Prop. Neum-Psychophormocol. f? Bid. Psychiot. 1988, Vol. 12, pp. S157-Sl64 Printed in Great Britain. All rights reserved

027~5948/89 $0.09 + .50 copyright gI 1999 Pergamon Press plc

SUBSTANCE P INVOLVED IN MENTAL DISORDERS

KOJI TAKEDCRI, MASAYLJKI DEMATSU, MA!MIRO OFDJI, HIKIYA WRIKIYO and HISArmBU KAIYA

DEPARThENT OF NEDROUJGY ARD PSYCRIATRY, GIFD DNIYERSITY SCRGOL OF MEDICINE, GIFD, JAPAN

(Final fom, June 1988)

Contents

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2: 2: 7.

Abstract Introduction Anatomy of SP Physiology of SP Effects of Antipsychotic Drugs on SP SP in Mental Disorders Baclofeu in the Treatment of Mental Disorders Conclusions References

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Abstract

Takeuchi, Koji, hasayuki Uematsu, hasahiro Oftiji, Mikiya Morikiyo and Hisanobu Kaiya: Substance P involved in mental disorders. Prog. Neuro-Psychophamacol. 6 Biol. Psychiat. 1988, 12(Supple) :S157-S164 -

1. This review clarifies the involvement of substance P (SP) in mental disorders especially schizophrenia. One of the main SP pathways in the brain is the striate- nigral pathway. SP applied in the substantia nigra activates the nigro-striatal dopamine system.

2. Administration of antipsychotic drugs decreased SP concentration in the substantia nigra. Some post mortem studies of schizophrenic patients showed elevated SP concentratiou in some brain regions. Effects of baclofen, a SP antagonist, on schizophrenic patients are uncertain.

3. SP lay be involved in the pathophysiology of schizophrenia.

Keywords : antipsychotic drug, baclofen, post mortem study, schizophrenia, substance P

Abbreviations: acetylcholine (Ach), central nervous systea (CNS), dopamine (DA), gaua- anmotmtyric acid (GABA), substance P (SP), ventral tegmental area (VTA)

1. Introduction

The physiological properties of the neurotransmitter and/or neuroaodulator of

substance P (SP), a neuropeptide consisting of eleven amino acids, have been studied.

This peptide is possibly involved in the pathophysiology of some mental disorders,

especially schizophrenia. This review clarifies such involvement of SP.

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2. Anatomy of SP

It is well established that the substantia nigra contains the highest concentration of

SP in the rat brain. The hypothalaams, spinal cord, caudate nucleus, olfactory tubercle

and frontal cortex also coutain s-hat lower levels of the peptide (Gilbert and Eusou

1979). Many SP pathways have already been shown in the central nervous system (CNS).

Table 1 shows some of these identified SP pathways. In addition to Table 1, the pathways

frou brain stem nuclei to the spinal cord also have been deuonstrated (Nicoll et al.

1988). liany SP interneurons also have been identified in the cerebral cortex (Ljungdahl

et al. 1978).

Table 1

Substance P Pathways in Central Nervous System

origin --+ temination

1. caudate-putaxen --, substantia nigra(pars reticulata) (Kanaxawa et al. 1977)

2. globus pallidus + substautia nigra(pars reticulata) (Kanazawa et al. 1977)

3. septum + hippocaupus (Vincent and McGeer, 1981)

4. amygdala --, hypothalamus (Sakanaka et al. 1981)

5. aedial habenular nucleus --, interpeduncular uucleus (Hong et al. 1976)

---, ventral tegmental area (Cue110 and Kanaxawa, 1978)

6. lateral dorsal tegmental nucleus + frontal cortex (Vincent et al. 1983)

3. Physiology of SP

The striato-nigral pathway contains SP and gauma-aminobutyric acid (CABA) as an

excitatory and inhibitory transmitter, respectively. (Fig 1.) The highest concentration

of both of these transaitters was found in the pars reticulata of the substautia nigra.

SP neurons were seen uainly in the oral part of the striatun, while CABA neurons were

located in the caadal part (Brownstein et al. 1977). An ultrahistocherical study on the

rat striatuu revealed SP imwnoreactivity in fnsiforu or ovoid mediuu-sized neurons

which were thought to have long axons. The uediuu-sized neuron was also observed to be

cholinoceptive and to be oue of the haloperidol binding sites in the striate (Kaiya and

Nanba 1982).

