Quantitative Auto Radio Graphic Mapping of Serotonin Receptors in the Rat Brain

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Brain Research, 346 (1985) 205 - 230 205Elsevier

BRE 11091

Research Reports

Quan t i ta t ive Au toradiographic M apping o f Serotonin Receptors in the Rat Bra in .

I . Serotonin-1 R eceptors

A. PAZOS and J. M. PALACIOS

Preclinical Research, Sa ndo z Ltd., CH -4002 Basel (Switzer/and)

(Accepted January 15th, 1985)

Key words: [3H]serotonin - - serotonin-1 receptor subtype - - quantitative autoradiography - -hippocampus -- basal ganglion - - choroid plexus - - substantia nigra - - septal nucleus

The distribution of serotonin-1 (5-HT 0 receptors in the rat brain was studied by light microscopic quantitative autoradiography.Receptors were labeled with [3H]serotonin (5-[3H]HT), 8-hydroxy-2-[N-dipropylamino-3H]tetralin 8-OH-[aH]DPAT), [3H]LSD and[3H]mesulergine, and the densities quantified by microdensitometry with the aid of a computer-assisted image-analysis system. Com-petition experiments for 5-[3H]HT binding by several serotonin-1 agonists led to the identification of brain areas enriched in each oneof the three subtypes of 5-HT1 recognition sites already described (5-HT1A, 5-HT m, 5-HTlc . The existence of these 'selective' areasallowed a detailed pharmacological characterization of these sites to be made in a more precise manner than has been attained in mem-brane-binding studies. While 5-[3HINT labeled with nanomolar affinity all the 5-HT 1 subtypes, the other 3H-labeled ligands labeledselectively 5-HT1A (8-OH-[aH]DPAT), 5-HTIc ([3H]mesulergine) and both of them ([3H]LSD). Very high concentrations of 5-HT1receptors were localized in the choroid plexus, lateroseptal nucleus, globus pallidus and ventral pallidum, dentate gyms, dorsal subi-culum, olivary pretectal nucleus, substantia nigra, reticular and external layer of the entorhinal cortex. The different fields of the hip-pocampus (CA rCA4), some nuclei of the amygdaloid complex, the hypothalamic nuclei and the dorsal raph6, among others, alsopresented high concentrations of sites. Areas containing intermediate densities of 5-HT 1 receptors included the claustrum, olfactory

tubercle, accumbens, central grey and lateral cerebellar nucleus. The nucleus caudate-putamen and the cortex, at the different levelsstudied, presented receptor densities ranging from intermediate to low. Finally, in other brain areas -- pons, medulla, spinal cord - -only low or very low concentrations of 5-HT1receptors were found. From the areas strongly enriched in 5-HT 1sites, dentate gyrus andseptal nucleus contained 5-HTIA sites, while globus pallidus, dorsal subiculum, substantia nigra and olivary pretectal nucleus were en-riched in 5-HT m. The sites in the choroid plexus, which presented the highest density of receptors in the rat bra in, were of the 5-HTlcsubtype. The distribution of 5-HT 1 receptors reported here is discussed in correlation with the distribution of serotoninergic neuronsand fibers, the related anatomical pathways and the effects which appear to be mediated by these sites.

INTRODUCTION

Pharmacological, electrophysiological and bio-

chemical findings have revealed the existence of mul-

tiple brain serotonin (5-HT) recognition sitesl,90. On

the basis of the results ob tain ed in bindin g studies in

rat brain, Peroutka and Snyderl09 classified these

sites as 5-HT 1, labe led by 5-[3H]HT with high affini ty

and 5-HT2, which are recog nized with high affinity by

[3H]spiperone. [3H]LSD labels both recepto r sites.

The possibility of the existence of different sub-

types of 5-HTl-b indi ng sites has received considera-

ble support in the recent years. Some serotoninergic

agonists, such as the piperidin yl indole RU 24 969 (5-

methoxy-3-[1,2,3,6-tetrahydro-4-pyridinil] lH-in-

dole) 4° and the 8- OH -D PA T (8-hydroxy-2-[n-dipro-

pylamino]tetralin)55 present Hill coefficients lower

than 1 when displacing 5-[3H]HT binding in the rat

br ain cort ex 54,57,81. In a sim ila r way, the ne uro le pt ic

spiperone and some fl-blockers also inhibit 5-[3H]HT

binding in a biphasic ma nn er (refs. 80, 86, 105, and

Engel et al., in preparation). These results suggested

the presen ce of two subtypes of 5-HT~ sites, 5-HTIA

and 5-HT m, corresponding respectively to the high-

Correspondence: J. M. Palacios, Preclinical Research, Sandoz Ltd., CH-4002 Basel, Switzerland.

0006-8993/85/$03.30 © 1985 Elsevier Science Publishers B.V. (Biomedical Division)



206

a n d t h e l o w - a f f in i t y s i te s o f s p i p e r o n e - a n d 8 - O H -

D P A T - c o m p e t i t i o n c u r v e s 10 5. R e c e n t l y , w e h a v e

chara c te r i zed 1°3 a n ew type of 5- [3H ]HT -binding s i t e ,

m a i n l y l o c a l i z e d i n t h e m a m m a l i a n c h o r o i d p l e x u s

a n d w h i c h i s n o t r e c o g n i z e d w i t h h i g h a f f in i t y b y t h e

5 - H T IA o r 5 - H T m ' s e le c t i v e ' c o m p o u n d s d e s c r i b e d

a b o v e , n a m e l y R U 2 4 9 6 9 , 8 - O H - D P A T , s p i p e r o n e

a n d f i - b l o c k e r s , b u t i t i s l a b e l e d b y n a n o m o l a r c o n -

c e n t r a t i o n s o f [ 3 H ] L S D a s w e l l a s b y t h e s e r o t o n i n - 2

l igand [3H]mesule rg ine22. W e ha ve n am ed th i s s i t e 5-

H T Ic 103.

C o n s i d e r a b l e e f f o r t s a r e b e i n g m a d e i n a t t e m p t s t o

es tab l i sh fun c t iona l c or re la t es fo r 5- H T 1 s i te s . A l ink

o f 5 - H T 1 s it e s t o a 5 - H T - s e n s i t i v e a d e n y l a t e c y c l a se

has been the subjec t o f mu ch d i scuss ion ( re fs . 17 , 42 ,

88 , 107; s ee re f . 106 for a rev iew) . In a s imi la r way,

c o n t r a d i c to r y re s u lt s h a v e b e e n r e p o r t e d o n t h e p r o -

p o s e d m e d i a t i o n o f t h e d o g b a s i la r a r t e r y c o n t r a c t i o n

by 5- H T 1 sitesSSA0s.

A g o o d c o r r e l a ti o n h as b e e n f o u n d b e t w e e n t h e 5 -

HT1 a f f in i ti e s of s evera l d rugs a nd the i r e f fec t s in

mo dels of pr esy na pt ic 5- H T receptors38,48, 73, a l -

t h o u g h s o m e d i s c r e p a n c i e s b e t w e e n t h e a c t i v i t i e s o f

t h e d r u g s i n t h e ' p r e s y n a p t i c ' t e s t a n d i n t h e b i n d i n g

assay have a r i s en ( s ee re f . 44 for a d i s cus s ion) . I t has

b e e n s u g g e s t e d t h a t t h e s e d i s c r e p a n c i e s m i g h t r e f l e c t

t h e e x i s t e n c e o f t h e d i f f e r e n t s u b t y p e s o f 5 - H T 1 r e c -

o g n i t i o n s i t e s . I t h a s a l s o b e e n r e p o r t e d t h a t t h e ' 5 -

H T s y n d r o m e ' , a b e h a v i o r a l s y n d r o m e c o n s is ti n g o f

s e v e r a l c o m p l e x m o t o r r e f l e x e s , i s m e d i a t e d b y 5 -

HT~ s i tes69. I n a d d i t i o n t o 5 - H T i t se l f a n d s o m e 5 - H T

p r e c u r s o r s , t h is s y n d r o m e i s a l so p r o d u c e d b y 8 - O H -

D P A T 127 and blo ck ed by som e fl -blockers53A 27. Fur-

t h e r m o r e , b o t h 5 - H T a g o ni st s R U 2 4 9 6 9 a n d 8 - O H -

D P A T a p p e a r t o p r o d u c e c i r c l i n g b e h a v i o r i n r a t s

with s t r ia ta l lesions15,57 . The pa r t i c ipa t ion of the d i f -

f e r e n t s u b t y p e s o f 5 - H T 1 r e c e p t o r s i n t h e s e e f f e c t s is

n o t c l e a r a t t h e p r e s e n t t i m e ( s e e D i s c u ss i o n ) .

T h e k n o w l e d g e o f t h e a n a t o m i c a l d i s t r i b u t io n o f

t h e s e 5 - H T 1 s it e s in t h e b r a i n c o n s t i t u t e s a n i m p o r -t a n t r e q u i r e m e n t i n o r d e r t o b e t t e r c h a r a c t e r i z e th e s e

s it e s. I t w o u l d a l l o w ( 1 ) t h e d e t a i l e d p h a r m a c o l o g i c a l

c h a r a c t e r i z a t i o n o f t h e d i f f e r e n t s u b t y p e s o f 5 - H T 1

r e c e p t o r s , b y a n a l y z i n g t h e b i n d i n g o f 5 - [ 3 H ] H T i n

a r e a s e n r i c h e d i n o n e s u b t y p e , a n d ( 2 ) t h e c o r r e l a -

t i o n o f r e c e p t o r d e n s i t ie s i n d i f f e r e n t b r a in a r e a s w i t h

t h e p h y s i o l o g i c a l a c t i v i t i e s p r o p o s e d t o b e m e d i a t e d

by 5-H T 1 s i t es , c l a r i fy ing the i r func t iona l s ignif i -

c a n c e . I n t h i s r e g a r d , q u a n t i t a t i v e a u t o r a d i o g r a p h i c

t e c h n i q u e s p r o v i d e , b e s i d e s a h i g h l e v e l o f a n a t o m -

i c a l r e s o l u t i o n , t h e a d e q u a t e e s t i m a t i o n o f r e c e p t o r

dens i t i e s and a f f in i t ie s26,95,1°1.

A u t o r a d i o g r a p h i c v i s u a l i z a t i o n o f 5 - H T I s i t e s i n

t h e c e n t r a l n e r v o u s s y s te m h a s b e e n c a r r i e d o u t u s i n g

5-[3H]HT14, ~38 an d [3H]LSD75 as l igand s . A t te m pt s to

a n a l y z e s e p a r a t e l y t h e d i s t r ib u t i o n o f 5 -H T ~A a n d 5 -

H T m s i t e s h a v e b e e n r e c e n t l y r e p o r t e d u s i n g 5 -

[ 3H ]H T 3 4 a n d 8 - O H - [ 3 H ] D P A T T L W e h a v e d e m o n -

s t r a t e d t h e p r e s e n c e o f 5 - H T ~ c si te s i n th e r a t c h o r o i d

p l e x u s 25. W e r e p o r t h e r e a d e t a i l e d m a p p i n g o f t h e

s e r o t o n i n - 1 r e c e p t o r s i n t h e r a t b r a i n , u s i n g 5 -

[ 3 H ] H T , [ 3H ] L S D , 8 - O H - [ 3 H ] D P A T a n d [ 3 H ]m e s u -

le rg ine as l igands , and ana lyz ing the d i s t r ibu t ion of

t h e t h r e e s u b t y p e s t h r o u g h o u t t h e d i f f e r e n t b r a i n

a reas .

MATERIALS AND METHODS

R a t s ( m a l e , W i s t a r , 1 8 0 - 2 5 0 g ) w e r e s a c r i f i c e d b y

i n t r a c a r d i a l p e r f u s i o n w i t h p h o s p h a t e - b u f f e r e d s a -

l i n e c o n t a i n i n g 0 . 1 % f o r m a l i n , a f t e r p e n t o b a r b i t a l

a n e s t h e s ia ( 5 0 m g / k g ) . T h e b r a i n s w e r e r e m o v e d a n d

f rozen in l iqu id n i t rogen . 10 ~ tm th ick t i s sue sec t ions

w e r e c u t u s i n g a m i c r o t o m e - c r y o s t a t ( L e i t z 1 7 2 0 ,

f r o m L e it z , W e t z l a r , F . R . G . ) m o u n t e d o n t o g e la t in -

c o a t e d m i c r o s c o p e s l i d e s a n d s t o r e d a t - 2 0 ° C u n t i l

used .

I n c u b a t i o n c o n d i t i o n s f o r e a c h 3 H - l a b e l e d l i g a n d ,

i n c lu d i n g b u f f e r s o l u t i o n , c o n c e n t r a t i o n o f l ig a n d , i n -

c u b a t io n t i m e a n d e x p o s u r e t i m e a r e s u m m a r i z e d in

T a b l e I . B l a n k s w e r e g e n e r a t e d b y c o i n c u b a t i o n w i th

1 p M L S D i n t h e c a s e o f 5 - [ 3 H ] H T a n d w i t h 1 0 0 n M 5 -

H T f o r t h e o t h e r 3 H - l a b e l e d l i g a n d s . I n c o m p e t i t i o n

s t u d ie s , c o n s e c u t i v e t i s su e s e c t i o n s w e r e i n c u b a t e d i n

t h e p r e s e n c e o f i n c r e a s i n g c o n c e n t r a t i o n s o f d i s p la c -

ers .

