to correspond wlth temporary Insomnla In nocturnal rodents (51) In the dark phase, when locomotor actlvity is normally hlgh, PCPA may induce llttle change (3), or even a small decrease (44), although increases have also been reported by Marsden and Curzon (41) Importantly, however, whlle rats normally show episodes of high actlvlty interspersed wlth short perlods of lower activlty durlng the dark perlod, PCPA-treated rats were almost continuously actlve in the dark (3). More recently, Honma et al noted strlklng disruptlons in the clrcadlan rhythm of motor actlvlty In that normal rhythmlcity in constant light was suppressed by PCPA (50) p-Chloroamphetamlne

(PCA)

Studles of locomotor actlvlty have also been carried out followlng treatment of anlmals wlth PCA, the long-term effects of thls drug have been attrlbuted to a selectlve neurotoxlc actlon on indoleamlnerg~c neurons, resultlng in permanent reduction in braln 5-HT (52,53). Messing et al (54) have reported an increase ~n home cage locomotor activlty ~n rats for up to three days followlng a single in3ection of PCA. The peak increase occurred on the second day, at a tlme when braln catecholamlnes were normal but 5-HT levels were greatly reduced, particularly in forebrain areas Thls motor actlvatlng effect of PCA can be blocked by pretreatment wlth the 5-HT uptake-blocker fluoxetlne (54), suggesting that it is due to the actlon of PCA on central 5-HT neurons. However, these Investigators also found that the actlvity levels return to normal within a week after drug treatment, even though braln 5-HT levels remaln depleted Similarly, KShler and co-workers found no effect of PCA on home-cage spontaneous locomotion i0 days after treatment, when forebrain 5-HT content was low (55). On the other hand, in the same study, responses of rats to a novel object introduced into the home cage and exploratory actlvity in the open field (a novel environment) were greatly decreased by PCA-treatment. Vorhees et al. found a similar reductlon in locomotor actlvity in an open field environment up to a month after PCA injectlon (56). It is difflcult to explain this trend toward decreased exploratory locomotlon assoclated with persistently decreased 5-HT levels in several braln regions. Posslbly, either partially damaged 5-HT neurons recover functlonally over several days or, more likely, postsynaptlc 5-HT receptors increase in sensitivity and other neurons not damaged by PCA may compensate to maintaln activlty at normal levels (54).

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An Important conclusion to be drawn from the studles reviewed above ~s that the effects on motor actlvlty of various manipulations of 5-HT seem to depend on the conditions and testlng procedures employed, as well as on the method of amlne depletion. Motor behavlor in a novel environment (open fleld) is not the same as that in a familiar setting (home cage), due to the Introductlon of "emot~onal" inputs such as curloslty and fear in the novel s~tuatlon. Therefore, it Is not surprising that different experlmental results have been obtained dependlng on the settlng Dihydroxytryptamlnes

(DHTs)

