Cerebrospinal fluid cholecystokinin, bombesin and somatostatin in schizophrenia and normals

Prog. Neuro-Psychopharmocol. & Biol. Psychiat. 1985, Vol. 9, pp. 73-82 Printed in Great Britain. All rights reserved.

Copyright 0

0.278-5846185 $0.00 + SO 1985 Pergamon Press Ltd.

CEREBROSPINAL FLUID CHOLECYSTOKININ, BOMBESIN AND SOMATOSTATIN IN SCHIZOPHRENIA AND NORMALS

ROBERT H. GERNER"4,

DANIEL P. VAN KAMMEN', PHILIP T. NINAN3

'Departments of Ps chiatry, Veterans Administration Medical Center and X University of California, Irvine Long Beach, California, U.S.A. 'Psychiatry Service, Veterans Administration Medical Center Highland Drive Pittsburg, Pennsylvania, U.S.A. 3Clinical Neuroscience Branch, National Institute of Mental Health Bethesda, Maryland, U.S.A. (Final form, April 1984) Abstract Kammen and Philip T. Ninan: Robert H., Daniel P. Van Gerner, Cholecystokinin, Bombesin and Somatostatin in Cerebrospinal Fluid Prog. Neuro-Psychopharmacol. & Biol. Psychiat. Schizophrenia and Normals. 1985, !J(l): 73-82. 1.

2. 3. 4. 5. 6.

Cerebrospinal fluid from 31 normals and two groups of phenomenologically similar schizophrenics (n=72) were collected by identical methods. Radioimmunoassay of CSF was carried out for somatostatin, bombesin, and cholecystokinin. One group of schizophrenics had increased baseline somatostatin and cholecystokinin, and decreased bombesin. No CSF gradient effect was found for the peptides nor were their levels affected by probenecid or pimozide treatment. An inverse correlation was found between bombesin and *psychosis rating. Intercorrelation between the peptides and HVA, 5-HIAA, and MHPG were not significant.

Keywords: cerebrospinal bombesin, probenecid, schizophrenia, somatostatin

fluid,

cholecystokinin,

peptides,

Abbreviations: bombesin (BBS); cerebrospinal fluid (CSF); cholecystokinin acetic acid (DCPAC); gamma(DA); 3,4 dihydroxyphenyl (CCK); dopamine aminobutyric acid (GABA); homovanillic acid (HVA); S-hydroxyindoleacetic acid (S-HIAA); 3-methoxy 4 hydroxyphenyl glycol (MHPG); norepinephrine (NE) Introduction Recent studies have documented the importance of neuropeptides in the modulation of behavior and neuronal activity (Krieger and Martin 1981a, however, few attempts 198lb). In contrast to the major neurotransmitters, have been made to correlate brain peptide concentrations to specific diagnostic entities. We have therefore studied the peptides somatostatin (SRIF) , bombesin (BBS), and cholecystokinin (CCK) in schizophrenia. Biochemical hypotheses regarding the pathophysiology of schizophrenia have mainly focused on aminergic systems (Berger et al, 1978). Peptidergic Research, Special Treatment ,M.D., Chief, Psychiatric Professor, 2M.D., Chief of Psychiatry Service, 3M.D.

73

Unit,

4

Associate

74

R.H. Gerner et aZ.