T h e b i n d i n g o f t h e d i f f e r e n t 3 H - l a b e l e d l i g a n d s

u s e d , 5 - H T , L S D , 8 - O H - D P A T a n d m e s u l e r g i n e , t os li d e m o u n t e d b r a i n r a t s e c t i o n s h a s b e e n a l r e a d y k i -

n e t i ca l l y c h a r a c t e r i z e d , t h e s a t u r a t i o n p a r a m e t e r s

and incub a t ion pro ced ure s be ing de f in ed 14,72,

74,75,102,138. T h e co nd itio ns de fin ed in th es e stud ies

w e r e u s e d i n t h e p r e s e n t w o r k , w i t h s li g h t m o d i f i c a -

t ions .

A f t e r t h e w a s h i n g p e r i o d , t i s s u e s w e r e d r i e d w i t h

c o l d a i r a n d a u t o r a d i o g r a m s w e r e g e n e r a t e d b y a p -



207

TABLE I

Incubation conditions used for the labeling o f 5- HT 1 receptors

Ligand [Ligand] Preincubation Bu ffer

(nM ) pro toco l

Incubation Washing Expo sure

temperature time proto col t ime

5-[3HIHT 2

8-OH-[3H]-

D PAT 2

[3H]LSD 5

[3H]-

Mesulergine 5

30 min at room 0.17M Tris-temperature, HCL-4 mMin incubation CaCI2-buffer 0.01% ascorbic

acid (pH 7.6)

same as above same s above

5 min at room 0.17 M Tris-temperature, HCI--4mMin incubation CaCI2-0.01%buffer ascorbic acid-(-pargyline) 0.15 M NaCl-

10 ~M pargyline(pn 7.6)

15 rain at room 0.17M Tris-HCltemperature, (pH 7.7)in incubationbuffer

room temp. 60 min 1 x 5 min 60 days(4 °C)



room temp. 2 h 2 x 10 min 30 days(4 °C)

posing the labeled tissue to [3H]Ultrofilm (LKB,

Sweden) as descri bed b y Unne rsta ll et al. 130. Brain

grey and white matter standards, containing known

amounts of a non-volatile 3H-labeled compound

were eXposed to the film along with the labeled tissue

sections95. Films were analyzed using a comp uteriz ed

image-analysis system which provides values of re-

ceptor densities expressed in fmol/mg protein95. Four

to six bilateral measurements were made per nucleus

and the level described in each animal and the mean

value was calculated. Values of 'specific binding' for

each rat were obtained by subtracting the non-specif-

ic binding from the total value. The mean value from

equivalent areas in different animals was calculated.

Results reported in this study are from at least two

separate experiments for each 3H-labeled ligand, in-

volving tissues from 3 animals per experiment .

Percent occupancy of receptor sites by the differ-

ent 3H-labeled ligands was estimated according to

the equation:

% occupancy = 100 L / ( L + K d ( l + I / K i ) )

where L = concentration of radioactive ligand; K d =

equilibrium dissociation constant; I = concentration

of unlabeled drug, and K i = inhibition constant of un-

labeled drug.

Brain nuclei were identified and named using the

rat brain atlas o f Paxinos and Watso n 100. Cortical

areas were name d according to Krieg60,61.

5-[3H]HT (26.8 Ci/mmol) and [3H]LSD (69.3

Ci/mmol) were obtained from New England Nucle-

ar, Dreieich, F.R.G. [3H]Mesulergine (85 Ci/mmol)

was synthesized and labeled by Dr. R. Voges of the

Biopharmaceutical Department, Sandoz Ltd. (Basle,

Switzerland). 8-OH-[3H]DPAT (105 Ci/mmol) was

obtained from CEA, Saclay (France). Other sub-

stances were either purchased or kindly provided by

the original manufacturers.

RESULTS

P h a r m a c o l o g i c a l c h a r a c t e r iz a t io n o f 5 -H T 1 b i n d i n g

t o s o m e b r a i n a r e a s

The p harm acolo gy of the bindin g of the 5-HT1 3H-

labeled ligands was analyzed by quantitative autora-

diography in several brain areas showing relevant

densities of autoradiographic grains. The competi-



20 8

A

Q

1 0 9 8 7 6 5

- L o g . F M ]

B

'°°V° i /

5 0 ~

! / , , , , , , ,1 1 1 0 9 8 7 6 5

- L o g [M]

1 0 01 ~

° i l50

1 0 9 8

- L o g

5

Fig. 1. Compe tition curves for 5-[3H]HTbinding to the dentategyrus of the h ippocamp us (A), dorsal subiculum (B) and cho-roid plexus (C), measured by quantitative autoradiography.Curves correspond to (-)21 009 (©), RU-2 4 969 (O), 8-OH -DPA T (Or), LSD ('#), mesulergine (13) and spipero ne (O ).

t i o n p r o f i l e f o r 5 - [ 3 H ] H T b i n d i n g o f s e v e r a l d r u g s i n -

c l u d i n g ' s e l e c t iv e ' 5 - H T t a g o n i s ts a n d s e r o t o n i n e r g i c

a n t a g o n i s t s, w a s s t u d i e d . T h e a n a l y s is o f th e c o m p e -

t i t ion curv es , som e of them show n in F ig . 1 , as we l l a s

th e K i v a l u e s o b t a i n e d f o r t h e d i f f e r e n t d r u g s ( T a b l e

I I ) r e v e a l e d t h e p r e s e n c e o f t h r e e t y p e s o f 5 - [ 3 H ] H T

b i n d i n g s i te s , w i t h d i f f e r e n t p h a r m a c o l o g i c a l p r o p -

e r t ie s . 5 - [ 3 H ] H T b in d i n g t o t h e d e n t a t e g y r u s o f th e

h i p p o c a m p u s w a s i n h i b i t e d w i t h n a n o m o l a r a f f i n i t y

b y 8 - O H - D P A T , L S D , R U 2 4 9 69 a n d t h e f l - b lo c k e r

( - ) 2 1 0 0 9 ( 4 [ t e r - b u t y l - a m i n o - 2 - h y d r o x y p r o p o x y ] i n -

d o l - 2 - c a r b o n i c a c i d i s o p r o p y l e s t e r ) , w h i l e t h e o t h e r

c o m p o u n d s u s e d s h o w e d l o w t o v e r y lo w a f f i n it y f o r

these b inding s i t e s (F igs . 1A, 2-5 , 7 and 8 , and Table

1I) . In cont ras t , 5 - [3H]H T binding to the d orsa l subi -

c u l u m w a s d i s p l a c ed w i t h n a n o m o l a r a f f i n i t y b y R U

2 4 9 6 9 a n d ( - ) 2 1 0 0 9. W h i l e L S D s h o w e d a n i n t e r -

m e d i a t e a f f i n i ty f o r t h e s e s i te s , t h e o t h e r d r u g s t e s t e d

i n h i b i t e d 5 - [ 3 H ] H T b i n d i n g t o t h i s a r e a w i t h l o w o r

very low a f f in i ty (F igs . 1B , 2 , 3 , 5 and 8 , and Table

1 I) . F i n a ll y , in t h e c h o r o i d p l e x u s , o n l y L S D , m e s u -

l e r g in e a n d m i a n s e r i n r e c o g n i z e d t h e b i n d i n g o f 5-

[ 3 H ] H T w i th h i g h a f fi n i ty (F i g s. 1 C , 3 - 5 , 7 - 9 , a n d

T a b l e I I ) .

A c c o r d i n g t o t h e d e f i n i t i o n o f t h e d i f f e r e n t s u b -

t y p es o f 5 - H T r r e c o g n i t i o n s i te s a l re a d y m e n t i o n e d ,

a n d t o t h e a f f in i t ie s p r e s e n t e d b y t h e ' s u b t y p e - s e l e c -

t ive ' l igands , 5- [3 H]H T s i t es in the d ent a te gy rus cor -

r e s p o n d t o t h e 5 - H T t A s u b t y p e , w h i l e t h o s e i n t h e

dorsa l subiculum exhib i t t he charac te r i s t i c s of 5-

H T 1 B s it e s. T h e p h a r m a c o l o g y o f 5 - [ 3 H ] H T b i n d i n g

t o t h e c h o r o i d p l e x u s i s c l o s e l y c o m p a r a b l e t o t h a t

p r e s e n t e d b y 5 - H T I c s i t e s , a s d e f i n e d i n m e m b r a n e -

b inding s tudies (Table I I I ) .

I n a d d i t i o n t o t h e s e t h r e e a n a t o m i c a l a r e a s , o t h e r

r a t b r a i n n u c l e i p r e s e n t e d a s im i l a r e n r i c h m e n t i n o n e

o r t h e o t h e r s u b t y p e o f 5- HT ~ s i te s . T a b l e I I s u m m a -

r i z e s t h e K , v a l u e s o f d i f f e r e n t c o m p o u n d s f o r 5 -

[ 3 H ] H T b in d i n g i n t h e a r e a s a l r e a d y d e s c r i b e d , a s

wel l a s in o the rs . A c lose cor re la t ion ex i s t s be tween

K i va lues for the d i f fe rent drugs in the dorsa l subicu-

lum, g lobus pa l l idus and subs tan t i a n igra (Table I I ) .

O n t h e o t h e r h a n d , K i v a l u e s f o u n d i n d e n t a t e g y r u s ,

s t r a tu m o r i e n s o f t h e C A j f i e ld o f t h e h i p p o c a m p u s

a n d l a t e r o s e p t a l n u c l e u s a r e a l so v e r y s i m i l ar ( T a b l e

I I ) . T h i s p h a r m a c o l o g i c a l c h a r a c t e r i z a t i o n d e m o n -

s t r at e s t h e e x i s t e n c e o f t h e t h r e e s u b t y p e s o f 5 - H T t -

recogn i t ion s i te s in d i f fe r ent nuc le i of the ra t b ra in . In



2 0 9

T A B L E I I

Affinities (K~ t o f several drugs fo r 5[3H]HT binding to rat brain areas measured by quantitative autoradiography

Drug Brain area

Dorsal Globus Substantia nigra Lateral septal Dentate CA 1 ield Choroidsubiculum pallidus (re tic ul ar ) nucleus (dorsal) gyrus hippocampus plexu s

LSD 29.9 25.2 44.9 ND 3.6 7.2 4.1R U 24 969 1.5 0.6 3.5 9.0 5.4 10.2 130.28-O H-D PA T >3000 >3000 >5000 19.2 4.8 11.4 >4000(-) 21 009 0.6 1.7 0.9 6.0 7.2 48.1 >4000Mesulergine >5000 >3000 ND ND > 1000 >3000 11.8Spiperone >3000 >3000 >300 0 N D 359.3 209.6 710.1Ketanserin 1796.4 >1000 >1000 ND 598.8 >1000 354.0Mianserin 143.7 ND 2 ND ND 269.5 ND 13.6Cinanserin >3000 >5000 ND >5000 >2000 ND 2000(+ ) Propranolol 149.7 173.7 ND ND 257.5 509.0 >5000Pirenperone >5000 >5000 ND >2000 >5000 ND 1000

1 nM .

2 N ot determined.

c o n t r a st t o t h e s e a r e a s , w h e r e a p r e d o m i n a n t p r e s -

e n c e o f o n e s u b t y p e w a s f o u n d , i n m a n y o t h e r b r a i n

n u c l e i, t h e e x i s t e n c e o f s e v e r a l s u b t y p e s o f 5 -

[ 3 H ] H T - b i n d in g si te s w a s d e m o n s t r a t e d . A n e x a m p l e

o f t h e s e a r e a s i s t h e n e o c o r t e x . I n t h e l a m i n a I V o f

t h e f r o n t o p a r i e t a l s o m a t o s e n s o r y c o r t e x , b i p h a s i c

c o m p e t i t i o n c u r v e s w e r e o b t a i n e d w i t h s e ve r a l d r u g s

( n o t s h o w n ) .