Studies on the effects of 5,6- and 5,7-DHT on locomotor actlvlty have also produced varied results (57-64) Intraclsternal (i c.) administration of 5,7-DHT In rats (followlng pretreatment wlth deslpramlne, DMI, to protect noreplnephrlne cells) led to marked diminution of 5-HT levels in the CNS associated wlth sllghtly increased spontaneous daytime locomotor activity measured by an electronic activity monitor in an unfamiliar cage (9) Other studies have found that chemically-lnduced degeneratlon of 5-HT neurons produces either no slgnlflcant effect on locomotlon or a reduction In actlvlty (30,57,58,60,64). As noted above, in]ectlons of 5,7-DHT into the mldbraln raphe nuclei were reported by Lorens et al. not to alter actlvlty in rats in an open fleld (30). In contrast, Hole and co-workers found that 5,7-DHT lesions of the medlal and lateral ascending 5-HT-contalnlng tracts greatly reduced motor activity in the open field (57), however, locomotion in the hone cage (where there should be few new stlmull) was not affected (58) Experiments in whlch 5,7-DHT was administered l.c. to neonatal rats (such injections depleted brain 5-HT more than in adults) indlcated that locomotor actlvlty was significantly increased at 14 days of age, but was reduced at 28 days of age when measured in activity cages (59). A similar study in which 5,6-DHT was injected i c to 5-day old rats found no alteration in locomotor actlvlty in the open fleld at later times (60) Many of these results are thus at variance wlth the simple hypothesis that lesions of 5-HT neurons and decreased availab111ty of 5-HT regularly increase motor activity under all conditions; variance from predlctlons is especlally great when presumed "emot~onal" characterlstlcs of the sltuat~on, adaptation over tlme, or the effects of maturation are consldered. The posslbllity has been suggested that lowered motor activlty in DHT-lesloned rats may reflect the influence of compensatory mechanisms over tlme (30,61). For example, axonal sproutlng and regeneration, as well as a partial recovery of bralnstem 5-HT levels have been shown to occur and could mask some behavloral effects of DHT (62,63); in addltlon, post-synaptlc adaptatlons may occur (1,9). In contrast to results with open-field or home-cage activity, data more consistent wlth a slmple motor-lncrease hypothesis have been obtained after 5-HT depletion when the behavioral paradigm was locomotor activity in a tilt-cage. While PCPA and electrolytic lesions of the median raphe nucleus have both been reported to produce hyperactivity in rats placed in tilt-cages (35-42), more recently, Mackenzie and co-workers have found that injections of 5,7-DHT into the median forebraln bundle or into the lateral ventrlcle that depleted 5-HT by up to 80% in forebrain also resulted in several-fold Increases in tilt-cage activlty, in contrast, the 5,7DHT-treated rats were hypoactlve when tested in an open field (64). These opposite effects of 5-HT depletion on two measures of locomotor activity (also found after PCPA) indicate that open-fleld tests and tilt-cages or other electronic activity monitoring devices (especially wlth a famlllar or home cage) do not measure the same aspects of locomotor behavior. Thus, central 5-HT depletion may be responslble for general hyperactivity detected

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by a tilt-cage or actmvlty monltor, but may have negligible or opposite effects on open-fleld activity associated with presumed emotional arousal. The fact that tilt-cage hyperactivity was produced by all methods of 5-HT depletion suggests that this effect is not the result of nonspeciflc damage but could be due to subnormal 5-HT synaptlc activity (Table I). TABLE I Serotonln and spontaneous motor activity in rodents Treatment

Type of Behavio ~

Effect

(Refer@nces)

Increased Serotonln TP TP

a,c a

decrease no change

(1,2) (3-6)

5-HTP 5-HTP + DDCIp

a a

decrease increase

(1,7,9) (7,8,10,11)

5-HT (CNS in3ectmon) 5-HT (CNS infusion)

a a

decrease decrease

(12,13) (14)

a,c a,c

increase increase

(29,32-35) (28-31)

a,b a c a a

increase mixed decrease decrease no change

(35,41-43) (43,44) (3) (47) (3,28,45-47)

PCA (late PCA (late) PCA (late)

a c a

increase decrease no change

(54) (55,56) (55)

DHT DHT DHT DHT

a,b a c a,c

increase mixed decrease no change

(9,58,64) (59) (57,64) (30,58,60)

Decreased Serotonln Electrolysis Electrolysis PCPA PCPA PCPA PCPA PCPA

(B8) (B7 +BS)

(acute) (acute) (acute) (repeated) (acute)

Behavlors.

a. b. c

Electronic activity monitor or tilt cage. Social, aggressive or sexual. Open-field activity.

Abbreviations:

TP 5-HTP DDCIp PCPA PCA DHT

= tryptophan = 5-hydroxytryptophan = peripheral decarboxylase inhibltor = p-chlorophenylalanine = p-chloroamphetamine = 5,6- or 5,7-dihydroxytryptamine

Another polnt of interest is that the hyperactivity following 5,7-DHT treatment occurred during both the light and dark phases of the day; however, the relative variation of activity levels was preserved in the DHT-animals,