A strong relationship between the striato-nigral SP systen and nigro-striatal dopaaine

(DA) system is suggested. Indeed, intranigrally applicated SP increases the release of

newly synthesized sH-DA (Cheramy et al. 1977) and increases the tnruover of DA in the

ipsilateral caudate nucleus (J-es and Starr 1979). Nigral application of antibodies

against SP reverses this synthesis (Cherauy et al. 1978). SP infusion into the

Substance P involved in mental disorders s159

snbstantia nigra produces a strong increase in stereotyped rearing and sniffing, this

effect is blocked in 6-hydroxydopamine candate lesioned rats (Kelley and Iversen 1979).

Thns, the striato-nigral SP neurons exert a tonic facilitator-y inflwnce on the activity

of the nigro-striatal dopaminergic nenrons. Conversely, striato-nigral SP is activated

through the nigro-striatal DA system. Indeed, the enhancement of DA activity with

repeated administrations of methamphetamine, an indirect DA agonist, increases the SP-

like immmoreactivity in the substantia nigra (Ritter et al. 1984).

The ventral tegmental area (VTA), the origin of the aeso-limbic and meso-frontal DA

systems, receives SP projections from the medial habennlar nncleus (Cue110 and Ranaxaua

1978). A microinjection of SP into the VTA of rats produces a &se-related increase in

spontaneons motor activity (Kalivas 1985). This result indicates that SP can activate DA

nenrons in this area in the same manner as in the substantia nigra.

Mesencephalic Dopamine Cell Group

hg 1. Anatomical relationship between nigro-striatal DA system and striatnm

In several regions of the CRS, SP coexists with several other nenrotransmitters in the

same neurons, i.e. SP is found in nenrons containing serotonin (in raphe nnclens and reticular formation of mednlla), and cholecystokinin (in central gray) (Chan-Palay 1979, Skirboll 1982). It is also demonstrated that SP has a very similar distribution to that

of DA in the prefrontal cortex &son 1978).

S160 K. Takeuchi et al.

4. Effects of Antipsychotic Drugs on SP

Many authors have studied the effects of antipsychotic drugs on SP concentration in

the CNS. An acute injection of haloperidol @q/kg, i.p.) did not alter SP-like

iznunoreactivity in the rat brain, but chronic treatment for two weeks decreased it by

40% in the substantia nigra, but not in the striatum and the hypothalamus (Hong et al.

1978). A decrease in SP level in the substantia nigra was also seen after injections of

pimozide (l.hsg/kg, i.p., 2 weeks) (Hong et al. 1978) and fluphenazine (5mg/kg, i-p., 2

weeks) (Hanson et al. 1981), but neither clozapine (lOmg/kg, i.p., 2 weeks) (Hong et al.

1978) nor sulpiride (8Omg/kg, i.p., 10 days) (Hanson et al. 1981) altered the level of

SP in this region. According to Hong et a1.(1978), this change, the decreaese in the SP

concentration in the substantia nigra, was possibly caused by the increased turnover of

SP induced by the removal of dopaminergic tonic inhibition following the injection of a

DA receptor blocker. The SP level in the forebrain was increased 90 min after injection

of haloperidol (0.2mg/kg, i.p.), with the amount of this change being more than the

lag/kg i.p. treatment (Janiclci et al. 1981). The results of this acute treatment study

are thought to be caused by the change of the release of SP at the presynaptic membrane

rather than the change of synthesis or metabolism of SP following the administration of

haloperidol. SP concentration in the striatum was increased by the chronic treatment of

lithium and was decreased by treatment of amphetamine, and both these effects were

prevented by coadministration with haloperidol (Hong et al. 1983, Pettibone et al.

1978). The relationship between SP and DA receptor was also investigated. SP reduced the

specific binding of SH-spiroperidol by 50% in the striatum in vivo (Czlonkowski et al.