A s im i l a r p h a r m a c o l o g i c a l c h a r a c t e r i z a t i o n w a s

c a r r i e d o u t i n t h e s a m e a r e a s f o r t h e o t h e r 3 H - l a b e l e d

l i g an d s . W h i l e [ 3 H ] m e s u l e r g i n e l a b e l e d s i te s in t h e

c h o r o i d p l e x u s w i t h t h e c h a r a c t e r i s ti c s o f 5 - H T l c -

b i n d in g s it es , b i n d i n g o f 8 - O H - [ a H ] D P A T t o t h e d e n -

t a t e g y r u s a n d t o t h e l a t e r o s e p t a l n u c l e u s d i s p l a y e d

t h e p r o p e r t i e s o f 5 - H T 1A s it es . F i n a l l y , [ 3 H ] L S D l a -

b e l e d w i t h h i g h a f f i n i t y , a r e a s e n r i c h e d i n b o t h 5 -

T A B L E I I I

Comparison o f the affinities o f several drugs fo r 5-[3H]HT bind-

ing in rat choroid plex us (autoradiographic studies) and in pig

choroid plexus (binding assays)

Drug Binding 1 A utoradiography

K i (nM) g i (nM)

LSD 4.8 4.1RU 24 969 165.1 130.28- O H - D PA T > 5000 > 4000(-) 21 009 2120.6 >4000Me sulergine 5.2 11.8Spiperone >2000 710.1Ketanserin 155.0 354.0Mianserin 12.6 13.6Cinanserin 1676.2 2000

1 Taken from ref. 103.

H T I A a n d 5 - H T 1 c ( n o t s h o w n ) .

I t m u s t b e p o i n t e d o u t t h a t , i n a d d i t io n t o 5 -H T 1 A

a n d 5 - H T l c [ 3 H ] L S D la b e l e d 5 - H T 2 a n d d o p a m i n e r -

g i c r e c e p t o r s , a s i t h a s b e e n a l r e a d y r e p o r t e d . S i m i -

l a r l y , [ 3 H ] m e s u l e r g i n e , a s i d e f r o m l a b e l i n g 5 - H T I c

s it es , a l s o l a b e l e d 5 - H T z r e c e p t o r s . A l l t h e s e b i n d i n g

s i t e s w e r e n o t d i s p l a c e d b y 1 0 0 n M 5 - H T , c o n c e n t r a -

t i o n u s e d t o d e f i n e n o n - s p e c i f i c b i n d i n g .

D i s t r i b u t io n o f 5 - H T 1 r e c e p to r s i n r a t b r ai n

I n t h e f o l l o w i n g , t h e d e t a i l e d d i s t r ib u t i o n o f 5 - H T 1

s it e s in t h e r a t b r a i n is a n a l y z e d . 5 - [ 3 H ] H T b i n d i n g

w a s m e a s u r e d i n al l t h e a r e a s s t u d i e d . I n s o m e s e -

l e c t e d n u c l e i , [ 3 H ] L S D a n d [ 3 H ] m e s u l e r g i n e b i n d i n g

w e r e a l s o q u a n t i f i e d . I n a d d i t i o n , b i n d i n g o f 8 - O H -

[ 3 H ] D P A T w a s q u a l i ta t i v e l y e v a l u a t e d i n s e v e r a l

s t r u c t u r e s .

I n o r d e r t o d e t e r m i n e t h e p r e s e n c e o f t h e d i f f e re n t

s u b t y p e s o f 5 - H T 1 s it e s in e a c h b r a i n a r e a , w e c o m -

b i n e d t h e m a x i m a l d e n s i ti e s o b t a i n e d u s i n g t h e 3 H - l a-

b e l e d l i g a n d s , w i t h d a t a f r o m d i s p l a c e m e n t e x p e r i -

m e n t s . F o r t h a t , t h e i n h i b i ti o n o f 5 - [ 3 H ] H T b i n d i n g

i n d u c e d b y 1 0 n M ( - ) 21 0 0 9 a n d 1 0 n M 8 - O H - D P A T

w a s q u a n t i f i e d i n e a c h a r e a . T h e p e r c e n t i n h i b i t i o n

p r o d u c e d b y t h es e c o n c e n t r a t i o n s o f b o t h c o m p o u n d s

i n s o m e a r e a s p r e v i o u s l y d e f i n e d a s ' s e l e c t i v e l y ' e n -

r i c h e d i n 5 -H T x A , 5 - H T m a n d 5 - H T l c s i t e s w e r e a n a -

l y z e d a n d , f r o m t h e s e d a t a , t h e i n t e r v a l f o r th e i n h i b i -

t i o n o f 5 - [ 3 H ] H T b i n d i n g i n t h e t h r e e p o p u l a t i o n s w a s

c a l c u l a t e d ( T a b l e I V ) . P e r c e n t i n h i b i t i o n v a l u e s i n

a r e as p r e s e n t in g m o r e t h a n o n e s u b t y p e o f 5 - H T 1 s it e



210

T A B L E I V

Inh ib i tion o f 5 -[3H]HT b ind ing by ( - ) 21 009 and 8-O H- DP A T

in different brain areas

A rea % 5 - [ 3 H ] H T % 5 - [ 3 H ] H T

binding in the binding in the

p r e se n c e o f l O n M p r e s en c e o f l O n M

( - ) 2 1 0 0 9 8 - O H - D P A T

5-HTIA sites

D e n t a t e

g y r u s 7 1 . 1 1 6 . 3

C A 1 ( o r i e n s ) 7 1 . 9 3 2 . 3

L a t e r a l

s e p t a l

n u c l e u s

( d o r s a l ) 7 9 . 6 4 2 . 7

M e a n +

S . E . M . 7 4 . 2 + 2 . 7 3 0 . 4 + 7 . 8

(95%confidence

limits) (68.8 - 79.6 ( 14.8 46.4)

5-H T18 sitesDorsal

subiculum 26.3 100.0Globus

pallidus 36.3 100.0Substantia

nigra(reticular) 29.5 77.4

Mean +S.E .M . 30 .7 ___ 3.0 92.5 + 7.7

(95%confidencelimits) (24.7-36.7) (77.1-100)

5-HTlcsitesChoroid plexus

(lateralventricle ) 90.3 88.5

Choroid plexus(thirdventricle ) 91.0 100.0

Choroid plexus(fourthventricle ) 76.1 94.7

Mean +S.E.M. 85.8 + 4.9 94.4 + 3.4

(95%confidencelimits) (76.0- 95.6) (87.6-100)

m a g i v e n p r o p o r t i o n , c o u l d b e a l s o o b t a i n e d . I n t h is

w a y , t h e p r e s e n c e o f 5- HT 1 A , 5 - H T l a a n d 5 - H T 1 c

s i te s in e a c h b r a i n a r e a w a s p r e d i c t e d .

W e h a v e a r b i t r a r i l y d e s i g n a t e d a r e a s w i t h ' v e r y

h i g h ' d e n s i t y o f 5 - H T 1 s i te s , a s t h o s e p r e s e n t i n g m a x -

i m a l d e n s i ti e s o f b i n d i n g a b o v e 2 7 0 0 f m o l / m g p r o t e -

i n , w h e n l a b e l e d w i t h 5 - [ 3 H ] H T . H i g h d e n s i t i e s w e r e

b e t w e e n 2 1 0 0 a n d 2 7 0 0 f m o l / m g p r o t e in . I n t e r m e -

d i a t e l e v e l s o f s i t e s w e r e b e t w e e n 1 2 00 a n d 2 1 0 0

f m o l / m g p r o t e in . L o w d e n s i t y a r e a s w e r e b e t w e e n

4 0 0 a n d 1 2 00 f m o l / m g p r o te i n . A r e a s p r e s e n t i n g d e n -

s i ti e s b e l o w 4 0 0 w e r e c o n s i d e r e d a s ' v e r y l o w ' a r e a s .

T h e v a l u e s o f t h e s e d e n s i t i e s fo r t h e i n d i v i d u a l b r a i n

a r e a s a r e l i s t e d i n T a b l e V . V a l u e s c o r r e s p o n d t o

m a x i m a l d e n s i t i e s o f r e c e p t o r s , o b t a i n e d f r o m t h e

p e r c e n t o c c u p a n c i e s , w h i c h w e r e c a l c u l a t e d a s p r e -

v i o u s l y d e s c r i b e d . T h e d i s t r i b u t i o n o f th e s e r e c e p t o r s

i s i l l u s t r a t e d i n t h e p h o t o g r a p h i c a t l a s p r e s e n t e d i n

F i g s . 2 - 1 0 . T h e r e a d e r i s r e f e r r e d t o t h e t a b l e a n d

f i g u r e s f o r f u r t h e r d e t a i l s.

Olfactory system. T h e e x t e r n a l p l e x i f o r m l a y e r o f

t h e o l f a c t o r y b u l b , a n t e r i o r o l f a c t o r y n u c l e u s , o l f a c -

t o r y t u b e r c l e a n d p i r i f o r m c o r t e x ( a r e a 5 1 b ) p r e s e n -

t e d i n t e r m e d i a t e c o n c e n t r a t i o n s o f 5 - H T 1 s i te s , w h i l e

i n t h e i n t e r n a l g r a n u l a r l a y e r o f t h e b u l b , a s o m e w h a t

l o w e r d e n s i ty o f s i t es w a s f o u n d . T h e p i r i f o r m c o r t e x ,

o l f a c t o r y t u b e r c l e a n d a n t e r i o r o l f a c t o r y n u c l e u s a p -

p e a r e d t o c o n t a i n t h e t h r e e s u b t y p e s o f 5 -H T 1 r e c e p -

t o r s . I n c o n t r a s t , t h e e x t e r n a l p l e x i f o r m l a y e r w a s e n -

r i c h e d i n 5- HT 1 A s it e s a n d t h e i n t e r n a l g r a n u l a r l a y e r

c o n t a i n e d p r e d o m i n a n t l y 5 - H T I B s i te s ( T a b l e V a n d

F ig s. 3 - 6 a n d 7 A - C ) .

Amygdala. T h e d i f f e re n t n u c l e i o f t h e a m y g d a l o i d

c o m p l e x p r e s e n t e d a n i m p o r t a n t c o n c e n t r a t i o n o f

a u t o r a d i o g r a p h i c g r a i n s . I n t h e p o s t e r o m e d i a l a n d

a n t e r i o r c o r t i c a l n u c l e i , h i g h d e n s i t i e s o f 5 - H T 1 r e -

c e p t o r s w e r e f o u n d . T h e o t h e r n u c l e i sh o w e d i n t e r -

m e d i a t e c o n c e n t r a t i o n o f si te s . A l l t h e se a m y g d a l o i d

n u c le i w e r e m a i n l y e n r i c h e d i n 5 - H T m - r e c o g n i t i o n

s i te s (T a b l e V a n d F i g s . 4 , 5 a n d 7 D - F ) .

Septal region. T h e l a t e r o s e p t a l n u c l e u s p r e s e n t e d

v e r y h i g h c o n c e n t r a t i o n s o f 5 - H T 1 r e c e p t o r s , t h e m a -

j o r i t y b e i n g o f t h e 5 - H T I A c la s s . T h e b e d n u c l e u s o f

t h e s t r i a t e r m i n a l i s c o n t a i n e d a n i n t e r m e d i a t e d e n s i t y

o f s p e c i fi c b i n d i n g ( T a b l e V a n d F i g s . 3 , 6 D - F a n d

7 A - C ) .

Basal ganglia. I n t h e b a s a l g a n g l i a , v e r y h i g h c o n -

c e n t r a t i o n s o f 5 - H T 1 si t e s w e r e p r e s e n t i n t h e g l o b u s

p a l li d u s a n d v e n t r a l p a ll i d u m . W h i l e t h e e n t o p e d u n -

c u l a r n u cl e u s p r e s e n t e d a h i g h d e n s i t y o f a u t o r a d i o -

g r a p h i c g r a i n s , t h e n u c l e u s a c c u m b e n s a n d t h e c a u -

d a t e - p u t a m e n o n l y c o n t a i n e d i n t e r m e d i a t e c o n c e n -

t r a t i o n s o f sp e c i f i c b i n d i n g . M o s t o f t h e b i n d i n g f o u n d



TABLE V

Maximal densit ies o f 5-H T1 receptors in the rat brain

211

Are a Specific binding (fmo l/mg protein)

5-[3H]HT

Mean + S.E.M. % binding

in th e presence

o f 1 0 n M(-)21009

% binding

in the presence

o f l O n M8 - O H - D P A T

[3H] L S D [3H] M esulergine

(mean+ S.E.M . ) (mean+_S.E.M. )8-OI'tPH1-

D P A T

(qualitative)