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which contrasts with the dlsruptlon of this rhythm reported in PCPA-induced hyperactivity (3,50). AmphetamineFlnduq.edBehavlor Arousal and locomotor stimulatlon induced by amphetamine is generally believed to reflect the potentlation of CNS catecholamlne (CA) activlty by these agents (65,66) Serotonln projections may dimlnish these effects. Results of a variety of pharmacologic or leslonlng experlments consistently support the conclusion that increased availability of 5-HT inhlblts, while decreased availablllty increases, the effects of amphetamines on locomotion in rodents (see Table II) Thus, adminlstration of TP or 5-HTP prlor to damphetamine was found to antagonize the enhanced response to the stimulant in starved rats and those glven diets low in TP (67) Likewlse, amphetamineinduced locomotor activity was reduced by the intra-accumbens injection of 5-HT (68,69) or by its infuslon into the cerebral ventricles (14). Conversely, amphetamine-lnduced activlty was found to be potentiated by a TPfree diet or food deprivation, drugs proposed to antagonlze 5-HT receptors in the CNS (cyproheptadine, methysergide), and by PCPA (47,67,70-73). Simllarly, electrolytic lesions of raphe nuclei and ascendlng 5-HT pathways, as well as DHT-induced lesions have also enhanced motor responses to amphetamine (32,69,73-78). In additlon, a report on the effects of 5,6-DHT on the social behavior of mice suggests a slmilar proflle of behavioral effects (includlng inhibition of aggresslon and increased incldence of alert postures) as observed after amphetamine (79). These findings seem compatible wlth the hypothesis that 5-HT neurons might have an inhibitory actlon on CA neurons responsible for amphetamine-induced motor activity (73) and with antagonlstic roles of 5-HT and CAs in some brain functions (see ref. 80 for a re~lew). These generalizations apply to relatlvely low doses of amphetamine (less than i0 mg/kg). At high doses (I0-i00 mg/kg), amphetamines exert paradoxical effects that almost certainly reflect their ability to activate 5-HT receptors in the brain, probably by release of endogenous 5-HT, in addition to effects on CAs. Thus, high doses of amphetamine are reported to induce a complex syndrome of normal locomotion as well as abnormal motor responses, including TABLE II Serotonin and locomotion induced by low doses of amphetamlne Treatment

Actlvity ......

References

decreased decreased decreased

(67) (67-70) (14,68,69)

increased increased increased increased increased increased

(32,69,74-77) (67) (67,71) (47,67,70,72,73) (67) (73,78)

Increased Serotonin TP (to starved rats) 5-HTP (to starved rats) 5-HT (into CNS) Decreased Serotonin Electrolysis TP-free diet Food deprivation PCPA (acute) 5-HT-antagonists DHT compounds

