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Differential effect of haloperidol on DOPAC levels in the substantia nigra and ventral tegmental area
683
Pharmacological Research Communications, Vol. 12, No. 7, 1980
DIFFERENTIAL EFFECT OF HALOPERIDOL ON DOPAC LEVELS IN TIlE SUBSTANTtA N IGRA AND VENTRAL TEGMENTAL AREA, ~:A. ARGIOLAS, F. FADDA, M.R. MELIS and G.L. GESSA
I n s t i t u t e s of Pharmacology and Physiology, University o f Cagl i a r i , Italy,
SUMMARY The e f f e c t of acute (i m9/k9) and c h r o n i c 0 mg/kg daily For 15 days) haloperldol treatment on DOPAC concentration in the subst~ntia Jllgra and ventral tegmental area was compared. Neither acute nor chronic haloperldol treatment modified DOPAC concentration in the VTA or DA concentration in both the areas. Two hrs a f t e r acute haloperidol DOPAC increased by about 130% in the substantla nigPa, remained elevated For about 6 hrs and returned to normal w i t h i n 24 h r s . On t h e c o n t r a r y , a f t e r c h r o n i c h a l o p e r l d o l treatment, DOPAC levels in the substantia n l g r a remained maximally e l e v a t e d For s e v e r a l days and r e t u r n e d t o c o n t r o l v a l u e on the 5th day F o l l o w i n g h a l o p e r l d o l withdrawal, INTRODUCTION
dopamine
Acute n e u r o l e p t i c
administration
(DA) synthesis
in the striatum,
(see Carlsson, ]g75;
cortex
Julou etal,
is known t o
increase
n, accumbens and Frontal
1977) p r e s u m a b l y by b l o c k -
ing DA r e c e p t o r s ,
The change
parallel
in the content o f 3 , 4 - d l h y d r o x y p h e n y l a c e t l c
increase
in DA s y n t h e s i s
is correlated
with a acid
(DOPAC), the deaminated DA metabolite (see Westerink and KorF, Ig76). Tolerance to the effects on DA synthesis develops after chronic neuro|eptic administration cortical
in the nigrostriatal
t976),
DA system (see Julou e t a l ,
but not in the mesa-
The cell bodies oF the
mesocortical DA system a r e m a i n l y l o c a t e d in the v e n t r a l
tegmental
area (VTA), the area I0, while those of the n i g r o s t r i a t a l system are in the p a r s compacta o f the s u b s t a n t i a
I964),
Recent e v i d e n c e
in the nerve t e r m i n a l s
has shown t h a t but also
nigra
( S N ) ( D a l h s t r o m and Fuxe,
DA i s p r e s e n t n o t o n l y
in t h e c e l l
b o d i e s and d e n d r i t e s
dopamlner9ic neurons in the SN and VTA (see Lindvall e t a l , Presented at the Third Italian-Soviet Brain Function
~31-~89/80~3--0~2.00~
of
1978).
Symposi~im on Ncurotransmitt~rs
and
Q19~Thelt~li~nPharma~l~lS~,ety
PharmacologicalResearchCommunication&VoL 14 No, ~ 1980
684 Moreover
it
thereby
has been s u g g e s t e d t h a t
exherting
activity
an i n h i b i t o r y
control
1975;
Nieoullon
(groves et
shown t h a t gesting
al,
haloperidol
that
DA i s r e l e a s e d
on d o p a m i n e r g i c
1977),
et al,
c a u s e s DOPAC a c c u m u l a t i o n
nedroleptics
From d e n d r i t e s
i n c r e a s e DA r e l e a s e
neuronal
We have
in t h e SN, s u g -
From d e n d r i t e s
in
this area (Fadda eb al, 1977), The present report was at clarifying i f
the d i f f e r e n t
response of nigrostriatal
DA s y s t e m s t o c h r o n i c different
effect
of
neuroleptlc
was c o r r e l a t e d
t h e s e d r u g s on DA m e t a b o l i s m
t i l e VTA. We show t h a t
chronic
sistent
increase
neither
acute nor chronic
DOPAC l e v e l s
treatment
and m e s o c o r b l c a l
haloperidol
in t h e DOPAC c o n t e n t haloperidol
of
to a
in the SN and in
treatment
causes a per-
the SN. On t h e c o n t r a r y
treatment
is able
to m o d i f y
in the VTA,
MATERIAL AND METHODS Maie Sprague Dawley r a t s ,
weighing
initially
160-180 g
were u s e d , The a n i m a l s were housed 4 p e r cage a t ~4°C, 50-60~, before
and 12 hr
llght-dark
the experiments.