Olfactory system

External plexiform

layer of the

olfactory bulb

Internal granular

layer of the

olfactory bulb

Anterior olfactory

nucleus

Olfactory tubercle

Primary olfactory

cortex

Amygdala

Lateral amygdaloid

nucleus

Basomedial amygdaioid

nucleus

Central amygdaloid

nucleus

Medial amygdaloid

nucleus

Anterio r cortical

amygdaloid nucleus

Posteromedial cortical

amygdatoid nucleus

Sepml regionLateral septal nucleus,

dorsal part

Lateral septal nucleus,

intermediate part

Lateral septal nucleus,

ventral part

Bed nuc leus of the

stria terminalis

Basal ganglia

Accumbens nucleus

Globus pallidus

Ventral pallidum

Entopeduncular

nucleusCaudate-putamen,

head

Caudate-putamen,

body

Caudate-putamen,

tail

Hippocampus

Dentate gyrus

CA I field,

oriens layer

CA 1 field,

stratum radiatum

1286.8 + 175.8

1034.1 + 49.5

1757.8 + 180.2

1787.3 + 210.9

1647.3 + 43.9

2075.6 + 286.3

1420.9 _+ 139.0

1361.4 + 212,6

1627.3 -+ 214,8

2230.9 + 362.2

2439.0 -+ 487.3

3047.3 + 289.5

2802.4 + 412.4

2988.0 + 199.7

1971.7 + 118.7

1309.2 + 9.0

3431.9 + 180.4

3614.8 + 400.2

2266.0 + 195.1

1178.2 + 114.6

1230.9 + 2.9

1081.7 + 47.3

3401.9 + 168.7

2082.4 + 80.4

1788.2 + 386.3

85.7

59.4

65.9

58.9

69.1

33.5

41.9

56.9

42.5

45.8

35.0

79.6

69.0

74.9

52.1

52.7

36.3

28.5

15.7

42.4

44.4

61.1

71.1

71.9

64.7

57.6

81.2

49.1

78.3

86.9

90.0

100.0

100.0

83.3

67.0

68.4

42.7

53.7

46.7

74.8

97.2

100.0

100.0

100.0

96.2

97.0

97.6

16.3

32.3

41.1

- 204.2 + 31.8

607.4 + 143.6 180.3 + 12.1

559 .1+ 116.6 -

808.6 + 51.7 178.7 + 34.0

602.3 + 145.8

2012.1 + 327.3

102.3 _+ 52.1

91.5 + 8.7

2903.1 + 145.0

high

high

very low

low

very high

high



2 1 2

T A B L E V continued

Maximal densities of 5-HT receptors in the rat brain

Area Specific binding (fmol/mg protein)

5-[3H]HT

Mean + S. E. M. % binding

in the presenceoflOnM

(-)21009

% binding

in the presenceoflO nM

8-OH-DPA T

C A 1 f ie l d ,

l a c u n o s u m

m o l e c u l a r l a y e r

C A 2 f i el d ,

o r i e n s l a y e r

C A 2 f i el d ,

p y r a m i d a l l a y e r

C A 3 f ie l d ,

o r i e n s l a y e r

C A 3 f i el d ,

p y r a m i d a l l a y e r

C A 4 f i el dD o r s a l s u b i c u l u m

2 5 0 1 . 2 + 2 8 3 . 4

1 0 3 0 . 9 + 6 1 . 7

1 3 4 1 . 9 + 1 3 0 . 9

1 8 6 0 . 7 -+ 8 . 3

77 3.1 _-+ 55 .6

26 15 .6 _-+ 475 .12 8 4 1 . 7 + 4 6 . 0

6 5 . 1

7 3 . 0

7 0 . 1

6 0 . 8

8 4 . 4

7 3 . 72 6 . 3

2 8 . 6

4 2 . 1

4 1 . 5

4 1 . 2

5 9 . 8

2 1 . 71 0 0 . 0

Hypothalamus

V e n t r o m e d i a l

h y p o t h a l a m i c

n u c l e u s

L a t e ra l h y p o t h a l a m i c

a r e a

D o r s o m e d i a l


n u c l e u s

P o s t e r i o r


n u c l e u s

M e d i a l m a m m i l l a r yn u c l e u s

2 6 6 7 . 5 _+ 2 3 4 . 1

1 3 6 3 . 6 + 1 4 4 . 6

1 9 7 7 . 0 _+ 2 4 7 . 3

1 3 5 5 . 6 + 6 1 . 9

1 7 9 2 . 9 _+ 2 0 4 . 8

4 3 . 2

4 1 . 3

4 7 . 3

3 6 . 6

4 8 . 6

6 9 . 3

9 0 . 6

8 6 . 3

8 0 . 1

8 9 . 2

Thalamus

L a t e ra l h a b e n u l a r

n u c l e u s

A n t e r i o r p r e t e c t a l

a r e a

O l i v a r y p r e t e c t a l

n u c l e u s

C e n t r a l m e d i a l

t h a l a m ic n u c l e u s

L a t e r o d o r s a l

t h a l a m i c

n u c l e u s

V e n t r o l a t e r a lt h a l a m i c

n u c l e u s

V e n t r o p o s t e r i o r

t h a l a m i c

n u c l e u s , l a t e r a l p a r t

P a r a f a s c i c u l a r

n u c l e u s

R e u n i e n s t h a l a m i c

n u c l e u s

R e t i c u l a r t h a l a m i c

n u c l e u s

D o r s a l l a t e ra l

g e n i c u l a t e n u c l e u s

8 5 5 . 1 + 1 1 1 . 9

996 .5 _+ 11 .4

2 7 6 1 . 4 + 3 3 1 . 2

1 7 0 7 . 3 _+ 2 3 6 . 0

1 1 9 3 . 6 + 8 7 . 0

3 4 9 . 2 _+ 3 2 . 9

1 9 4 . 3 + 3 1 . 7

9 6 1 . 9 + 1 5 1 . 9

1 5 2 9 . 5 + 1 3 2 . 1

1 8 1 . 2 + 3 0 . 9

1 0 7 4 . 1 + 1 4 6 . 8

5 6 . 7

3 3 . 6

3 2 . 7

6 7 . 4

4 8 . 6

4 2 . 0

5 0 . 3

6 1 . 6

3 8 . 3

4 8 . 5

2 4 . 9

6 3 . 8

5 3 . 6

9 3 . 2

8 4 . 7

9 5 . 2

8 7 . 9

8 6 . 8

8 9 . 3

1 0 0 . 0

8 9 . 5

1 0 0 . 0

[3H]LSD [3H]Mesulergine

(rnean+ S.E.M.) (mean+ S.E.M.)

2 1 1 2 . 1 + 4 5 1 . 6 1 6 6 . 9 + 5 4 . 3

1428 .1 _+ 168 .4

1 2 4 3 . 6 _ + 1 0 1 . 1

1 0 8 . 2 + 3 5 . 6 - l o w

4 5 4 . 8 + 2 0 . 3 - l o w

69 .3 + 12 .1

8 4 . 1 + 1 3 . 2

91 2.1 _+ 10 1.8 13 3.9 ___ 42 .7

8-OHI3H]-

DPA T

(qualitative)

h i g h



TABLE V continued

Maximal densities of 5-HT receptors in the rat brain

21 3

Area Specific binding (finol/mg protein)

5-Pnln7

Mean ± S. E. M. % binding

in the presenceoflO nM(-)21009

% binding

in the presenceoflO nM8-OH-DPAT

ffH]LSD(meun+ S.E.M.)

[ZH]Mesulergine(mean+ S.E.M.)

8-OH[3H]-DPAT

(qualitative)

Medial geniculate

nucleus 595.8 + 88.3 47.4

Claustrum, neo and cingulate cortexCla ust rum 1491.4 + 178.5 67.5

Frontal cortex (Area 10)

lami na I 1309.0 + 69.5 69.6

lami na II 1149.7 + 38.3 59.3

laminae II I- IV 1681.9 + 66.0 69.7

lam ina V 1715.3 ± 159.2 62.8

lamin a VI 1573.1 + 48.7 57.3

Frontoparietal motor cortex (Area 2)

lami na I 798.7 ± 115.8 65.4

laminae II -II I 1002.6 + 166.8 60.8

lamin a IV 1554.6 ± 208.3 69.0

lam ina V 1744.6 + 110.7 61.0

lami na VI 1316.3 ± 90.0 53.3

Frontoparietal somatosensory cortex (Are a 2a)

lamin a I 1053.1 + 67.5 57.1

laminae II- III 917.3 + 146.3 58.9

lam ina IV 1461.4 ± 184.3 54.7

lam ina V 1532.9 + 80.7 70.1

lam ina VI 1243.1 + 128.5 58.6

Striate cortex (Area 18)lami na I 600.4 + 89.7 66.0

laminae II- III 688.2 ± 195.8 56.2

lami na IV 782.4 ± 172.9 65.3

lami na V 715.8 + 109.0 72.8

lami na VI 686.8 + 153.4 67.0

Anterior cingulate cortex (Are a 24)

lami na I 1860.4 ± 31.9 28.9

laminae II -II I 1633.1 ± 203.4 32.1

lamin a IV 2333.4 + 332.6 44.5

lamin a V 2109.2 + 50.2 35.3

Retrosplenial cortex (Area 29b)

lam ina I 1100.9 + 136.3 40.9

lami nae II -I II 798.5 _+ 65.8 51.3lamina IV 740.2 ± 89.0 52.9

lami na V 624.1 ± 100.9 54.5

lami na VI 572.4 ± 64.6 59.1

Entorhinal cortexPrincipalis

external layer 2844.6 ± 140.2 69.8

Interm ediate layer 1213.9 ± 40.7 28.2

Principalis

inter nal layer 2499.0 ± 359.2 60.3

CerebellumStratum molecular e 265.3 ± 48.7 32.7

Stratum gran ulosu m 374.6 ± 5.8 52.8

63.2

75.2

92.3

91.9

79.1

72.7

73.2

90.5

93.0

76.7

71.4

61.1

98.2

94.8

73.7

60.4

57.5

67.2

72.1

50.4

59.5

59.5

72.2

59.9

49.8

68.4

75.8

88.777.7

77.3

72.3

49.5

63.9

48.1

72.8

29.7

1028.5 + 195.9

483.9 +__18.3

803.4 + 166.6

321.8 + 74.7

907.4 ± 270.1

718.4 + 200

634.1 + 112.8

w

952.8 ± 104.5

1071.8 ± 148.8

185.2 + 19.8

102.3 ± 35.8

84 .2±7.9

51.3 + 9.8

low

l ow

very low

intermediate

intermediate

l ow

intermediate

high



2 1 4

T A B L E V continued

Maxim al densi ties o f 5 -H T 1 receptors in the rat brain

Area Specific binding (fm ol/m g protein)

L a t e r a l n u c l e u s

I n f r a c e r e b e l l a r

n u c l e u s

I n t e r m e d i a te n u c l e u s

Midbrain

S u p e r f i c i a l g r e y

l a y e r o f t h e

s u p e r i o r c o l l ic u l u s

O p t i c n e r v e

l a y e r o f t h e

s u p e r i o r c o l l ic u l u sP r i n c i p a l

o c u l o m o t o r

n u c l e u s

C e n t r a l g r e y

( p e r i a q u e d u c t a l )

D o r s a l r a p h 6 n u c l e u s

M e d i a n r a p h 6 n u c l e u s

S u b s t a n t i a n i g r a ,

r e t i c u l a r

S u b s t a n t i a n i g r a ,

c o m p a c t a

V e n t r a l t e g m e n t a l

a r e a

I n t e r p e d u n c u l a r

n u c l e u s

Pons

N u c l e u s o f t h e s p i n a l

t r a c t o f t h e t r i g e -

m i n a l n e r v e , o r a l p a r t

F a c i al n u c l e u s

P o n t i n e n u c l e i

N u c l e u s o f t h e

s o l i t a r y t r a c t

R a p h 6 o b s c u ru s

n u c l e u s

Medulla oblongata

A m b i g u u s n u c l e us

G r a c i l e n u c l e u sC u n e a t e n u c l e u s

I n f e r i o r o l i v e

H y p o g l o s s a l n u c l e u s


s p i n a l t r a c t o f t h e

t r i g e m i n a l n e r v e ,

c a u d a l p a r t


s p i n a l t r a c t o f t h e

t r i g e m i n a l n e r v e ,

g e l a t i n o s u s

s u b n u c l e u s

M e d i a l v e s t i b u l a r

n u c l e u s

5 - [ ~ H ] H T

Mean ± S . E . M. % b ind ing

in the presenceo f l O n M

(-)21009

% b ind ing

in the presenceo f l O n M

8 - O H - D P A T

1 2 8 3 . 9 ± 3 5 2 . 9 2 1 . 0

4 5 6 . 0 + 8 3 . 6 3 7 . 1

5 4 3 . 4 ± 3 6 . 0 1 8 . 3

8 9 . 1

9 4 . 1

8 9 . 6

1 6 0 4 . 3 + 9 7 . 5 3 2 . 8

9 2 8 . 0 ± 6 7 . 5 3 2 . 9

1 2 6 6 . 5 + 1 3 1 . 4 3 3 . 6

1 4 5 6 . 0 _+ 2 1 . 4 3 9 . 6

2 3 4 8 , 7 ± 3 1 7 . 3 6 0 . 1

11 50 .0 ___+ 66 .0 49 .8

2 7 4 2 . 4 ± 1 3 5 . 8 2 9 . 5

8 1 9 . 7 ± 2 8 . 0 2 8 . 3

8 2 3 . 6 -+ 4 0 0 . 7 3 1 . 5

1 1 4 0 . 4 ± 2 9 7 . 5 3 9 . 4

7 6 . 5

8 1 . 4

5 4 . 6

8 1 . 1

4 3 . 6

5 0 . 8

7 7 . 4

1 0 0 . 0

6 2 . 4

5 1 . 8

7 0 7 . 0 ± 9 0 . 4 4 8 . 3

7 7 3 . 9 ± 5 1 . 8 3 3 . 1

4 1 9 . 7 _+ 5 4 . 3 2 1 . 8

1 1 8 4 . 6 ± 1 0 6 . 8 5 0 . 4

7 6 1 . 4 ± 1 5 5 . 8 4 8 . 2

5 3 . 4

5 3 . 1

7 1 . 0

5 9 . 3

8 9 . 6

7 4 5 . 8 + 7 7 . 8 2 1 . 8

8 6 0 . 9 + 7 9 . 5 1 8 . 46 1 6 . 0 + 8 5 . 8 2 3 . 0

7 9 3 . 7 ± 1 5 8 . 0 4 4 . 4

7 1 0 . 0 ± 3 . 6 2 6 . 4

8 3 6 . 3 + 1 2 3 . 8 3 9 . 4

1 3 2 2 . 1 ± 1 9 3 . 9 5 9 . 3

7 9 1 . 7 ± 4 1 . 9 3 5 . 7

7 2 . 2

5 7 . 25 1 . 0

7 7 . 5

9 5 . 4

5 2 . 3

4 3 . 1

6 9 , 0

[3H ]LS D [3H]Mesulergine 8-0141314]-

( m e a n + S . E . M . ) ( m e a n + S . E . M . ) D P A T

(qualitative)