investigations of various peptides in schizophrenics have been minimal (Van Kammen et al, 1981). Intravenous cholecystokinin (.3ug/kg) has been reported to improve schizophrenic thought disturbance and energy (Nair et al, 1982), while beta-endorphin has been reported to have a negative (Gerner et al, 1980) or essentially no effect on schizophrenia (Berger et al, 1980). Cholecystokinin is present both peripherally and centrally. Three forms of naturally occurring CCK have been found with varying amino acid links: CCK-8, CCK-33, and CCK-39. All three forms have been identified in the mammalian The major portion of CCK in the brain, however, is CCK-8 (Dockray brain. 1978). At present, CCK constitutes the most abundant cortical peptide yet discovered, the largest concentrations being in the forebrain, specifically the cortical areas (Saito et al, 1980; Emson et al, 1980). CCK is also found in the olfactory bulb, the caudate (Saito et al, 1980) the striatum radiatum of the hippocampus, the medial amygala, the medial preoptic periventricular and lateral hypothalamic nuclei, the septum, the paraventricular gray area and the dorsal horn of the spinal cord (Saito et al, 1980; Emson et al, 1980). Unfortunately, regulation of CCK synthesis and metabolism is not well understood. Lamers et al, (1980) found that tryptophan or morphine both decreasd CCK activity in rat brain suggesting that the concentration of CCK may be modulated by a serotinergic or opiate mechanism. No effect was found following administration of naloxone, parachlorophenylalanine, alphamethylparatyrosine, tyrosine, tyrosine, L-DDPA, or clonidine. Bombesin has been more completely studied than CCK. It exists in at least two active forms; BBS-9 and BBS-14 (Walch et al, 1979). Bombesin like immunoractivity has been found in the rat brain with the highest concentrations in hypothalamus; intermediate levels in the thalamus and midbrain; low levels in the parietal cortex, striatum, hippocampus, and medulla; and very low and none in the cerebellum and pituitary, respectively (Moody and Pert. 1979, Brown et al, 1978). Injection of bombesin intracraniallv in rats lowers body temperature.(Brown et al, 1977a), suppresses feeding (Gibbs et al, 1979), suppresses gastric acid secretion (Tache et al, 1980) and produces analgesia (Brown et al, 1977b). Intravenous BBS stimulates certain endocrine factors (growth hormone and prolactin) suggesting an effect on hypothalamic function (Pearse et al, 1977). Thus, it is possible that bombesin plays a part in satiety, pain, and the central regulation of digestion, although its relationship to behavior is not clear. Somatostatin (SRIF) has numerous relationships with classic neurotransmitters. SRIF increases the turnover of norepinephrine, dopamine, and serotonin SRIF releas-e is stimulated by both (Garcia-Sevilla et al, 1978). norepineohrine and donamine (Nesro-Vilar et al. 1978: Chihara et al, 1979). and is inhibited by GABA (Gamse et al, 1980). SRIF has. analgesic effects when administrated intercerebrally (Havlicek et al, 1977) and has partial agonist activity at the opiate receptor (Terenius, 1976). SRIF has been previously diagnoses known to be altered in patients with numerous neurological including multiple sclerosis (Sorensen et al, 1980, senile dementia, (Oran et al, 1981) Parkinson's disease (DuPont et al, 1982) and Huntington dementia (Schroter 1981). examines the relationship This study 2) neuroleptic treatment; Schizophrenia; cerebrospinal fluid (CSF).

BBS and SRIF to: of CCK, and 3) other neurochemicals

1) in

Methods First phase study. Cerebrospinal fluid was obtained by lumbar puncture from thirty-one normals and nineteen schizophrenics at the University of California from all subjects. Written informed consent was obtained All (UC). schizophrenics had been ill for more than six months and had undifferiented schizophrenia. Diagnosis was made by a research diagnostic criteria (Spitzer Patients were rated for illness using a modiefied Bunneyet al, 1975). Hamburg Scale for psychosis (Bunney and Hamburg 1963). All lumbar punctures

75

CSF CCK in schizophrenia and normals

preformed between 8 to 9 a.m. after the subjects were fasted overnight andmaintainedina medication free state for aminimum of seven days and free of neuroleptics for at least fourteen days. The fifteenth through twentysixth milliliter of cerebrospinal fluid were chilled immediately on wet ice and stored within one hour -80°C. All samples were measured using previously cited methodology (Gerner and Yamada 1982). Unextracted CSF was used for assay. The assays for the 3 peptides produce an intra-and inter-assay variation of 10%.