cycle,
starting
The a n i m a l s r e c e i v e d
dol
below.
saline time.
injections
the brain
30°C u n t i l
analyses,
was r a p i d l y
(Fadda eb e l ,
Control
1977;
analyzed.
ble
Tassin'et
labot~atoryf
acute or chronic received rats
halopenl-
t h e same numbe
of
a t the c o r r e s p o n d i n g
were k i l l e d
al,
1978)
by d e c a p i t a t i o ~
on i c e and s t o r e d
DA and DOPAC were d e t e r m i n e d
(Serenase,
Form. The s t a t i s t i c a l
t e d by t h e S t u d e n t ' s
rats
one week
removed and t h e SN and VTA were d i s s e c t e d at -
in t h e same
and Fadda,
1978),
J a n s s e n ) was used in c o m m e r c i a l l y
availa-
sample by o u r r a d l o e n z y m a t i c Haloperidol
rats
as t h e e x p e r i m e n t a l
For b i o c h e m i c a l
least
They had w a t e r and s t a n d a r d
Food ad l i b i t u m . as i n d i c a t e d
at
humidity
method ( A r g i o l a s
significance E best.
of
the results
was e v a l u a -
Pharmaco/ogica/ Research Communicat(ons, Vol, 12, No. 7, 1980
685
RESULTS Fig I shows the time course oF the eE~ects oF I rag/k9 i . p . haloperidol on DOPAC levels reported, DOPAC increased
in the SN ai~d VTA. As prev~)usly
in the SN by about 13C~ 2 hrs af~t'eP
treat:manE, remained elevated Fop about.6 hrs and returned to control value in approxim.~tely 24 hrs. On the contrary no chanoe in DOPAC concentration was observed in the VTA. Haloperidol Failed to change DA levels e i t h e r
in the SN or in the VTA.
,1.O
=,-o S N . A
"
..
~
VTA
,
-- 200" 0 t,.
c 0 (J qk.
0
C) <
o. 0 r~ v 0 o
,
ill
i,
i
? 1.
_. . . . . . . . . . .
,,,6. . . . . . . . . 1
Fig
-
Time course
2
of
3
the
changes
4
5
i n d u c e d by !
hours
> /
~........ 24
m g / k 9 oF h a l o p e -
t i d a l i . p . on DOPAC levels in the substantia nigra (SN) and ventral tegmental area (VTA). Each value is the mean + S.E. oF 5 determinations. In control P a t s the DOPAC c--ontent in the SN and VTA was 1724+154 ng/g and I554+_142 n9/g r e s p e c t i v e l y . ~ P(O.O01; ~ P(O.O5 in respect o f saline c o n t r o l s .
Pharmacological Research Communications, Vol. 12, No. 7, 1980
686
F i g 2 shows DOPAC l e v e l s after
khe l a s t
injection
(J mg/kg,
daily
injection
treatment
24 h r s , elevated
ruption,
oF a c h r o n i c
For JS d a y s )
DOPAC l e v e l s
As a f t e r
was p r e s e n t
returned
treatment
up the 4 t h day a f t e r only
treatment
, While after
Followlng a chronic
ned to c o n t r o l v a l u e
in the SN a t d i F F e r e n t
to control
haloperidol
the a c u t e t r e a t m e n t chronic
haloperidol haloperidol value within
they remained maxlmally withdrawal
no change
and r e t u r -
haloperidoi
inter-
in DOPAC l e v e l s
treatment,
SUBSTANTIA [~
a single
a t the 5th day a f t e r
in the VTA a f t e r
with
times
NIGRA
CHRONIC SALINE CHRONIC
HALOPERIDOL
200 0
L.