4 5 . 6 + 1 1 . 8 v e r y l o w

v e r y l o w

1 4 2 , 1 + 2 3 . 4 -

2 2 0 7 , 4 ± 1 2 1 . 5 - h i g h

2 4 3 . 1 + 3 7 . 8 - l o w

7 1 . 6 ± 9 . 8



TABLE V continued

Maximal densi ties o f 5-H T1 receptors in the rat brain

215

A tea Specific binding (fmo l/mg protein)

5-[3H]HT

Mean + S.E.M. % binding

in the presence

o f l O n M(-)21009

% binding

in the presence

o f l O n M8 - O H - D P A T

[3H ] LS D [3H] Mesulergine

(mean+ S.E.M . ) (rnean+ S.E.M . )8 - O H p N ] -

D P A T

(qualitative)

Spinal cord

Layer 1 of Rexed 1011.2 + 16 9.8 89 .6Layer 4 of Rexe d 1099.1 + 31.2 73.0Layer 9 of Rexed 303.8 + 27.9 43.8Layer 10 of Rexe d 458.5 ± 63.2 54.3

42.462.868.978.4

91.4 + 21.6

Choroid p lexus

Lateral ventricle 3496.0 ± 53 0.2 90 .3T h i r d ve ntr icle 338 1.7 ___4 0 2 . 5 9 1 . 0Fourth ventricle 4265.3 _-_ 27 9. 5 76 .1

8 8 . 5

100.094.7

3787.9 + 391 15 63 .7 82.1 very low2751.4 + 23.2 -3381.0 + 293 .7 1444.5 + 308 .7 verylow

i n th e b a s a l g a n g l ia c o r r e s p o n d e d t o t h e 5 - H T m c l a ss

( T a b l e V a n d F ig s. 3 - 5 , 6 D - F a n d 7 ).

H i p p o c a m p u s . T h e h i p p o c a m p a l f o r m a t i o n w a s

v e r y e n r i c h e d i n 5 - H T 1 r e c e p t o r s . T h e d e n t a t e g y r u s

a n d t h e d o r s a l s u b i c u l u m c o n t a i n e d v e r y h i g h c o n -

c e n t r a t i o n s o f s it e s . I n t h e d i f f e r e n t f i e l d s o f t h e h i p -

p o c a m p u s ( C A 1 - C A 4 ) , h i g h t o i n t e r m e d i a t e d e n s i -

t ie s o f s p e c if i c b i n d i n g w e r e f o u n d , d e p e n d i n g o n t h e

l a y e r a n a l y z e d . W h i l e b i n d i n g t o t h e d o r s a l s u b i c u -

l u re s h o w e d t h e p h a r m a c o l o g i c a l c h a r a c t e ri s t ic s o f 5 -

H T 1B s i te s , t h e o t h e r h i p p o c a m p a l a r e a s m o s t l y c o n -

t a i n e d 5 -H T 1 A s i te s ( T a b l e V a n d F i g s . 2 - 5 , 7 D - F

a n d 8 ) .

H y p o t h a l a m u s . H i g h c o n c e n t r a t i o n s o f 5 - H T 1 r e -

c e p to r s w e r e f o u n d i n t h e v e n t r o m e d i a l h y p o t h a l a m -

i c n u c l eu s . O t h e r h y p o t h a l a m i c n u c le i p r e s e n t e d i n -

t e r m e d i a t e d e n s i t i e s o f s p e c i f i c b i n d i n g . M o s t o f t h e

b i n d i n g t o t h e s e s t r u c t u r e s e x h i b i t e d c h a r a c t e r i s t i c s

o f t h e 5 - H T I B cl a s s ( T a b l e V a n d F i g s . 3 - 5 a n d

7 D - F ) .

T h a l a m u s . M a r k e d d i f f e r e n c e s w e r e o b s e r v e d i n

t h e d e n s i t y o f 5 - H T 1 r e c e p t o r s t h r o u g h o u t t h e t h a l a -

m u s . S o m e n u c l e i, s u c h a s t h e v e n t r o l a t e r a l a n d t h e

r e t ic u l a r n u c l e i p r e s e n t e d v e r y l o w d e n s i t ie s o f s p e -c if ic b i n d i n g . L o w c o n c e n t r a t i o n s w e r e f o u n d i n t h e

l a t e r o d o r s a l n u c l e u s a n d t h e d o r s a l l a t e r a l g e n i c u l a t e

n u c l eu s . T h e c e n t r a l m e d i a l a n d t h e o l i v a r y p r e t e c t a l

n u c l e i w e r e r i c h i n 5 - H T 1 s i t es . 5 - H T 1 r e c e p t o r s i n t h e

t h a l a m u s p r e s e n t e d t h e p h a r m a c o l o g i c a l p r o f i le o f 5 -

H T I B si te s , a lt h o u g h s o m e 5 - H T I c b in d i n g a p p e a r e d

t o e x i s t i n t h e c e n t r a l m e d i a l n u c l e u s ( T a b l e V a n d

F ig s. 3 - 5 a n d 7 D - F ) .

C l a u s t r u m , n e o a n d c i n g u l a t e c o r t e x . T h e c laus -

t r u m p r e s e n t e d a n i n t e r m e d i a t e d e n s i t y o f 5 - H T 1 r e -

c e p t o r s . T h e t h r e e s u b t y p e s o f 5 - H T 1 s i te s a p p e a r e d

t o b e p r e s e n t i n t h i s s t r u c t u r e ( T a b l e V a n d F i g s . 3 , 5

a n d 6 ) .

I n t h e n e o c o r t e x , i n t e r m e d i a t e c o n c e n t r a t i o n s o f

s p e c i f i c b i n d i n g w e r e f o u n d i n t h e d i f f e r e n t l a y e r s o f

t h e f r o n t a l ( a r e a 1 0) a n d f r o n t o p a r i e t a l c o r t e x ( a r e a s

2 a n d 2 a ) , w h i l e t h e s t ri a t e c o r t e x ( a r e a 1 8 ) p r e s e n t e d

o n l y l o w c o n c e n t r a t i o n s o f si t e s. I t c a n b e s a i d t h a t

t h e i n t e r n a l l a m i n a e ( I V - V I ) w e r e r i c h e r i n 5 - H T 1

b i n d i n g t h a n t h e e x t e r n a l o n e s ( I - I I I ) . I n t h e f r o n t a l

c o r t e x , m o s t o f th e b i n d i n g t o a ll th e l a m i n a e w a s o f

t h e 5 - H T m c l a s s , a l t h o u g h 5 - H T 1A a n d 5 - H T I c s i te s

w e r e a l s o p r e s e n t . I n c o n t r a s t , i n t h e o t h e r r e g i o n s

s t u d i e d , 5 - H T m s i te s w e r e p r e d o m i n a n t i n th e e x t e r -

n a l l a m i n a e , b u t b o t h 5 - H T 1 A a n d 5 - H T I B s i t e s a p -

p e a r e d t o c o e x i s t i n l a m i n a e I V - V I . A s i n d i c a t e d

a b o v e , t h e p r e s e n c e o f l o w d e n s i ti e s o f 5 - H T I c s it e s

a t th e s e l e v e l s , c a n n o t b e e x c l u d e d .

R e g a r d i n g t h e c i n g u l a t e c o r t e x , i n t h e a n t e r i o r c i n -

g u l a r c o r t e x ( a r e a 2 4 ) i n t e r m e d i a t e t o h i g h c o n c e n -

t r a t i o n s o f sp e c i f i c b i n d i n g w e r e f o u n d , t h e i n t e r n a l

l a y e r s b e i n g t h e m o s t e n r i c h e d . A p r e d o m i n a n t b u t

n o t e x c l u s i v e p r e s e n c e o f 5 - H T I B s i t e s w a s d e t e c t e d .F i n a l l y , t h e r e t r o s p l e n i a l c o r t e x ( a r e a 2 9 b ) p r e s e n t e d

l o w d e n s i t i e s o f 5 - H T 1 r e c e p t o r s i n a l l t h e l a y e r s

( T a b l e V a n d F i g s . 2 - 8 ) .

E n t o r h i n a l c o r t e x . T h e e x t e r n a l l a y e r o f t h e e n t o -

r h i n a l c o r te x p r e s e n t e d a v e r y h i g h c o n c e n t r a t i o n o f

5 - H T 1 r e c e p t o r s . I n t h e i n t e r n a l l a y e r , a h i g h d e n s i t y

o f a u t o r a d i o g r a p h i c g r a i n s w a s f o u n d , w h i l e o n l y i n-

t e r m e d i a t e c o n c e n t r a t i o n s w e r e p r e s e n t i n t h e i n t e r -

m e d i a t e l a y e r . B o t h 5 - H T I A a n d 5 - H T I B s i te s a p -



216

Figs. 2 -10. Atlas of autoradiog raphic lo calization of 5-[3H]HT-binding sites in the rat brain. D ark reg ions represent areas with high

recepto r densities. Ana tom ical levels shown in these figures correspo nd to th e plates 9, 12, 15, 20, 26, 30, 36, 42, 50, 55, 60, 65 and 66

of the rat brain atlas from Paxinos and W atson ~°°. Abb reviatio ns used are listed separately in the text. Auto radio gram s shown c orre-

spond to the total binding of 5-[3H]HT (A, D ) and that in the presence of 10 nM (-)21 009 (B, E) and 100 nM 8- OH -DP AT (C, F) . See

text for further details.

!i!

iiii!!iiiii

Fig. 2.5-[3H]HT-binding sites in a dorsal horizontal section. Note the high concentrations of binding in the dorsal subiculum (S) and

other regions of the hippocampus, such as the CA I f ield (CA1). The superior col liculus (SC) and the internal layers of the n eocortex

also present impo rtant d ensities of 5-H T receptors. B inding to the dorsal subiculum and the superior colliculus is inhibited by

(-)21 009 (B) and not by 8 -OH -DP AT (C), corresponding to 5-HT1B sites. T he opposi te pat tern is seen in the other areas of the hippo-

campus (5-HTIA sites). Bar = 0.2 cm.

Fig. 3.5-[3H ]HT-bind ing sites in a horizon tal section more ventral than tho se in Fig. 2. Very high concen trations of receptors are pres-

ent in choroid plexus (ChP), lateral septal nucleus (LS), globus pal l idus (GP), hippocampus (H p) and entorhinal cortex (Ent) . The

caudate-putamen nucleus (CPu), som e thalamic nuclei , the dorsal raph6 nucleus (DR) and the deep cerebel lar nuclei are also labeled

by 5-[3H]HT. Sites whe re the binding is displaced by (-)21 009 (5-HT1B sites) include the globus pallidus, caudate-p utame n and cere-

bellar nuclei (B). Areas where 8-OH-DPAT shows high affinity for 5-[3H]HT binding (5-HTIA sites) are the lateral septal nucleus, the

hippocampus and the entorhinal cortex (C). 5-[3H]HT binding to the choroid plexus is not inhibited by these drugs (5-HTIc sites). Bar

= 0.2 cm.



21 7

Fig. 4.5-[3H]HT-binding sites in a ventral horizontal section. Note the high affinity of (-)21 009 (B) for the binding to the ventral pal-lidum (VP) and substantia nigra (SNR), while 8-OH-DPAT (C) inhibits 5-[3H]HTbinding to the hippocampus (Hp). Bar = 0.2 cm.

peared to exis t in these a reas , a l though 5-HTIAsites

were predominant in the in te rna l and exte rna l layers

(Table V and F igs . 3 , 4 and 8D -F ) .