1978). Involvement of the D2 dopamine receptor in the neuroleptic-induced decrease in

nigral SP was suggested by Oblin et al. (1984)

5. SP in Mental Disorders

The above-mentioned evidence implies the possibility of a close interaction between SP

and DA in the CNS. It is generally recognized that the DA system plays some critical

roles in biochemical dysfuuctions in major psychosis, especially in schizophrenia. In

the brain of the patients with schizophrenia, hyperfunction of SP is also inferred.

Rim6n et al. (1984) found that the CSF level of SP was significantly higher in patients

with depressive disorders than in controls. However, a following study could not

reproduce their findings (Berretini et al. 1985). The former authors reported elevated

SP levels in the CSF in schizophrenic patients but without any statistical significance

(Rim6n et al. 1984). Kaiya et al. (1981) found that untreated schizophrenic patients did

not have any differences in the level of plasma SP-like imunoreactivity to that of

normal controls. However, after more than one year of treatment with antipsychotic

drugs, the patients showed significantly higher plasma SP levels than controls.

post mortem brain tissue from patients with mental disorders including schizophrenia

has been studied for neurochemical analysis, but these studies showed inconsistent

Substance P involved in mental disorders S161

results. Cue110 et al. (1977) found no abnormality in the irmmoreactive SP content in

the globns pallidus, the substantia nigra or the amygdala of post mortem schizophrenic

patients. Zech and Rogerts (1985) examined SP immmoreactivity in the basal ganglia of untreated schizophrenics, using the peroxidase-antiperoxidase method, but they failed to

show any detectable alteration or destruction of SP containing structures. Kleinman et al. (1985) found no significant differences in SP concentration in any brain regions of

schizophrenic patients, but it was increased in the caudate nucleus in some patients with psychosis other than schizophrenia. Crow and his colleagues have measured the concentrations of several centrally active neuropeptides in the brain regions of

schizophrenics and controls (Roberts et al. 1983). They showed a significant increase in

SP concentration in the hippocampus of schizophrenics as compared to controls. Toru and

his colleagues found that SP was significantly increased in the substantia nigra, the

globus pallidus pars externa, the lateral nucleus of the thalamus and the centromedian

nucleus of the thalamus of medicated schizophrenic patients, and it was also increased in the orbitofrontal cortex of both medicated and nonmedicated schizophrenic patients

(Ichikawa et al. 1984). A recent report of Toru et a1.(1986) revealed that SP was significantly increased in the orbitofrontal cortex, the anterior portion of the

pyriform cortex, the insular cortex and the cornu Anmtonis of the hippocampus of

schizophrenic patients.

The increased level of SP immunoreactivity in some brain regions, especially in the

substantia nigra, of schizophrenic patients will have a significant implication for the

DA hyperactivity hypothesis in schizophrenia. Indeed, Ichikawa et al. (1984) showed a

positive correlation between the immunoreactivity of SP and tyrosine hydroxylase activity or homovanillic acid content in the brain stem and the basal ganglia of

schizophrenic and control brains.

6. Raclofen in the Treatment of Mental Disorders

Reports that intranigrally applied SP increases turnover of DA neuron and chronic

treatment with haloperidol decreases SP levels in the substantia nigra support the DA

hypothesis of schizophrenia. Thus, it is speculated that the antagonist of SP may have a

positive effect on schizophrenia. Administration of baclofen, a CARA analogue and an

antagonist of SP, showed remarkable improvement in the treatment of chronic schizophrenic patients (Frederiksen et al. 1975). However, subsequent studies have

demonstrated no change or even exacerbation (Simpson et al. 1976, Yamauchi et al. 1977). Tardive dyskinesia and tardive dystonia are late-onset neurologic complications of

neuroleptic medication, and some authors found an improvement in such complications,

using baclofen (Stewart et al. 1982, Rosse et al. 1986). However, the mechanism of how it functions is still unclear.

7. Conclusions

The data referred to above do not clearly show a relationship between SP and mental

S162 K. Takeuchi et al.

disorders, but suggest that SP is involved in the pathophysiology of schizophrenia.

Further investigations, e.g. using the animal models of psychosis, need to be carried

out in order to assess more clearly the involvement of SP in mental disorders.

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Inquiries and reprints requests should be addressed to:

Dr. Koji Takeuchi Department of Neurology and Psychiatry Gifu University School of Medicine 40 Tsukasamachi Gifu 500 Japan