0 U
U 9K
tOO
L
o
o
2
;P4
48
72
t20
h r a f t e r HAL
F i g 2. DOPAC l e v e l s in the s u b s t a n t i a n i g e a a t v a r i o u s t i m e s a f t e r the l a s t i n j e c t i o n o f a c h r o n i c t r e a t m e n t w i t h h a l o p e r i d o l (1 mg/k9 i , p , d a i l y f o r 15 d a y s ) and a f t e r the a c u t e i n j e c t i o n oF 1 mg/kg h a l o p e r i d o l in r a t s c h r o n i c a l l y t r e a t e d w i t h s a l i n e . Each v a l u e i s the mean + S.E= oF 5 d e t e r m i n a t i o n s . DOPAC l e v e l s in the VTA were n o t mod i f i e d e i t h e r by a c u t e o r c h r o n i c h a l o p e r i d o l , * P ¢ 0 , 0 0 1 in r e s p e c t oF sai ine t r e a t e d r a t s =
Pharmacological Research Communications, VoL 12, No. 7, 1980
687
IU scuss I ON, The p r e s e n t r e s u l t s i n f l u e n c e s DOPAC l e v e l s to haloperidol cteristics
show t h a t h a l o p e r i d o l
differentially
in the SN and VTA. Two d i s t i n c t
suggest d i f f e r e n t
o f the n i g r o s t r i a t a l
increase on DOPAC l e v e l s
regulatory
and F u n c t i o n a l
and m e s o c o r t i c a l
in the SN a f t e r
ted on axonal nating
chara-
DA systems. The
acute h a i o p e r i d o l
be due to the blockade o f DA a u t o r e c e p t o r s p r e s e n t (Nagy e t a l ,
responses
might
in t h i s
area
1978) or o f the D A - s e n s l t i v e a d e n y l a t e c y c l a s e t e r m i n a l s o f neurons i n n e r v a t i n g
in the striatum ( Gale et e l ,
1976t Spano e t e l ,
loca-
the SN and o r i g i -
1977; Kebabian and Saavedra,
1977).
In co,,trast to the SN, no evidence has been provided as yet For the existence in the VTA of DA autoreceptors, nor o f DAsensitive adenylate cyclase (Premont et e l ,
1976).Moreover,
there
is no evidence For a Feedback loop From the l imbic or c o r t i c a l areas to the VTA. Thus, none of those elements on which h a l o p e r i dot might operate when modifying DOPAO content seems to be present in the VTA. The p e r s i s t e n t increase in SN DOPAC content: a f t e r
inter-
ruption of chronic haloperidol treatment might indicate a stable modification in DA synthesis and cannot be correlated with the
presence o f h a l o p e r i d o l
in the b r a i n ,
even up to the 4 t h day a f t e r
haloperidol
drug i s c o m p l e t e l y el i m i n a t e d , t h e s i s might r e f l e c t
since the
increase p e r s i s t s
withdrawal,
The p e r s i s t e n t
an enhanced s t i m u l a t i o n
when the
change in DA syno f a u t o r e c e p t o r s clue
to an increased r e l e a s e o f DA From d e n d r i t e s ,
T h i s mechanism might
contribute to the development o f tolerance to the e f f e c t s o f haloperidol
in the n i g r o s t r i a t a l system, On the contrary, the absence
o f changes in DA metabolism in the VTA a f t e r chronic haloperidol treatment m i g h t explain the lack of tolerance to the e f f e c t s of
haioperidoi
on DA s y n t h e s i s
in the m e s o c o r t l c a l
DA system,
688
Pharmacological Hesearch Communications, VoL 12, No. 7, 1980
REFERENCES Argiolas A, and Fadda F,, Experientia 34, 739-741 (1978), Carisson A,, in Pre- and p o s t - s y n a p t i c Receptors, ads E, Usclin end W,E, Bunney,jr, Marcel Dekkert New York, pp, 45-63 (1975). Dalhstrom A. and Fuxe K,, Acta PFysiol. Scand, 6.22, suppl. 232,
t-55 (1964). Fadda F,, Argiolas A., Stefenini E. and Gessa G.L,, Life Sci. 21, 411-418 (1977), Gale K., Guidotti A. and Costa E., Science 195, 503-505 (1977). Groves P.M,, Wilson C,J., Youn9 S,J, and Rebec G.V., Science 190,
522-529 (1975), Julou t , , Scatton B, and Glowlnski J., in Advances in Biochemical Psychopharmacology, eds E, Costa and G,L, Gessa, Vol 16, Raven Press, New York, pp, 617-624 (1977). Kebabian J,W. and Saavedra J,M., Science 193, 683-685 (1976). Lindvall 0,, Bjorklund A. and Divac I , , Brain Res. [42, [-24
(1978). Nagy J,T,, Lee P,, Seaman P. and Fibiger H.Clp Nature 274, 278-
281 (1978). Nieoullon A,, Cheramy A. and Glowinski J., Nature 266, 375-377
(1977). Premont J , , T h i e r r y A.M., Tassin J , P , , Glowinski J . , Blanc G, and Bockaert J,, FEBS Letters 68, 99-104 (1976), Spano P.F., Trabucchi M. and Di Chiara G., Science 196,13431345 (1977). Tassin J , P , , Stinus L., Simon H., Blanc O,, T h i e r r y A,M,, [e Meal M,, Cardo B, and Glowinski J . , Brain Res. 141,,, 267-281 (1978). Westerink B.H.C, and Karl J,, Brain Res. 113, 429-434 (1976).