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altered postural tone and head movements (81,82), that typlcally follows strong potentlatlon of serotonln activlty in the CNS (83-85) These actions of hlgh doses of amphetamlnes are blocked by condltlons that remove 5-HT or prevent its action, such as pretreatment wlth DHT, PCPA, or 5-HT-receptor antagonlsts (81,82) In contrast, potentlatlon of these same effects follows treatments that increase the availability of 5-HT, such as admlnistratlon of TP or of 5-HTP (81,82). In additlon, CA antagonlsts elther have not prevented these motorlc effects of amphetamine (81), or have selectlvely ellmlnated certaln features that also occur at lower doses of amphetamine and are more llkely due to release of CAs (82) Thus, the abnormal posture and movements Induced by hlgh doses of amphetamine may depend on their ability to release 5-HT as well as CAs The Serqtonln Syndrome The observatlons already revlewed, when taken together, strongly suggest a central inhlbltory role of 5-HT in spontaneous locomotor behavlor, partlcularly when animals are in thelr normal environment and are not subject to novel sensory st~mul~ or emotlonally arouslng sltuat~ons Nevertheless, the results are not entlrely consmstent w~th such an effect, and under certain condltlons 5-HT may exert stlmulatory influences on some motor behavlors. In addltlon, many recent studles have descrlbed apparent excltatory effects of 5-HT in relatlon to a complex behavIorsl syndrome (83,86-88) Thls reactlon pattern conslsts of restlng tremor (especlally of the head and forellmbs), llmb and axlal rlgldity or hypertoniclty, hindllmb abductlon, Straub (rigldly arched) tall, lateral head weavlng, rhythmlc, reclprocal dorso-ventral treadlng movements of the forelimbs; hyper-reactivity to audltory stimuli, and a variety of autonomic responses including sallvatlon, penile erection and ejaculatlon, and flushlng of the footpads, under some condltions, widespread muscle jerks or myoclonus, followed by generalized eplleptlc selzures may occur (for reviews, see 83,86,88). Such behavioral activatlon appears to be qualltatlvely dlfferent from simple arousal and locomotor actlvatlon Treatments that produce the syndrome Various aspects of thls increased behavloral actlvlty have been reported to follow the admlnlstratlon of a 5-HT precursor (such as TP or 5-HTP), in most cases in animals pre-treated wlth drugs that further increase the ava11ab111ty of 5-HT in the CNS Thus, the "hyperactivlty" has been observed in rats and guinea plgs given TP followlng an Inhlbltor of monoamlne oxldase (MAO) (89-99), thls effect is prevented if the anlmals are pretreated with PCPA (89,91) It has also been reported in gulnea pigs after 5-HTP alone (98-100) and in mice and rats followlng 5-HTP in combination with a peripheral inhlbitor of aromatlc amino acld decarboxylase (7,8,97). S1mllarly, the syndrome is seen in rodents following drugs that block the neuronal reuptake of 5-HT (e.g chlorlmlpramine, fluoxetin~, provided the animals have been pretreated wlth an MAO inhlbitor (8,101) Grahame-Smlth suggested that the hyperactlvlty is mediated by an accumulatlon and "spill-over" of 5-HT at extraneuronal sltes (89). The appearance of thls syndrome following inhlbitlon of 5-HT uptake strongly supports this view (8,101). Agents believed to stlmulate postsynaptic 5-HT receptors dlrectly, such as 5-methoxy-N,N-dimethyltryptamlne (5-MeODMT) (102) also produce thls abnormal motor response (9,84-86,90,97,99), suggestlng that actlvatlon of 5-HT receptors is involved. The flndlngs of behaviorally actlvatlng (rather than inhlbltory) effects of 5-HT on certain types of essentlally abnormal motor behavlor have been conflrmed and extended in studles with DHT compounds. In rats treated wlth intracranlal injectlons of 5,7-DHT followlng systemlc DMI, the admlnlstratlon