were

Cerebrospinal fluid (CSF) was obtained fox 53 Second phase study. schizophrenics hospitalized at the schizophrenia clinical research unit at the National Institutes of Health (NIH) and two additional normals from UC using All samples were stored continuously at -75O C except the same methodology. when shipped in dry ice. This NIH group had 26 males and 27 females; age range 78 to 55; days drug-free: 14 to 77 for drug-free samples. Diagnosis was 13 were paranoid, 23 All patients had chronic schizophrenia: by RDC. undifferentiated, 12 schizoaffective, 1 catatonic, and 4 disorganized. Eight of these patients were reexamined after 14 to 64 days while receiving 2 to 20 mg/day of the neuroleptic pimozide; and 7 after receiving a probenecid LP (Ebert et al, 1980) to determine if the acid-based transport system is involved in excreting peptides from the CSF. CSF from 9 of the first group of patients was examined to evaluate a cephaladcaudal gradient for peptides by comparing aliquots from the Ist-12th cc, 15th-26th, and 26th-30th cc. Lastly, in order to further explore the relationship of these three peptides to other important neurotransmitters, CSF-peptide levels in the UC group were compared to vaLues for total protein, beta-endorphin (Gerner and Sharp, 1982), HVA, 5-HIAA, MHPG, Tyrosine, Tryptophan (Gerner et al, 19841, GABA (Gerner and Hare, 1981), and cortisol (Gerner and Wilkins, 1983). Patient (UC) height, weight, age, and sex were also correlated with peptide levels. Statistical appropriate.

analysis

was

by ANOVA,

Pearson's

correlation,and

t-test

as

Results CSF peptides in Normals and Two Medication-Free Schizophrenic Groups The two groups of patients were considered separately in analyses since the groups were tested and assayed separately. Figure 1 shows the values of SRIF, BBS,and CCK for the normals, UC schizophrenics, and NIH schizophrenics. Both groups (UC - 30.2k1.77 fmol/ml; NIH - 26.3k1.88 fmollml) had lower levels of BBS than the normals (34.4*1.64 fmol/ml, although this was significant (pc.01) only for the NIH group. CCX was elevated in both patient groups (UC! 19.11*4.15 fmol/ml; NIH 40.2k1.73 fmol/ml) compared to normals (12.42k1.93 fmol/ml), but again the difference was significant only for the NIH group (p<.OOl). Further, schizophrenics from the NIH group also had significantly higher CCK than the UC schizophrenics (pc -001). SRIF was elevated in the NIB group (25.8k 1.26 fmol/ml) compared to normals (15.211.24 fmol/ml) (p<.OOl)and to the UC schizophrenic group (14.7kl.63 fmol/mY.) (p< .OOl). Effect of the neuroleptic, pimozide, on CSF SRIF, BBS and CCK Paired t-test showed no significant change during drug treatment. While the n for BBS was too small to test statistically, one subject's level decreased and the other was unchanged. (Fig. 2). Effect of Probenecid on CSF Peptides Probenecid effect could only be tested statistically for the SRIF group and was not significant. Figure 3 shows nonsystematic changes for all 3 peptides in the few patients studied with probenecid.

76

R.H.

Gerner

@t

al.

Lack of Gradient for CSF Peptides A gradient effect was not found for anv of the three wewtides (fiaure 4). when carried out on aliquots A, B, & C, nor-when A and C w&-e compa;ed*sepa&'tely.

CSF PEPTIDES IN NORMALS AND TWO MEDICATIONFREE SCHIZOPHRENIC GROUPS (MEAN AND SD.1

EFFECT

r

~matostatin

OF PIMOZIDE

ON CSF

Bombesin

PEPTIDES

Ch~cysiukinin

50-

*P< .ot *us P < .OOl

N=8

N= 2

40.

10-

N=S

O-

NI S S UC NIH

UC

UC

NIH

Nili

Fig.1.

Significant difference for NIH schizophrenics were found from normals and University of California sehizophrenics for somatostatin and cholecystokinin.