Pharmacological Research Communications, Vol. 12, No. 7, 1980
DIFFERENTIAL EFFECT OF HALOPERIDOL ON DOPAC LEVELS IN TIlE SUBSTANTtA N IGRA AND VENTRAL TEGMENTAL AREA, ~:A. ARGIOLAS, F. FADDA, M.R. MELIS and G.L. GESSA
I n s t i t u t e s of Pharmacology and Physiology, University o f Cagl i a r i , Italy,
SUMMARY The e f f e c t of acute (i m9/k9) and c h r o n i c 0 mg/kg daily For 15 days) haloperldol treatment on DOPAC concentration in the subst~ntia Jllgra and ventral tegmental area was compared. Neither acute nor chronic haloperldol treatment modified DOPAC concentration in the VTA or DA concentration in both the areas. Two hrs a f t e r acute haloperidol DOPAC increased by about 130% in the substantla nigPa, remained elevated For about 6 hrs and returned to normal w i t h i n 24 h r s . On t h e c o n t r a r y , a f t e r c h r o n i c h a l o p e r l d o l treatment, DOPAC levels in the substantia n l g r a remained maximally e l e v a t e d For s e v e r a l days and r e t u r n e d t o c o n t r o l v a l u e on the 5th day F o l l o w i n g h a l o p e r l d o l withdrawal, INTRODUCTION
dopamine
Acute n e u r o l e p t i c
administration
(DA) synthesis
in the striatum,
(see Carlsson, ]g75;
cortex
Julou etal,
is known t o
increase
n, accumbens and Frontal
1977) p r e s u m a b l y by b l o c k -
ing DA r e c e p t o r s ,
The change
parallel
in the content o f 3 , 4 - d l h y d r o x y p h e n y l a c e t l c
increase
in DA s y n t h e s i s
is correlated
with a acid
(DOPAC), the deaminated DA metabolite (see Westerink and KorF, Ig76). Tolerance to the effects on DA synthesis develops after chronic neuro|eptic administration cortical
in the nigrostriatal
t976),
DA system (see Julou e t a l ,
but not in the mesa-
The cell bodies oF the
mesocortical DA system a r e m a i n l y l o c a t e d in the v e n t r a l
tegmental
area (VTA), the area I0, while those of the n i g r o s t r i a t a l system are in the p a r s compacta o f the s u b s t a n t i a
I964),
Recent e v i d e n c e
in the nerve t e r m i n a l s
has shown t h a t but also
nigra
( S N ) ( D a l h s t r o m and Fuxe,
DA i s p r e s e n t n o t o n l y
in t h e c e l l
b o d i e s and d e n d r i t e s
dopamlner9ic neurons in the SN and VTA (see Lindvall e t a l , Presented at the Third Italian-Soviet Brain Function
~31-~89/80~3--0~2.00~
of
1978).