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of 5-HTP has conslstently produced tremor and myoclonus (muscle twltches involv~ng the entire trunk and extremlt~es) (1,9,84) Th~s behavioral supersensitivity to the 5-HT precursor d~d not occur ~n control rats g~ven 5-HTP without DHT In fact, spontaneous locomotor activity was reduced after 5-HTP •n both ~ntact and les~oned animals ~n experiments ~n which the behavior was analyzed uslng a combination of v~sual rating scales and continuous electron• c monitoring (9). The myoclon~c response to 5-MeODMT was also potentiated in 5,7-DHT animals (84,85), however, the response ~n DHT-an~mals was much more pronounced follow~ng a challenge w~th 5-HTP than w~th 5-MeODMT In addition, recent experiments in one of our laboratories (103) has demonstrated that slow, sustained ~ntraventrlcular ~nfusion of 5-HT ~n rats pretreated wlth 5,7-DHT, slm~larly, produced a dose-dependent pattern of hyperactivity, muscle twitches, myoclon~c jerking movements, postural changes and autonomlc responses. The same ~nfus~on of 5-HT ~n ~ntact anlmals produced a marked decrease in normal spontaneous actlv~tv (14) The "myoclonus syndrome" followlng 5-HTP in 5,7-DHT-anlmals appears to be speclflcally related to central 5-HT neurons it has been blocked by pretreatment wlth the putative 5-HT receptor antagonlsts cyproheptadine, methyserglde, lyserglc acld dlethylamlde (LSD), bromo-LSD, lisurlde, and others, it was also inhlblted when the converslon of 5-HTP to 5-HT was blocked wlth centrally actlve hlgh doses of a decarboxylase inhlbitor In addltlon, drugs that increase or decrease the effects of other proposed CNS neurotransmltters, such as dopamlne, norepinephrine, acetylchollne, and y-amlnobutyrlc acld (GABA), nelther reproduced the syndrome nor altered the myoclonus followlng 5-HTP (i) Recently, responses to 5-HTP have been examlned in adult rats pretreated with 5,7-DHT at postnatal day 3 to determine If the enhanced senSltlvlty to the 5-HT precursor perslsts The behavloral responses to 5-HTP were markedly and perslstently potentlated in the 5-7-DHT-treated rats, indlcating that compensatlon for the increased responslveness to 5-HT agonlsts induced by the destructlon of 5-HT flbers in the neonates dld not occur during development (104). There have been reports that PCA too can ellclt postural abnormalltles, tremor and autonomlc slgns withln minutes of its systemlc admlnlstratlon, thls syndrome appears to involve 5-HT neurons selectlvely and is slmllar to the behavlor seen followlng injectlon of 5-HTP in 5,7-DHT-lesloned rats (92,105-108) These acute effects of the drug probably involve a release of endogenous 5-HT and are not dlrectly related to its long-term neurotoxlc action (109). Thus, whlle no correlatlon was found between brain levels of 5-HT and thls "PCA syndrome," pretreatment wlth drugs that interfere with the uptake of PCA into the 5-HT nerve terminals (fluoxetine), depress braln 5-HT levels (PCPA), or block 5-HT receptors (methyserglde) suppressed the syndrome; drugs that antagonlze the effects of other neurotransmltters had no such effect, suggesting that thls acute behavloral effect of PCA is due to the release of 5-HT (105-107) The possible involvement of indoles other than 5-HT in trlggerlng motor actlvatlon in DHT-lesloned anlmals has also been invest~gated. Warbrltton et al recently found that the deamlnated indole metabolltes (5-hydroxyindoleacetlc acld (5-HIAA) and indoleacetaldehyde may be even more potent than 5-HT in produclng excitatory motor responses and myoclonus in 5,7-DHTlesloned rats. Neither of these compounds, nor 5-HT, produced the syndrome in unlesloned rats (103). These flndlngs suggest that the aldehyde and acid metabolltes of 5-HT in the CNS may not merely be ~nactlve products of 5-HT, but may be involved in the regulatlon of 5-HT neurotransmlsslon The idea that an indole other than 5-HT could ellc~t motor actlvatlon has also

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been suggested by Foldes and Costa (91) and by Marsden and Curzon (93,94) mn studies of ~ntact rats Their results ~ndlcate that ~ncreased endogenous tryptam~ne accumulation after admmnzstratmon of an MAO ~nh~b~tor plus TP may be responsible for the behavior. Hyperactlvmty was reduced and the behavioral syndrome was prevented by administration of ~nhib~tors of brain aromatic ammno acid decarboxylase which reduced the accumulation of tryptamine • n the bra~n w~thout altering levels of 5-HT or CAs (94) In addltlon, wh~le the administration of tryptammne itself provoked the full behavioral syndrome •n MAO-~nh~b~ted rats, tryptamine may act Indirectly by releasing 5-HT, or d~rectly at postsynapt~c 5-HT receptors (91-93) Specificity of t h e s y n d r o m e The speclflclty of the "5-HT syndrome" has been questloned by some investlgators who have suggested that CAs may be involved as well as 5-HT (90, 91,99) For example, Green and Grahame-Smlth have proposed that dopamlne may contrlbute to the expresslon of the syndrome, as prlor depletlon of brain dopamlne wlth ~-methyl-~-tyroslne (AMPT) prevented the usual increase in actlvlty followlng ~ 0 inhibltlon plus TP or 5-Me0DMT (90). Llkewlse, others have reported that 6-hydroxy-dopamlne (6-OHDA) abollshed the hyperactlvlty due to TP loadlng in rats (91), suggestlng that an Intact CA system is requlred for the expresslon of the behavlor. Recent studles by Slovlter and coworkers (85) do not support thls hypothesls: they found that the 5-MeODMT-induced behavior was not prevented by AMPT or by the CAreceptor blockers phenoxybenzamlne and pimozide, but was inhlblted by the putative 5-HT receptor blocker methyserglde. In addltlon, a strlklngly slmllar behavioral syndrome has been observed in rats treated wlth an MAOinhlbltor and L-dopa (85,110-112) and here, as well, the questlon of whether CA or 5-HT receptor stlmulation ms necessary has been a polnt of debate Since the behavloral response was prevented by prlor depletion of 5-HT by PCPA or 5,7-DHT as well as by methyserg~de (but not phenoxybenzam~ne or p~moz~de), the syndrome may be mediated by the release of 5-HT (85). One posslble explanation for confllctlng experlmental results obtained In studies on the "5-HT syndrome" is that methods of evaluation employed by dlfferent investlgators may have emphasized dlfferent behavloral components, for example, automated electronlc recordings of general actlvlty (90) vs observer ratings of head weaving, tremor, etc (86). Conclusions based on quantitatlve measurements of general motor actlvity assoclated wlth the syndrome may be mlsleadlng. For example, Crow and Deakin assessed the syndrome caused by MAO inhlblt~on plus TP by two methods and found that whereas qualitative manlfestatlons of the syndrome could be completely prevented by 5-HT receptor antagonlsts, "activlty" was elther unaffected or increased (113). Although actlvlty meters can probably signal the presence of the syndrome, thls method may be unsuitable for testing drugs that modify it (85) Presynaptlc basls of the syndrome Synaptlc mechanlsms leadlng to altered and apparently increased sensitlvlty to 5-HTP or to 5-MeODMT in DHT-lesioned rats as characterlzed by abnormal posture, stereotyped movements and myoclonus are unclear, however, both pre- and postsynaptlc effects may be involved. Trulson et al. hypothesized that the behavioral syndrome might in part reflect loss or impalrment of presynaptic hlgh-afflnity reuptake into 5-HT-contalnlng cells in DHT-lesloned rats, wlth little or no concomitant change in the sensitlvlty of the postsynaptlc receptor (84,114) Impairment of uptake, which is assumed to be important for inactlvation of extracellular 5-HT (115), could