Cerebellum. While the densi ty of receptors in the

dif fe rent layers of the ce rebe l lum was very low, the

deep nuc le i presented de tec table amounts of spec i f ic

binding ranging f rom in te rmedia te ( la te ra l nuc leus)

to low densit ies ( inf racerebe l la r and in te rme dia te nu -

c le i ) . B inding to these nuc le i presented the pharma-

cologica l charac te r is t ics of 5-H T m s i tes (Table V and

Figs. 2, 3, 5 an d 9).

Midbrain. A he te ro gene ous d is t r ibut ion of 5-HT1

receptors was found in the midbra in , the r iches t a reas

be ing the substant ia n igra ( re t icula r ) , the dorsa l

raph6 and the super f ic ia l grey layer of the super ior

colliculus. In contrast , other structures, such as the

opt ic layer of the super ior col l iculus or the ventra l

t e gm e n ta l a r e a p r e se n te d on ly low c onc e n t ra t ions o f

spec if ic b inding. In mo st of the a reas , 5-H T m s i tes

we r e p r e dom ina n t , a l t hough the o the r 5 - HT 1 sub -

types were a lso present . An except ion was the dorsa l

raph6 nuc leus , which ap pea red to be r icher in 5-HT1A

si tes (Table V and F igs. 2- 5 and 8) .

Fig. 5. Sagittal sections showing 5-[3H]HT binding. Areashighly labeled include CA 1 field of the hippocampus (CA1) (5-HTIA sites), dorsal subiculum (S), globus pallidus (GP), sub-stantia nigra reticular (SNR) (5-HTm sites) and choroid plexus(ChP) (5-HTlc sites). Bar = 0.2 cm.



21 8

A D

AoP

B E

Acb LSZCPu~

P ~

F

qf~

Fig. 6.5-[3H]HT binding in coronal sections through the frontal cortex (A- C) and the caudate-putamen (D -F ). Note that 5-[3H]HTbinding to caudate-putamen (CPu,h) and accumbens (Acb) is inhibited with high affinity by (-)21 009 (E), showing that it is of the 5-HT m subtype. In contrast, binding to the lateral septal nucleus (LSI) is displaced by 8-OH -DPA T. Binding to the different areas o f theneocortex is partially affected by both drugs. Bar = 0.2 cm.

Pons. O n l y l o w c o n c e n t r a t i o n s o f 5 - H T 1 r e c e p t o r s

w e r e f o u n d i n t h e p o n s , a l t h o u g h t h e n u c l e u s o f th e

sol i ta ry t rac t conta ined a h igher dens i ty of au toradio-

graphic gra ins . As in midbr a in , 5-H T m s i t es ap-

p e a r e d t o b e p r e d o m i n a n t ( T a b l e V a n d F i g s. 4 , 5 a n d

9) .

Medulla oblongata. T h e d i f f e re n t n u c l e i o f t h e m e -

dul l a presen ted low conc ent ra t io ns of 5-HT1 recep-

tors, except the ge la t inosus su bnuc leus of the nuc leus

of the sp ina l t rac t of the t r igemina l n e rve , wher e an

in te rmedia te dens i ty of spec i f i c b inding was found.

The presence of 5-HT1A and 5-HTIB s i te s was appar -

ent in these a reas , a l thou gh in mos t of them , 5-HTIB

was pre dom inan t (Table V and F igs . 4 , 5 and 9) .

Spinal cord. In the ce rv ica l pa r t of the sp ina l cord ,

l a m i n a e o f t h e d o r s a l h o r n p r e s e n t e d i n t e r m e d i a t e

densi t ies of s i tes, wh ich had th e char acteris t ics of 5-

HTyA-recogni t ion s it e s. In cont ras t , i n the ven t ra l

horn , the conce nt ra t io n of spec if i c b inding was low or

very low, and o f the 5-H T m c las s . The presenc e of



some 5-HTlc binding in the dorsal horn was also

found (Table V and Fig. 10).

Choroid plexus. T he choroid plexuses presented

the highest concentrations of 5- HT 1 receptors, hav-

ing the characteristics of 5-HTlc sites (Table V and

Figs. 3-5 , 7 -9).

DISCUSSION

The results presented in this paper provide a quan-

219

titative ma pping of the 5-HT 1 receptors in the rat

brain. Furthermore, they demonstrate the presence

of three different populations of 5-HTl-binding sites,

supplying a detailed pharmacological characteriza-

tion of these sites, as well as their anatomical distri-

bution throughout the different areas and nuclei of

the brain.

Since several com poun ds inhibit 5-[3H]HT binding

to the cort ex in a biphasic manner , two subtypes of 5.-

HT 1 sites, 5-HT1A and 5-HT m hav e been prop osed

Fig. 7.5-[3H]HT binding in coronal sections through the globus pallidus (A-C) and the anterior thalamus (D-F). Structures where 5-HT1Asites are present include lateral septal nucleus, dentate gyrus (DG) and CA 1 field of the hippocampus (CA1). Areas enriched in5-HTm are globus pallidus (GP), ventral pallidum (VP), caudate-putamen (CPu,b) and hypothalamus (VMH). The binding to thechoroid plexuses (ChP) is of the 5-HTlc class. Bar = 0.2 cm.



22 0

~:ii !~ ;~! i~:~!ii~i!i!̧I̧~i! ii~ ~i~i~i~ii!i ii ~

Fig. 8.5-[3H]HT binding in coronal sections through the upper ( A- C) and the lower midbrain (D -F ). Autoradiograms show the m-tense labeling of the dorsal subiculum (S), substantia nigra reticular (SNR) and superficial grey layer of the superior colliculus (SuG),among others, having the characteristics of 5-HT m sites. On the oth er hand, th e dentate gyrus (DG) and oth er areas of the hippocam-pus present binding of the 5-HTIA class. Bar = 0.2 cm.

( s ee I n t r o d u c t i o n ) . R e c e n t l y , w e h a v e r e p o r t e d t h e

presence of a th i rd subty pe of 5-HT~ s it e : 5-HT lc , in

pig ch oroid p lexus me mb ran es 103. By com binin g

q u a n t i t a t i v e a u t o r a d i o g r a p h y w i t h b i n d i n g - c o m p e t i -

t ion exper iments , we have (1) ident i f i ed bra in a reas

e n r i c h e d i n o n l y o n e o f t h e s e 5 - H T l r e c e p t o r s u b -

t y p e s , a n d ( 2 ) c a r r i e d o u t t h e p h a r m a c o l o g i c a l c h a r -

ac te r i za t ion o f these s i t es by ana lyz in g the a f f in i t ie s

of s evera l drugs for the 5-H T 1 recepto rs loca ted in

t h e s e a r e a s . T h i s p h a r m a c o l o g i c a l a p p r o a c h w o u l d

h a v e b e e n d i ff i cu l t t o a t t ai n b y m e m b r a n e - b i n d i n g

technique s , because of the d i f f i cu l ty in d i s sec t ing by

h a n d n u m e r o u s s m a ll b r a in a r e a s .

In th i s way, we have ident i f i ed a reas enr iched in 5-

HTIA s i te s : denta te gyrus , s evera l f i e lds of the h ipp o-

camp us , l a t e rosepta l nuc leus ; f inding tha t 8-OH -

D P A T , L S D , R U - 2 4 9 6 9 a n d t h e fl - b l o c k e r ( - ) 2 1 00 9

(ref . 39) recognized these s i tes with very high aff ini ty.

In cont ras t to o the r resu l ts publ ished105, sp iperon e

s h o w e d o n l y l o w a f f i n i t y f o r t h e a b o v e - m e n t i o n e d



s i tes , a l though c lea r ly h igher than those presented

for the o ther 5 -HT 1 s i tes (Table I I ) . Are as present ing

only 5-H T m s i tes inc luded globus pa l l idus , subs tant ia

nigra re t icula r pa r t and dorsa l subiculum, am ong oth-

e r s. Whi l e 8 - OH 2DP AT showe d low a f fin i ty f o r the se

s i tes , RU-24 969 and ( - ) 21 009 recognized them with

very h igh a f f in i ty . In the case of the f l -b locker , the a f -

f in i ty for these 5 -HT m s i tes was h igher than the o ne

shown for 5-HT IA s i tes . I t appears c lea r f rom these

da ta tha t 8 - OH- DP AT a nd ( - ) 21 009 a r e the c om -

221

pounds showing a be t te r d isc r imina tory capac i ty to

dif fe rent ia te both subtypes (Table I I ) . F ina l ly , 5-

HT Ic s i tes were found in a very h igh concentra t io n in

the choroid p lexuses , and the i r phar maco logy was

very s imi la r to tha t repo r ted 103 in m emb rane-b indin g

studies (Tables I I and I I I ) .

The ana lysis of the a reas labe led w i th the d i f fe rent

3H- labe led l igands was in agreement wi th the da ta

f r om c om pe t i t i on e xpe r im e n t s . 8 - OH- [ a H] DP AT la -

be led wi th h igh a f f in i ty those bra in a reas which p re -

Fig. 9.5-[3H]HT binding in coronal sections through the p ons (A -C ) and medulla oblongata (D-F ). Note the labeling of the lateralcerebellar nucleus (LatC), which is inhibited by (-)21 009 (B), and that on the choroid plexus, which is not affected by (-)21 009 (B)or 8-OH-DPAT (C). Bar = 0.2 cm.



222

sented the character istics of 5-HT1A sites, whe n 5-

[3H]HT was used as a l igand. Bmax va lues of [3H]LSD

binding were s imi la r to those o bta ined wi th 5- [3H]HT

in the a reas wh ere no 5-HTIB s i tes were present , but

c lea r ly lower in those enr iched in th is subtype . Bind-

ing of [3H]mesule rgine only reached high concen tra -

t ions in the choroid p lexus , an a rea ext remely en-

r iched in 5-HT~c receptor s i tes . The d i f fe rence be-

tween the maximal densi t ies found in th is s t ruc ture

with 5- [3H]HT and [3H]mesule rgine could be d ue to

the d i f fe rent labe l ing condi t ions used for bot h l igands

(Table V) . A mul t ip l ici ty of se rotoninergic recogni-

t ion s ites has a lso been pro pose d on the bas is of da ta

obta ined f rom e lec t rophysiologica l s tudies l . How ev-

er , fur ther work is need ed in order to c la ri fy the pos-

s ib le re la t ionship be tween the d i f fe rent 'S ' r eceptors

. C

d

Fig. 10.5-[3H]HT binding in a coronal section through the cer-vical spinal cord. 5 -HT1 ites on the do rsal horn (2) appear to beof the 5-HTIAclass, while those on the ventral horn (9) could beconsidere d as 5-HT1Bsites. Bar = 0.2 cm.

propos ed by Agha janian I and the 5 -HT s i tes def ined

with ra diola beled ligands t15.

I t must be pointed out tha t , in addi t ion to 5-H T t re -

ceptors , [3H]LSD and [3H]mesule rgine labe led 5-

HT 2 receptors in the ra t bra in , a s has been a l ready

described22,102,1°9. [3H]LSD also labeled dopaminer-

gic rec ept ors 19.

The dis t r ibut ion of 5-H T 1 s i tes repo r ted here cor -

re la te wel l wi th the resul ts obta ined in membrane-

binding assays per f orm ed in hand-dissec ted ra t bra in

regions us ing 5- [3H]HT and [3H]LSD16,11°. Similar

dis t r ibut ion of 5-H T 1 receptors has b een found in

other mammalian spec ies , inc luding guinea-pig and

human29, t l0. Ou r results are also in ve ry g ood

agreement wi th those repor ted in previous autoradi-

ographic s tudies , pe r formed us ing 5- [3H]HT,

[ 3H] LS D a nd 8 - OH- [ 3H] DP AT, bo th in the pa t t e r n

of g ene ral dist ribu tion of 5 -HT1 rec ep tor s 14,75,138 and

in the distr ibution of 5-HTIA and 5-HT1B sub-

types34,72. In our s tudy, we conf i rm an d ex tend these

results, providing a quantita tive analysis, and defi-

n ing the pharma cologica l prof i le of the three 5-HT 1-

recognition sites.

5-HT1 receptors presented a very he te rogeneous

dis t r ibut ion in the ra t bra in . Choroid p lexus , basa l

gangl ia and hippocampus were very r ich in these

s i tes . The neocor tex and the hypotha lamus a lso

showed high concentra t ions of receptors . In contras t

to th is, in bra ins tem and spina l cord , the densi ty of 5-

HT 1 r e c e p to r s wa s low , a l though som e m e se nc e pha i -

ic structures, i .e . , substantia nigra, st i l l presented

high concentra t ions of spec if ic b inding (F igs . 2-5 ) .