EFFECT

OF PROBENECID ON CSF PEPTIDES

Somotostotin

LACK

OF GRADIENT

FOR CSF PEPTIDES

Cholecystoklnln

&Imbesln

Bomb&n

NZ2

Cholecystohinin

r

A-

40- /

;ld T

‘i

kz$

E 20. 2

Fig. 2. No consistent effect was found on the CSF peptides in sam,ples obtained before and during treatment with the neuroleptic pimozide.

30-

~~

Ns3

10 GfOUQ mecn sx.:

B?-K&& 68

10

Bi-%&“ecid

Bk--%&necti

48

48

5

6

Fig. 3. No systematic effect was found on the CSF peptides before and after receiving probeneeid.

Fig. 4. CSF peptides did not demmonstrate cephalad-caudal concentration gradient. A=? --I 2cc; B=15-2Gcc; C=26-3Occ.

Correlational analyses for UC subjects with all CSF parameters are shown in Table 1. Two correlations were significant for the schizophrenics: BBS wi.th psychosis (r- -.59, p < .05) and BBS with SRIF (r=,64, p <.05), whil.e 4 were significant for the normals: Tryptophan with SRIF (r-.57, p <.Ol); and with BBS (r=.38, p ~-05); and CCX with B-Ep (r=.97, p <.QOlt and with cortisol (r=.49, p c.05).

77

CSF CCK in schizophrenia and normals

Table 1 Significant correlations with CSF Peptides in Schizophrenia (S, n=13) and Normals (N, n=29) SRIF Psychosis Rating

.Ol

BBS

. 64(S)a

Tryptotphan

.57(N)b

BBS

CCK

-.59(S)a

.38(N)a

Beta-Endorphin

.97(N)c

Cortisol

.49(N)a a=p .05; b= .Ol; c= .OOl (Pearson's correlation)

No significant correlations were found between SRIF, BBS, CCK, and parameters of sex, height, weight, age or CSF, HVA, 5-HIAA, Tyrosine, GABA, 5-MHPG, Cortisol, or total protein. Discussion These investigations offer significant but preliminary information regarding peptide relationships to schizophrenic and normal brain function. Utilizing identical methodology with two similar populations of schizophrenics is unique to most clinical studies and offers an opportunity to interpret the results in a more sophisticated manner. These two groups of schizophrenics were similar in age and sub-type of illness, but varied to some extent in their CSF peptide levels. A common finding for both schizophrenic groups was a decrease of BBS compared to normals. The increased significance of.the NIH group (pc.01) compared to the UC group reflects in part the higher number of the former, since their standard deviation was even greater than the UC group. To a lesser extent, CCK showed a similar relationship, with more significance and a smaller standard deviation in the NIH group being due in part to the larger number of that group. The increased SRIF in the NIH group is not similar to the UC patient group, however. A reason for this is not clear. While sampling and storage methodologies were virtually identical for the two assay time. The NIH group was qroups, one aspect of the study did differ: assayed separately. However, the standard curves were valid and similar for both assay times. Two additional normals (female age 29, male age 28) were also run with the NIH group. Their values for BBS and SRIF were similar to the earlier normal group, but increased for CCK (Table 2). This second small group of mormals confirms the first SRIF and BBS normal group results, but suggests that interpretation of the CCK values must be made cautiously. Both norepinephrine and dopamine (Chihara et al, 1979) stimulate release of SRIF. The finding of elevated SRIF in the NIH schizophrenic group is thus consistent with both a NE (Lake et al, 1980) and DA hypothesis of schizophrenia. However, t% lack of correlation of SRIl?with the NE or DA metabolite, MHPG and BV& respectively suggest that a simple associationis not part of schizophrenia pathophysioloqy. SRIF has been shown to densely innervate the amyqdala (Palkovits et al, 1982), a structure linked to basic emotional states and hallucinatory phenomena. SRIF inhibits stress-induced growth hormone release (Terry et al, 1976) and although the mechanism is unknown, such a relationship of SRIF to stress may be associated with psychotic development.