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lead to some increase in the availability of exogenous 5-HT to its receptors after conversion of administered 5-HTP to 5-HT by ubiquitous decarboxylasecontaining cells other than 5-HT neurons (116). This group reported that the increase in sensitivity of 5,7-DHT-treated rats to 5-HTP is greater than to the 5-HT agonist 5 - M e O D ~ , which is believed to have a direct postsynaptic action and not to be inactivated by neuronal uptake or by MAO (117). Because of the discrepancy in potency between these agents, it is possible that the great potentiation of 5-HTP in the lesioned rats results in part from the loss of presynaptic uptake of newly formed 5-HT after destruction of the 5-HT terminals so as to increase the availability of 5-HT to the receptors. Other evidence suggests that the apparent supersensitivity which develops after treatment with 5,7-DHT may be specifically dependent on the destruction of the presynaptic nerve terminal. For example, prolonged inhibition of 5-HT synthesis with PCPA (which produced long-term depletion of brain 5-HT equal to 5,7-DHT) did not lead to supersensitivity (84,118) In additlon, the finding that prolonged blockade of 5-HT receptors with methysergide also produced no supersensitivity in rats supports this hypothesis (119), but Is inconsistent with observations In guinea pigs that repeated administration of methysergide increased a myoclonic response to 5-HTP (120), and similar suggestive results in rats pretreated repeatedly with cyproheptadine (9) There is some evidence against altered inactivation of 5-HT as the critical factor in the development of the myoclonic response. In one of our laboratories, it was found that the administration of powerful and selective blockers of 5-HT uptake, such as chlorimipramine or fluoxetine, had little ability to provoke myoclonus in the intact rat given 5-HTP unless very large doses of the uptake blockers were used (i). Moreover, increasing 5-HT levels in the CNS of intact rats up to, or above levels associated with the production of myoclonus in lesioned rats failed to produce the motor responses characteristic of DHT-lesioned animals, even when high doses of 5-HTP raised 5-HT to more than twice the levels present in 5,7-DHT rats that exhibited myoclonus (9). In addition, even high levels of 5-HT in3ected acutely or infused into the lateral ventricles of normal rats failed to induce myoclonus, although low concentrations did so in lesioned animals (103,108). In intact rodents, the myoclonic response has also been produced by systemic administration of 5-HTP or of the potent 5-HT agonist 5-MeODMT (which is not readily taken up by presynaptic terminals or degraded by MAO) (84,85) or following intracisternal 5-HT, provided that animals had been pretreated with an MAO-inhibitor (9) Postsyna~tic basis of the syndrome Impaired presynaptic metabolism of 5-HT seems unlikely to account entirely for the behavioral supersensitlvlty to a 5-HT agonist or precursor in DHT-lesloned rats. Another possibillty is one involving postsynaptic cells sensltive to 5-HT Postsynaptic indoleamine receptors mlght he altered by denervatlon induced by DHT so as to become more sensltive to 5-HT However, as noted above, 5-HT depletion or receptor blockade alone without denervatlon does not appear to be sufficient condition for the production of myoclonus (at least in rat) as this behavior was not obtained by prolonged depletion of 5-HT by repeated pretreatment with PCPA (84) or methysergide (119). Stewart et al tested the prediction that repeated injectlons of a 5-HT agonist or precursor should attenuate the development of a myoclonic response if postsynaptic receptor mechanisms are important, and found that repeated treatments with 5-HTP or 5-MeODMT inhibited the development of supersensitivity after leslonlng with 5,7-DHT (9) In addition, the fact that raising brain levels of 5-HT did not itself produce myoclonus in intact rats or mice (9, 121), whereas even small increases in 5-HT levels in lesioned animals were