Regarding the func t iona l s ignif icance of 5 -HT 1 re -

ceptors , some behaviora l responses have been pro-

posed to be l inked to these s i tes . While m any of the 5-

HT m oto r e f fe c ts a r e m e d ia t e d by 5 - HT 2 r e c e p -

tors23,67,107,135, in o ther mode ls , 5-HT~ s i tes seem to

be invo lve d . The 5 - H T syndr om e , a c om ple x be ha v -

io ra l syndr om e , ha s be e n p r opose d to be m e d ia t e d by

5-HT 1 receptors 69. This s yndro me is produ ced by 5-HT i tse l f , a s wel l a s by some se rotoninergic precur -

sors and consists of several mot or activit ies, including

forepaw t reading, S t raub ' s ta i l , h indl imb abduc t ion

and head weav ing, amo ng othersS0, 5s. Altho ugh no

full agr eem ent exists on this po int 93, the 5 -H T 1 me-

dia t ion of th is behavior i s fur ther conf i rmed by the

fac t tha t 8-O H- DP AT induces the synd rome ~27 and

som e r-b loc ker s antago nize i t 53,127. A secon d mo tor



223

e f f e c t w h i c h a p p e a r s t o b e r e l a t e d t o 5 - H T 1 a c t i v a t io n

i s t h e c i r c l i n g b e h a v i o r i n s t r i a t u m - l e s i o n e d r a t s .

B o t h a g o n i s t s R U - 2 4 9 6 9 a n d 8 - O H - D P A T p r o d u c e

t h i s b e h a v i o r lS , 57. F i n a l l y , i t h a s b e e n r e p o r t e d t h a t

t h e i n d o l e 5 - H T a g o n i s t s , s u c h a s R U - 2 4 9 6 9 , o r i g i -

n a t e m y o c l o n i c j e r k i n g i n g u i n e a - p i g s 70 a n d h y p e r l o -

c o m o t i o n i n m i c e a n d ra tsS 2,1 28 . A g o o d c o r r e l a t i o n

h a s b e e n s h o w n b e t w e e n t h e p o t e n c i e s o f t h e s e c o m -

p o u n d s d i s p la c i n g 5 - [3 H ] H T b i n d i n g i n t h e b r a i n s t e m

a n d t h o s e i n d u c in g m y o c l o n u s 70. H o w e v e r , c a u t i o n i s

r e q u i r e d i n an a l y z i n g th e m o t o r e f f e c t s p r o d u c e d b y

5 - H T a g o n i s ts , b e c a u s e o f t h e i n t e r a c t i o n s w h i c h

h a v e b e e n d e m o n s t r a t e d b e t w e e n 5 - H T a n d d o p a -

m i n e r g i c r e c e p t o r s i n t h i s r eg ar d3 6 , 52. A l t h o u g h m o s t

o f t h e s e 5 - H T 1 b e h a v i o r a l e f f e c ts h a v e b e e n c l a i m e d

t o b e b r a i n s t e m o r s p i n a l l y m e d i a t e d 59 , 70, r e c e n t r e -

s u l t s h a v e d e m o n s t r a t e d t h a t a t l e a s t s o m e c o m p o -

n e n ts o f th e 5 - H T s y n d r o m e a r e n o t d e p e n d e n t o n

t h e s e l o w e r s t r u c t u r e s 35. O u r a u t o r a d i o g r a p h i c d a t a

r e v e a l t h e p r e s e n c e o f 5 - H T 1 r e c e p t o r s i n m a n y s t ru c -

t u r e s k n o w n t o b e i n v o l v e d in m o t o r a c t i v it y . T h e s p i -

n a l c o r d , s u b s t a n t i a n i g r a , c e r e b e l l a r n u c l e i , b a s a l

g a n g l i a , e n t o p e d u n c u l a r n u c l e u s a n d m o t o r c o r t e x

p r e s e n t i m p o r t a n t c o n c e n t r a t i o n s o f r e c e p t o r s , m a i n -

l y o f t h e 5 - H T I B s u b t y p e . T h e c l a u s t r u m , a s t r u c t u r e

a l s o c o n n e c t e d t o t h e m o t o r c o r t e x 2 s i s a l s o r i c h i n 5 -

H T 1 s it e s. T h e s e r e s u l t s s u p p o r t a p r e d o m i n a n t r o l e

o f 5 - H T m - r e c o g n i t i o n s i t es in t h e s e e f f e c ts . H o w e v -

e r , a n i n v o l v e m e n t o f 5 - H T 1 A s i t es i s p o s s i b l e , s i n c e

t h e y a r e a l s o p r e s e n t i n t h e s e s t r u c t u r e s •

T h e r e i s a l so c o n s i d e r a b l e e v i d e n c e f o r a n i n h i b i to -

r y r o le o f c e n t r a l 5 - H T s y s t e m s o n m a l e r a t s e x u a l b e -

h a v i o r 3A17. I n c o n t r a s t , a d m i n i s t r a t i o n o f 8 - O H -

D P A T c a u s e s m a r k e d s t i m u l a t o r y c h a n g e s i n t h i s

s e x u a l b e h a v i o r , r e d u c i n g n u m b e r o f i n t ro m i s s i o n s

p r e c e d i n g e j a c u l a t io n a n d s h o r t e n i n g t h e e j a c u l a t o r y

l a t e n c y 4 . F u r t h e r m o r e , t h i s s e x u a l f a c i l i t a t o r y e f f e c t

o f 8 - O H - D P A T i s n o t b l o c k e d b y t h e a d m i n i s tr a ti o n

o f s e v e r a l s e r o t o n i n e r g i c a n t a g o n i s ts 2 , 4 . T h e s e r e s u l t s

c o m p l i c a t e t h e a n a l y s is o f t h e r e l a t i o n s h i p b e t w e e n 5 -

H T 1 r e c e p t o r s a n d s e x u a l b e h a v i o r , s u g g e s ti n g a p o s -

s i b l e p r e s y n a p t i c m e d i a t i o n , a s w i l l b e d i s c u s s e d l a t -

e r . N e v e r t h e l e s s , t h e p r e s e n c e o f h ig h c o n c e n t r a t i o n s

o f 5- H T z A r e c e p t o r s i n t h e d i f f e r e n t a r e a s o f t h e h i p -

p o c a m p u s , a s w el l as i n o t h e r s t r u c t u r e s o f t h e l i m b i c

s y s t e m , i n c l u d i n g t h e s e p t u m , w h i c h i s s t r o n g l y c o n -

n e c t e d t o h i p p o c a m p a l a r ea s S , 71, c o u l d i n d i c a t e a r o l e

o f t h e s e s i t e s in t h e m e d i a t i o n o f t h is b e h a v i o r •

A r o l e o f 5 - H T 1 r e c e p t o r s i n t h e c o n t r o l o f v i su a l

a c t i v i ty c a n b e s u g g e s t e d , a c c o r d i n g t o t h e d i s t r i b u -

t i o n o f t h e s e s i t e s i n s o m e b r a i n a r e a s • T h e o l i v a r y

p r e t e c t a l n u c l e u s a n d t h e s u p e r f i c i a l g r e y l a y e r o f th e

s u p e r i o r c o l l i c u l u s , b o t h c o n n e c t e d w i t h t h e v i s u a l

pathway120, TMp r e s e n t h i g h c o n c e n t r a t i o n s o f 5 -H T 1

r e c e p t o r s . O t h e r s t r u c t u r e s r e l a t e d t o t h e v i s u a l sy s -

t e m , s u c h a s t h e c l a u s t r u m 65, t h e s t r i a t e c o r t e x a n d

la te r a l gen icu la te nuc leus47 ,119 ,126 a l so con ta in im po r -

t a n t r e c e p t o r d e n s it i es . M o s t o f t h e s e a r e a s a r e m a i n -

l y e n r i c h e d i n 5 - H T 1 a - r e c o g n i t i o n s i t es •

5 - H T a g o n i s t s h a v e b e e n r e p o r t e d t o in d u c e s t i m u -

l a t i o n o f r a t p r o l a c t i n s e c r e t i o n ( s e e r e f . 7 7 ). A l -

t h o u g h t h is e f f e ct a p p e a r s t o b e m e d i a t e d b y 5 - H T 2

r e c e p t o r s 76, a r o l e o f 5 - H T 1 s i t e s c a n n o t b e e x -

c l u d e d 41. T h e i m p o r t a n t p r e s e n c e o f 5 - H T m - r e c o g n i -

t i o n s it e s i n d i f fe r e n t n u c l e i o f t h e h y p o t h a l a m u s , a n

a r e a w h i c h h a s b e e n r e l a t e d t o t h e s e e f f e c t s77, coul d

s u g g e s t a n i n v o l v e m e n t o f 5 -H T 1B s i t e s i n th i s e n d o -

c r i n e r e s p o n s e .

T h e c e n t r a l 5 - H T s y s t e m s a r e k n o w n t o b e i n -

v o l v e d i n t h e r e g u l a t i o n o f n o c i c e p t i v e a c t iv i t y , m a i n -

l y t h r o u g h a r a p h 6 - s p in a l p r o j e c t i o n i n t e r c o n n e c t e d

w i t h t h e e n d o g e n o u s o p i o i d p a t h w a y s ( s e e r e f. 1 0 f o r

a r e v i e w ) , a l t h o u g h b r a i n s t e m s e r o t o n i n e r g i c c o n -

n e c t i o n s a r e a l s o r e l e v a n t 12. I t h a s b e e n a l s o s h o w n

t h a t t h is s e r o t o n i n e r g i c r o le v a r i e s d e p e n d i n g o n t h e

m etho do log ica l ap pr oa ch used12,13,121 ,136 . Fu r the r -

m o r e , i t h a s b e e n r e c e n t l y s u g g e s t e d t h a t s p i n a l 5 - H T

r e c e p t o r s r e l a t e d t o n o c i c e p t i v e c o n t r o l a r e o f t h e 5 -

H T 1 cl a s s 121,139. O u r a u t o r a d i o g r a p h i c d a t a s u p p o r t

t h is h y p o t h e s i s , s h o w i n g t h e p r e s e n c e o f 5 - H T 1 r e -

c e p t o r s in t h e r a p h 6 n u c l e i a n d s p i n a l c o r d , a s w e l l a s

i n s o m e o t h e r b r a i n s t e m s t r u c t u r e s • R e g a r d i n g t h e

s p i n a l c o r d , m o s t o f th e r e c e p t o r s p r e s e n t i n t h e d o r -

s a l h o r n a r e o f t h e 5-HTIA s u b t y p e , s u g g e s t in g a r o l e

o f t h e s e s i t e s i n t h i s s y s t e m •

S o m e v e g e t a t i v e f u n c ti o n s , s u c h a s t h e c o n t r o l o f

b l o o d p r e s s u r e a n d r e s p i r a t io n a r e k n o w n t o b e i n fl u -

e n c e d b y c e n t r a l 5 - H T a ct iv it y8 ,6 3 . A l t h o u g h o u r d a t a

r e v e a l t h e p r e s e n c e o f 5 - H T 1 r e c e p t o r s i n s e v e r a l

b r a i n s t e m n u c l e i w h i c h p l a y a n i m p o r t a n t r o l e i n

t h e s e f u n c t i o n s , s u c h a s t h e n u c l e u s o f t h e s o l i t a r y

t r a c t , f u r t h e r w o r k i s n e e d e d t o c l a ri f y t h e 5 - H T i n -

v o l v e m e n t i n t h e se e f fe c t s.

I n t h e l a s t fe w y e a r s , t h e r o l e o f 5 - H T r e c e p t o r s i n

s o m e n e u r o l o g i c a l d i s ea s e s h a s b e e n t h e m a t t e r o f in -

c r e a s in g r e s ea r c h • A d e c r e a s e i n t h e n u m b e r o f 5 - H T



22 4

r e c e p t o r s i n t h e c o r t e x o f p a t i e n t s s u f f e r i n g f r o m s e -

n i le d e m e n t i a o f t h e A l z h e i m e r t y p e h a s b e e n r e p o r t -

edlS ,30,113 . A l tho ug h the dec r ease in 5 - H T 2 r ec ep tor s

a p p e a r s t o b e g r e a t e r , 5 - H T 1 r e c e p t o r s a r e a l so a f -

f e c t e d , m a i n l y i n t h o s e p a t i e n t s p r e s e n t i n g a l a t e r

s tage o f the d i sease18, 30. A r o le o f d imin ished nu m be r

o f 5 - H T 1 s it e s in t h e i m p a i r e d c o g n i t i v e a c t i v i t y c h a r -

a c t e r i s ti c o f th i s d i s e a s e i s t h e r e f o r e p o s s i b l e . R e -

l a t e d t o t h i s , t h e i n v o l v e m e n t o f s e r o t o n i n e r g i c t r a n s-

m i s s io n i n le a r n i n g a n d m e m o r y p r o c e s s e s , a s h a s

b e e n s h o w n i n a n i m a l s 7.92 a n d i n h u m a n s 132, m u s t b e

t a k e n i n t o c o n s i d e r a t io n .