R.H. Gerneret al.

78

Table 2 CSF normal values in two assays SRIF Normal Group I

( SEM) n=29

Normal Group II n=2

fmolfml BBS

CCK

14.9+1.28

34.4k1.76

10.08+1.11

14.6-25.1

33-35

45.6-40.0

Group I was assayed with the University of California schizophrenic group and Group II with the NIH patients. GABA inhibits SRIF release (Gamse et al, 1980). Thus, the observed high SRIF is consistant with low GABA hypothesis of schizophrenia (Van Kammen, 1977: Garbutt and Van Kammen, 1981), but the NIH group has reported decreased GABA only in good premorbid and recently ill schizophrenics (Van Kammen et al, 1982). A trend for a negative correlation of SRIF with psychosis rating (UC group) also suggests an intrinsic relationship to the illness. However,the lack of correlation of CSF, GABA, and SRIF (UC group) is not supportive. Therefore, an intrinsic relationship of GABA and SRIF to schizophrenia remains controversial. The low but significant correlation of SRIF with tryptophan and BBS are intriguing but await confirmation and physiological explanation. A CNS relationship may exist since peripherally administered SRIF does inhibit BBS induced gastric secretion (Varner, et al, 1981). The lack of correlation of SRIF with the serotonin metabolite 5-HIAA is somewhat surprising since SRIF increases release of serotonin (Tanaka and Tsujimoto, 1981) and we therefore expected a positive SRIF-5-HIAA correlation. Decreased serotonin (measured byits metabolite 5-HIAA) has been hypothesized to be associated with schizophrenia by a few investigators (Bowers et al, 1969; Ashcroft et al, 1966). Our findings of increased SRIF is thus not consistent with a serotonin hypothesis. Decreased BBS is the most consistent finding in the schizophrenics compared to normals. Specific relationship to the illness is supported by the significant negative correlation with the level of psychosis. Unfortunately BBS is less well understood than SRIF or CCK. BBS has no behavioral effects when given IV to rats (Brown et al, 1977a,b) or man (Basso et al, 1975; varner et al, 1981; Morley et a1,1980). However, these studies are inconclusive While it is a potent since BBS doesn't cross the blood-brain barrier well. stimulator of gastric acid secretion, intravenous human infusion produces no changes in growth hormone, prolactin, thyroid stimulating hormone, luteinizing hormone, or follicle stimulating hormone (Morley et a1,1980). Intracerebral decreased feeding, injection in rats does produce behavioral changes; analgesia, and lower body temperature. These effects, possibly mediated by a hypothalamic effect of BBS suggest that BBS may be a potent modulator of important neural systems. However, our correlational analysis did not reveal implicated neurotransmitters in a specific relationship to previously schizophrenia such as dopamine, norepinephrine, serotonin, or GABA. Thus, the BBS relationship to schizophrenia and to level of psychosis requires further study. The finding of elevated CCK are particularly provocative because of the association of CCK and dopamine. A CCK-like peptide has been found within a subpopulation of dopamine neurons in both rat (A-9, A-10) and man (nucleus accumbens and tuberuculum olfactorium) suggesting an effect of the peptide on CCK fragments can inhibit dopamine dopamine neurons (Hokfelt et al, 1980)