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associated wlth a strlk~ng myoclon~c syndrome (103), further suggests that events at postsynapt~c receptors may be required for the development of supersensit~vlty Other evmdence suggesting activation of postsynaptlc receptors ~n the motor syndrome is that the behavior ellcited by 5-HTP, 5-MeODMT, or TP plus an ~ 0 ~nh~bltor was antagonized by methyserg~de and other 5-HT receptor blockers but not blockers of other receptors (85,99) In addlt~on, s~nce B-adrenoreceptor antagonlsts ~nh~b~ted the hyperactivity response to TP + MAO ~nh~b~tor and to 5-MeODMT C95), postsynaptlc effects of 5-HT agonlsts may be mediated ~n part by CA neurons Yet another approach ~nvolves s~ngle cell studies. Wang et al recently demonstrated that in 5,7-DHT-les~oned anmmals there was an enhanced responsiveness of cells in the lateral gen•culate nucleus and ~n the amygdala to the ~nhib~tory effect of mlcro~ontophoretically appl~ed 5-HT and LSD (122) S~nce LSD ~s not a substrate for hmgh affinlty 5-HT uptake, this suggests that the supersensltiv~ty ~s prmmar~ly of the postsynapt~c type. In response to denervatlon, changes in the afflnlty or quantlty of postsynaptic receptors mlght develop Nelson et al (123) found that Intracerebral 5,7-DHT treatment resulted in an increased number of hlgh-afflnlty blndlng sltes for 3H-5-HT in a synaptosomal fraction of the hlppocampus when 5-HT was strongly depleted, with no change in the apparent affinlty of 5-HT for its presumed receptors The idea that synthesls of postsynaptlc macromolecular receptors mlght be involved in the development of the behavioral supersensltlvlty was investigated by Sperk and co-workers (121) who found that treatment with cyclohexlmlde both decreased cerebral proteln synthesis in mlce and ~nhlblted the development of behavloral supersensltivlty to 5-HTP after 5,7-DHT-induced destructlon of the presynaptlc 5-HT neurons. Cyclohexlmlde also exerted a slmllar, though smaller, effect followlng the development of full sensitlvlty to 5-HTP over ten days Thls result suggests the posslble involvement of a physlologically actlve pool of rapidly turnlng over proteins in the development of supersensltlvlty (or a nonspec~flc toxic art~fact). Whether such active proteins are associated with the postsynapt~c 5-HT receptor remains unresolved The studles just revlewed suggest that pre- and postsynapt~c mechanlsms contribute to supersensitivity follow~ng chemical denervatlon, although their relative ~mportance remains unclear Descending exq%tatory seroton~n mechanlsms As noted above, slow intraventrlcular infuslon of 5-HT in intact anlmals decreased spontaneous locomotor actlvlty (14), in contrast, the same infuslon into 5,7-DHT-treated rats produced a "myoclonic" syndrome (103) There is as yet no satlsfactory explanation for thls seemingly paradoxlcal qualitatlve shlft in behavlor from decreased motor actlvlty to hyperactivity of skeletal muscles and autonomlc arousal. It has been suggested that ascendlng and descending 5-HT projections may have dlssimilar physlologic effects in the CNS (103). One interpretatlon of the available evidence is that inhibitory effects of 5-HT on a variety of behavlors may be medlated by ascendin$ projectlons from the mldbraln raphe nuclei (B7-B9) to llmbic and motor-lnhibitory areas of the telencephalon, whereas the excltatory or facllitatory influences on motor output might be activated via the descendin$ 5-HT projections to the lower brainstem and spinal cord from nuclel BI-B 3. On the basls of braln transectlon experlments, Jacobs and Klemfuss (124) suggested that the syndrome provoked by TP after an MAO inhlbitor is mediated by 5-HT neurons present in the pons, medulla and splnal cord It has also been reporte4 that methergollne and methysergide were effectlve in blocking those behavioral changes that appeared to be splnal in origln (Straub tail, h~nd-limb abduction, fore-