A r o l e o f ce n t r a l 5 - H T a c t iv i t y i n th e m e c h a n i s m s

o f s c h i z o p h r e n i a h a s a l s o b e e n i n v e s t i g a t e d . W h i l e

a n i n c r e a s e i n t h e s t r i a t a l c o n c e n t r a t i o n o f 5 - H T

i n b r a i n s f r o m s c h i z o p h r e n i c p a t i e n t s h a s b e e n r e -

p o r t e d 31, a c l e a r d e c r e a s e o f [ 3 H ] L S D b i n d i n g t o

f r o n t a l c o r ti c a l m e m b r a n e s h a s a l so b e e n f o u n d n .

T h e s e d a t a d o n o t a l l o w a n y s t a t e m e n t o n t h e p o s s i -

b l e r o l e o f 5 - H T 1 r e c e p t o r s i n t h i s d i s e a s e . I n a s i m i l a r

w a y , w h i l e c o n s i d e r a b l e e v i d e n c e h a s a c c u m u l a t e d

o n t h e r e l a t i o n s h i p b e t w e e n a n t i d e p r e s s a n t t r e a t -

m e n t s a n d n u m b e r o f c o r ti c a l 5 - H T 2 r e c e p t o r s , n o

c l e a r e f f e c t h a s b e e n s h o w n i n t h e c a s e o f 5 -H T ~ s i t e s

( r e f s . 82 , 123; s ee r e f . 6 f or a r ev iew ) . F ina l ly , th e in -

v o l v e m e n t o f 5 - H T m e c h a n i s m s i n t h e p a t h o g e n e s is

o f m i g r a i n e h a s b e e n p ro p os ed 2 0,1 1 2 a n d t h e p r o p h y -

l a ct ic e f f e ct o f t h e 5 - H T a n t a g o n i s t m e t h y s e r g i d e i n

s o m e t y p e s o f m i g r a i n e i s w e l l - k n o w n ( s e e r e f . 6 4 ) .

W h e t h e r 5 - H T ~ s i t e s a r e i n v o l v e d i n t h i s p r o c e s s i s

u n k n o w n .

O n e o f t h e r e l e v a n t f i n d i n g s o f t h i s w o r k i s t h e

c h a r a c t e r i z a t i o n o f s o m e f l - b l o c k e r s a s d r u g s w i t h

h i g h a f f i n i t y a n d s e l e c t i v i t y f o r t h e 5 - H T i B - r e c o g n i -

t i o n s i t e . T h i s f a c t c o n f i r m s a n d e x t e n d s p r e v i o u s r e -

p o r t s s h o w i n g t h e a b i l i ty o f fl - b l o c k e r s t o d i s p l a c e 5 -

[ 3 H ] H T b i n d i n g i n a s t e r e o s p e c i f i c w a y S 0 ,86. It has

a l so b e e n e s t a b l is h e d t h a t s o m e f l - b l o c k e rs a n t a g o -

n i z e s e v e r a l in v i v o a n d i n v i t r o e f f e c t s i n d u c e d b y s e -

r o tonine r g ic agonis t s ( r e f s . 27 , 51 ; s ee r e f . 133 f or a

r e v i e w ) . O n t h e o t h e r h a n d , f l - a d r e n e r g i c a g o n i s t s

h a v e b e e n r e p o r t e d t o in c r e a s e s o m e 5 - H T b e h a v i o r -

al e f f e c t s 9 1,9 4. T a k e n t o g e t h e r , t h e s e d a t a s u g g e s t a n

i n t e r a c t i o n o f f l - a d r e n e r g i c d r u g s w i t h c e n t r a l 5 - H T 1

r e c e p t o r s . T h i s i n t e r a c t i o n c o u l d e x p l a i n s o m e o f t h e

n e u r o l o g i c a l e f f e c t s i n d u c e d b y fl - b l o c k e r s i n h u -

m a n s , s u c h a s t h e i r t h e r a p e u t i c a c t i v i t y i n s c h i z o -

ph ren ic sta te s 124A37 an d in m ig ra in e 43,131.

T h e l o c a li z a ti o n o f 5 - H T I r e c e p t o r s d e s c r i b e d h e r e

c o r r e l a t e s w e l l w i t h t h e d i s t r i b u t i o n o f s e r o t o n i n e r g i c

t e rm i n a l s . M o s t o f th e a r e a s p r e se n t i n g i m p o r t a n t

c o n c e n t r a t i o n s o f r e c e p t o r s h a v e b e e n f o u n d t o c o n -

t a in n e r v e - e n d i n g s f r o m t h e s e r o t o n i n e r g i c n e u r o n s ,

m ain ly l oc ate d in the rap h6 nuc lei 9,24,99,122. Th e hip -

p o c a m p u s , t h e s e p t a l n u cl e i, t h e n e o c o r t e x , t h e b a s a l

g a n g l i a , t h e d i f f e r e n t n u c l e i o f t h e h y p o t h a l a m u s , ; h e

o l f a c t o r y s y s t e m , o r t h e s u b s t a n t i a n i g r a a r e s t r u c -

t u r es w h e r e t h e p r e s e n c e o f 5 - H T , 5 - H T f i b e rs a n d

b i o c h e m i c a l m a r k e r s h a v e b e e n r e p o r t e d z4,

32,37,45,46,56,68,99,116,122. T h e c h o r o i d p l e x u s e s h a v e

a l s o b e e n s h o w n t o c o n t a i n s e r o t o n i n e r g i c i n n e r v a -

t ion21 .122 . H ow ever , some a r eas ve r y enr iched in 5-

H T 1 s i te s d o n o t p r e s e n t a h i g h l e v e l o f s e r o t o n i n e r g i c

i n n e r v a t i o n . T h i s i s t h e c a s e f o r t h e d o r s a l s u b i c u l u m

o r t h e e n t o p e d u n c u l a r n u c l e u s 24,122. T h e e x i s t e n c e o f

d i s c r e p a n c i e s b e t w e e n t h e d i s t r i b u t i o n o f f i b e r s a n d

r e c e p t o r s h a s b e e n f o u n d w i t h m a n y n e u r o t r a n s m i t -

ters96.98 a n d s e v e r a l e x p l a n a t i o n s h a v e b e e n p r o -

p o s e d ( s e e r e f. 6 2 ). F u r t h e r m o r e , i t s h o u l d b e k e p t i n

m i n d t h a t t h e b r a i n c o n t a i n s a l so 5 - H T 2 r e c e p t o r s ,

w h o s e d i s t r i b u t i o n i s d i f f e r e n t f r o m t h a t o f 5 - H T 1

s i te s 75,1°2 and th i s cou ld exp la in so me ap pa r en t d i s -

c r e p a n c i e s .

O u r r e s u l t s o n t h e d i s t r i b u t i o n a n d p h a r m a c o l o g y

o f 5 - H T l c s i te s c o n f i rm o u r p r e v i o u r r e p o r t s o n t h is

s u b t y p e 25.103, s h o w i n g t h a t t h e p h a r m a c o l o g i c a l p r o -

f il e o b t a i n e d b y q u a n t i t a t i v e a u t o r a d i o g r a p h y i s i d e n -

t i ca l t o t h a t o b t a i n e d i n m e m b r a n e - b i n d i n g a s s a y s 103.

T h e c h o r o i d p l e x u s e s a r e e s p e c i a l l y e n r i c h e d i n t h e s e

5 - H T I c s it e s, p r e s e n t i n g t h e h i g h e s t d e n s i t y o f 5 - H T I

r e c e p t o r s i n t h e r a t b r a i n . V e r y h i g h c o n c e n t r a t i o n s

o f 5 - H T 1 b i n d i n g i n t h e c h o r o i d p l e x u s h a v e a l so b e e n

f o u n d i n o t h e r m a m m a l i a n s p e c i e s , s u c h a s p i g 103 a n d

h u m a n 97. T h e c h o r o i d p l e x u s e s p r e s e n t a n i m p o r t a n t

5 - H T i n n e r v a t i o n , t h e f i b e r s a r i s i n g f r o m t h e r a p h 6

n u c l ei a n d e n d i n g o n t h e b l o o d v e s s e l s t h a t s u p p l y t h e

p lex uses 83 ,87 . I n a ddi t io n , the r e a r e 5- H T f ibe r s o n

t h e s u p r a e p e n d y m a l s u r f a ce o f t h e v e n t r i c u l a r sy s -t e m TM. B e s i d e t h e c h o r o i d p l e x u s , 5 - H T l c s i t e s a r e

a l s o p r e s e n t i n o t h e r b r a i n a r e a s , a s h a s a l r e a d y b e e n

r e p o r t e d i n p i g b r a i n ~04. T h e p o s s i b l e p h y s i o l o g i c a l

s i g n i fi c a n c e o f 5 - H T l c s i t e s is n o t k n o w n a t t h e p r e s -

e n t t i m e . S i n c e t h e y a r e m a i n l y l o c a l i z e d i n t h e c h o -

r o i d p l e x u s e s , t h e y m a y p l a y a r o l e i n th e r e g u l a t i o n

o f t h e p r o d u c t i o n o f c e r e b r o s p i n a l f l u id , a f u n c t i o n

s t r o n g l y l i n k e d t o t h e s e p l e x u s e s 33.



225

An important question concerns the cellular locali-

zation of 5-HT 1 receptors. Using several pres ynaptic

models, such as the inhibition of 5-HT release from

brain synaptosomes or the regulation of noradrena-

line release in the sympathetic endings of canine sa-

phenous vein, several authors have found a correla-tion between the activity of several agonists and an-

tagonists in these tests and their affinity for 5-[3H]HT

binding3S,43,73, although certain discrepancies have

been reported for some drugs48,84. Engel et al. have

shown a good correlation between a subpopulation of

5-HT 1 receptors and 'presynaptic' activity38. 8-OH-

DPAT produces some physiological effects which ap-

pear to be rela ted to 5-HT autoreceptors2,125. In ad-

dition, this compound has been shown to stimulate

presynaptic 5-HT autoreceptors in the central ner-

vous system, but only at micromolar concentra-

tions49,54. This fact, and other biochemical data sug-

gest a link of 5-HT autoreceptors to 5-HT1B sites78,79.

Anot her approach to study the cellular localization of

5-HT 1 receptors has bee n the analysis of the effects

of different types of lesions on 5-[3H]HT binding. I n

this regard, it has been reported that chemical le-

sioning of serotoninerg ic neurons with 5,7-dihydroxy-

tryptamine increased the amount of 5-[3H]HT bind-

ing in the hippocampus, where 5-HTtA sites are pre-

domin ant 89, indicating a supersensitivity of these re-

ceptors, similar to that observed in behavioral stud-

ies 129. In cont rast , electr olytic lesions of the raph6

nuclei did not modify 5-HT1 binding in the cortex 16

and the destruction of the 5-HT fibers of the fornix-

fimbria and cingulum bundle produce d no change in

5-[3H]HT binding to the hippo campus 111. Alt houg h

the clarification of this point is beyond the scope of

the present work, we have recently found (Pazos et

al., in preparation) that electrolytic lesions of the

septum in duce a decrease of 5-HTIA and 5-HT m sites

in different areas of the hippocampus, measured by

quantitative autoradiography. Since the septo-hippo-

campal project ion is one of the main central choliner-

gic pathways71, these results suggest the presence of

5-HT 1 receptors on cholinergic fibers. This finding is

not surprising, because an interaction between sero-

toninergic and cholinergic neurons in the central ner-

vous system has been demo nstr ated 118.

In conclusion, sites with the pharmacol ogical prop-

erties of 5-HTl-binding sites are h etero geneo usly dis-

tributed in the rat brain a nd thre e s ubtypes of 5-HT 1

sites can be identified with different pha rmacolog ical

profiles and anatomical distribution. The presence of

these receptors in different brain areas correlates

well with the prop osed role o f 5- HT 1 sites in several

central functions. Although there are some discrep-

ancies o n this point 66, these d ata seem to provide

good evidence to c onsider 5-HT 1 sites as receptors.

ACKNOWLEDGEMENTS

The authors wish to thank Drs. P. H. Kelly and F.

Nordt for critical reading of the manuscrip t.

ABBREVIATIONS USED IN FIGURES

2 layer 2 of Rexed7 facial nucleus9 layer 9 of Rexed10 layer 10 of RexedAoP anterior olfactory nucleus, posterior part

CA field CA 1of the hippocampusCb cerebellumCG central (periaqueductal) greyChP choroid plexusCI claustrumCPu caudate-putamenCP u, b caudate-putamen, odyCP u, h caudate-putamen, eadDG dentate gyrusDR dorsal raph6 nucleiEnt entorhinalortexEP entopeduncularucleus

FrFrPaMFrPaSSHp1oLatCLS

LSIRSplSSCSNRSp

StrSuGTuVMHVP

frontal cortexfrontoparietal cortex, motor areafrontoparietal cortex, somatosensoryareahippocampusinferior olivelateral cerebellar nucleuslateral septai nucleus

lateral septal nucleus, intermediate partretrosplenial cortexdorsal subiculumsuperior colliculussubstantia nigra, reticular partnucleus of the spinal tract of the trigeminal nerve,caudal partstriate cortexsuperficial grey layer of the superior colliculusolfactory ubercleventromedial hypothalamicnucleusventral pallidum



2 2 6

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