79

CSF CCK in schizophrenia and nomads

release in these mesofimbic areas and thus may be an endogenous modulator of dopamine mediated neurotransmission with the postulated site of action being A preliminary study has shown that i.v. at the presynaptic auto receptor. CCK-8 given to rats produces catalepsy in a dose dependent manner that was slightly less potent than haloperidol (zetler, 1981). Similar to haloperidol, CCK-8 antagonized methamphetamine effects in the CCK also reduced sterotypy. rat (Katsura and Itoh, 1982). These studies suggested that CCK may have a functional antidopaminergic effect. One can speculate that CCK might therefore be important in affective disorders where dopaminergic stimulation may produce mania (Gerner et al, 19761, Hokfelt et al, 1980) has postulated that CCK may be implicated in schizophrenia or manic psychosis through its regufation of dopamine. CCK has been shown to produce increased fixing of DA neuron in the rat (Skirboll et a1,3981) but this does not necessarily imply that CCK would increase To the contrary, Nair et al, 1982, DA and therefore worsen schizophrenia, 1983) have reported that CCK (.3mgfkg) given as a single i-v. infusion produced a long acting antipsychotic effect. But others have not found this to be true. The significant correlation of CCK with CSF beta-endorphin normals stand now as isolated findings.

and cortisol

in

Recent computerized tomographic scan findings of brain atrophy in schizophrenia has been associated with decreased CSF, dopamine, beta hydroxylase and homovanillic acid levels (Van Kammen et al, 39831, and with decreased 5-HIAA, NE, DOPAC (Van Kammen 8 Linnoila unpublished data, 19831. However, these peptides described above were not decreased in the patients with brain atrophy (Van Kammen, et al, in preparation). All three peptides SRIF, BBS, and CCK are peptides with apparent CNS activity and are located in regions of the brain known to be important in regulating behavior. The CSF findings reviewed here provide preliminary support for a role of each in schizophrenia: increased SRIF and CCK, and decreased BBS. However, inconsistancies of results in the two separate patient groups suggest that caution is indicated in interpreting these results. The positive correlations with other CSF constituents and behavioral rating suggest further work with these compounds may be fruitful. Conclusion We conclude that alterations of central peptides may occur in some schizophrenics, with possible increased somatostatin, cholecystokinin, and decreased bombesin. No correlations were found with MHPG, HVA, or 5-HIAA. Acknowledgement The authors gratefully acknowledge assistance in statistical analysis provided by Dr. L. Fairbanks, UCLA and CSF assays by Drs. T. Yamada at Universityof Michigan, Ann Arbor; D.J. Cohen, G.M. Anderson,J.G. Young, B.A. Shaywitz at Yale; and M. Linnoila and M. Scheinin at NIMH. This work was supported in part by USPHS Grant RR-05756, CRCRR-865, MH 28343, MHCRCM 30929, CCRC RR125, NICHD HD-03008, MH 17691, AM 17328, AM 26268, and Veterans Administration research fund, References ASHCROFT, G.W., ~AW~ORD, T.T.B., ECCLESTON, D. (1966) 5-hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet 2:1049-1050.