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paw treading ~nd head weaving) leavlng intact the locomotor hyperactivity (92) Similar observations were made in acutely splnallzed 5,7-DHT-pretreated rats given 5-HTP (A Campbell and R J Baldessarini, unpubllshed observatlons) Deakin and Green investigated the effects of selective destruction of spinal cord 5-HT neurons by intraspinal mlcroln3ection of 5,7-DHT on the motor syndrome ellcited by 5-MeODMT (92) 5,7-DHT admlnlstered in thls manner produced a 70% fall in cord 5-HT concentratlon wlth no effect on brain 5-HT levels. The behavloral response to systemlc 5-MeODMT was potentiated in these anlmals, suggesting agaln that the syndrome is predominantly medlated by splnal 5-HT systems It is not clear why inhlbltory behavioral effects predominate in the Intact rat given only 5-HT or 5-HTP, whereas these compounds produce behavloral excltatlon when central 5-HT pro]ectlons are lesioned or when drugs (such as MAO inhlbltors) are given that further increase 5-HT avallabillty

Conclusions Serotonergic pathways have been proposed to have an inhibltory functlon on locomotor activity in rodents Although not all studies agree on thls polnt, the bulk of the evidence indicates that in the famlliar home-cage envlronment wlth m~nimal outside sensory stimulation, and in sexual or aggresslve behavior, treatments whlch increase braln 5-HT levels (e g , 5-HT precursors or dlrect adminlstratlon of 5-HT into the CNS) tend to decrease activlty, whereas treatments that deplete 5-HT (electrolysls, PCPA, DHTs, PCA) produce hyperactlvlty. However, in a novel envlronment, where such "emotional" varlables as curlosmty and fear are presumably introduced, the results are much less clear-cut. The hlppocampus may be especlally Important in medlating effects of 5-HT on locomotlon In contrast, recent reports have described apparent excltatory effects of 5-HT in relatlon to a complex behavioral syndrome consisting of abnormal movements and tremor These responses follow treatments which increase the effectlve 5-HT concentratlon, presumably at key receptor sltes (e.g 5-HT precursors or receptor agonists following an MAO inhibltor). In addltion, animals wlth 5,7-DHT-induced leslons whlch deplete brain 5-HT show an exaggerated excitatory response to the administration of 5-HT precursors or agonlsts, posslbly due to the development of pre- and postsynaptlc supersensltlv~ty to 5-HT. Recent evldence suggests that dlfferent components of such motor behavior have dlsslmllar neurophyslologic bases We propose that Inhlbltory effects of 5-HT on spontaneous actlvlty may be medlated by ascendlng projectlons of 5-HT to forebraln, whereas excltatory influences on other motor behavlors may be actlvated by descendlng or splnal tracts Acknowledgments Thls work was supported in part by USPHS/NIMH grants and awards MB-31154, MH-34006, and MH-47370 Mrs M Cason prepared the typescrlpt.

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84 85 86 87, 88,

89. 90 91. 92 93 94 95 96 97 98. 99. I00 i01 102 103 104 105. 106. i07. 108. 109 ii0 iii. 112 113

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