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BASSO, N., GIR1, S., IMPORTA, G., LEXOCHE, E., MELCHIORRI, P., and SPERANZA, V. (1975) External pancreatic secretion after bombesin infusion in man. Gut 16:994-998. BEEER, P.A., ELLIOTT, G.R., and BARCHAS, J.D. (1978) Neuroregulators and Schizophrenia. In: Psychopharmacology: A generation of Progress, M.A. Lipton, A. DiMascio, K.F. Killam (eds), pp 1071-1082. Raven Press, New York. BERGER, P.A., WATSON, S.J., AKIL, H., ELLIOTT, G.R., RUBIN, R.T., PFEFFERBAUM, A DAVIS K-L., BARCHAS, J.D., LI, C.H. (1980) B-Endorphin and Schizophrenia. Arch. Gen. Psychiat. 37:635-640. BOWERS, M. B., HENmR, R., GERBODE, F. (1969) Cerebrospinal fluid Shydroxyindole acetic acid and homovanillic acid in psychiatric patients. International Journal Neuro pharm. g: 255-262. BROWN, M., ALLEN, R., VALLARREAL, RIVIER, J., and VALE, W. (1978) Bombesinlike activity: radioimmunologic assessment in biological tissues. Life Sci. 23: 2721-2728. BRAN, M., RIVIER, J., and VALE, W. (1977a) Bombesin: potent effects on thermoregufation in the rat. Science. 196:998-1000. BROWN, M-R., RIVIER, J., and VALE, W-W. (lmb) Bombesin affects in central nervous system to produce hyperglycemia in rats. Life Sci. 21: 1729-1734. BUNNEY, W. E. and HAMBURG, D. A., (1963) Methods for reliable longitudinal observation of behavior: development of a method for systematic observation of emotional behavior on psychiatric wards. Axch. Gen. Psychiat.17: 280-294. CHIHARA, K., ARIMURA, A., and SCHALLY, A. V. (1979) Effect of intraventricular injection of dopamine, norepinephrine, acetylcholine, and 5-hydroxytryptamine on immunoreactive somatostatin release into rat hypophyseal portal blood. Endocrinology* 104: 1656-1662. COLONNA, L., PETRIX, M., and LEPINE, J. p. (1979) Bromocriptone in affective disorders. Journal of Affective Disorders. 1: 173-177. COSTA, E. and TRABUCCHI, M. (1982) Regulatory Peptides: From Molecular Biology to Function, Raven Press, New York. Cholecystokinin-like peptides in brain. In: Gut DOCKRAY, G. J. (1978) Hormones, Bloom, S. R. and Grossman, M. I_ (eds), pp 530-553. Churchhill Livingstone Press, New York. DUPONT, E., CHRISTENSEN, S. E., HANSEN, A. P., DE FINE OLIVARIUS, B., and ORSKOV, H. (1982) Low cerebrospinal fluid somatostin in Parkinson Disease: An irreversible abnormality. Neurology. 32: 312-314. EBFRT, M. H., KARTZINEL, R., GOODWIN, F. K. (1980) Cerebrospinal Fluid Clinic Metabolites and the Probenecid Test. In: Neurobiology of Cerebrospinal Fluid, WOOD, J. H. (ed), pp 97-112. Plenum Press, New York. N., FAHRENKRUG, J. EMSON, P. C., HUNT, S. P., REHRELD, J. F., GOLTERMAN, Cholecystokinin and vasoactive intestinal polypeptide in the (1980) mammalian CNS: distribution and possible physiological roles, In: Neural Peptides and Neuronal Communication, Costa, E. and Trabucchi, M. (eds), pp. 63-74. Raven Press, New York. GAMSE, R., VACCARO, D. E., GAMSE, G., BIPACE, M., FOX, T. O., and LEEMAN, S. E. (1980) Release of immunoreactive somatostatin from hypothalamic cells in culture: Inhibition by gamma-aminobutyric acid. Proc. Natl. Acad. Sci. USA 118 No. 9, pp. 5552-5556. GARBUTT, J. C., and VAN KAMMEN, D. P. (1983) The Interaction Between GABA and Dopamine: Implications for Schizophrenia. Schizophrenia Bulletin, Vol.& No. 3,: 336-353. GARCIA-SEVILLA, J., MAGNUSSON, T., CARLSSON, A. Effect of (1978) intracerebroventricularly administered somatostatin on brain monoamine turnover. Brain Res. 155: 159-164. GERNER, R. H., CATLIN, D.., GORELICK, D. A., HUI, K. K., LI, c. w. (1980) B-Endorphin. Arch. Gen. Psychiat.37:642-647. GERNER, R. H., FAIRBANK, L., ANDERSON, G. M., YOUNG, J. G., SCHEININ, M., LINNOILA, M., COHEN, D. J., HARE, T-A., SHAYWITZ, B.A. (in Press) Cerebraspinal Fluid Neurochemistry in Depressed, Manic and Schizophrenic Patients Compared to Normal Controls, American J. Psychiatry. GERNER, R. H., AND HARE, T.A. (1981) CSF GABA in normals, depression, schizophrenia, mania and anorexia nervosa. American Journal Psychiat. 138: 1098-1101. GERNER, R. H., POST, R. M., and BUNNEY, W. E. (1976) A dopaminergic mechanism

CSF CCK in schizophrenia and normals

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