Symposi~im on Ncurotransmitt~rs
and
Q19~Thelt~li~nPharma~l~lS~,ety
PharmacologicalResearchCommunication&VoL 14 No, ~ 1980
684 Moreover
it
thereby
has been s u g g e s t e d t h a t
exherting
activity
an i n h i b i t o r y
control
1975;
Nieoullon
(groves et
shown t h a t gesting
al,
haloperidol
that
DA i s r e l e a s e d
on d o p a m i n e r g i c
1977),
et al,
c a u s e s DOPAC a c c u m u l a t i o n
nedroleptics
From d e n d r i t e s
i n c r e a s e DA r e l e a s e
neuronal
We have
in t h e SN, s u g -
From d e n d r i t e s
in
this area (Fadda eb al, 1977), The present report was at clarifying i f
the d i f f e r e n t
response of nigrostriatal
DA s y s t e m s t o c h r o n i c different
effect
of
neuroleptlc
was c o r r e l a t e d
t h e s e d r u g s on DA m e t a b o l i s m
t i l e VTA. We show t h a t
chronic
sistent
increase
neither
acute nor chronic
DOPAC l e v e l s
treatment
and m e s o c o r b l c a l
haloperidol
in t h e DOPAC c o n t e n t haloperidol
of
to a
in the SN and in
treatment
causes a per-
the SN. On t h e c o n t r a r y
treatment
is able
to m o d i f y
in the VTA,
MATERIAL AND METHODS Maie Sprague Dawley r a t s ,
weighing
initially
160-180 g
were u s e d , The a n i m a l s were housed 4 p e r cage a t ~4°C, 50-60~, before
and 12 hr
llght-dark
the experiments.
cycle,
starting
The a n i m a l s r e c e i v e d
dol
below.
saline time.
injections
the brain
30°C u n t i l
analyses,
was r a p i d l y
(Fadda eb e l ,
Control
1977;
analyzed.
ble
Tassin'et
labot~atoryf
acute or chronic received rats
halopenl-
t h e same numbe
of
a t the c o r r e s p o n d i n g
were k i l l e d
al,
1978)
by d e c a p i t a t i o ~
on i c e and s t o r e d
DA and DOPAC were d e t e r m i n e d
(Serenase,
Form. The s t a t i s t i c a l
t e d by t h e S t u d e n t ' s
rats
one week
removed and t h e SN and VTA were d i s s e c t e d at -
in t h e same
and Fadda,
1978),
J a n s s e n ) was used in c o m m e r c i a l l y
availa-
sample by o u r r a d l o e n z y m a t i c Haloperidol
rats
as t h e e x p e r i m e n t a l
For b i o c h e m i c a l
least
They had w a t e r and s t a n d a r d
Food ad l i b i t u m . as i n d i c a t e d
at
humidity
method ( A r g i o l a s
significance E best.
of
the results
was e v a l u a -
Pharmaco/ogica/ Research Communicat(ons, Vol, 12, No. 7, 1980
685
RESULTS Fig I shows the time course oF the eE~ects oF I rag/k9 i . p . haloperidol on DOPAC levels reported, DOPAC increased
in the SN ai~d VTA. As prev~)usly
in the SN by about 13C~ 2 hrs af~t'eP
treat:manE, remained elevated Fop about.6 hrs and returned to control value in approxim.~tely 24 hrs. On the contrary no chanoe in DOPAC concentration was observed in the VTA. Haloperidol Failed to change DA levels e i t h e r
in the SN or in the VTA.
,1.O
=,-o S N . A
"
..
~
VTA
,
-- 200" 0 t,.
c 0 (J qk.
0
C) <
o. 0 r~ v 0 o
,
ill
i,
i
? 1.
_. . . . . . . . . . .
,,,6. . . . . . . . . 1
Fig
-
Time course
2
of
3
the
changes
4
5
i n d u c e d by !
hours
> /
~........ 24
m g / k 9 oF h a l o p e -
t i d a l i . p . on DOPAC levels in the substantia nigra (SN) and ventral tegmental area (VTA). Each value is the mean + S.E. oF 5 determinations. In control P a t s the DOPAC c--ontent in the SN and VTA was 1724+154 ng/g and I554+_142 n9/g r e s p e c t i v e l y . ~ P(O.O01; ~ P(O.O5 in respect o f saline c o n t r o l s .
Pharmacological Research Communications, Vol. 12, No. 7, 1980
686
F i g 2 shows DOPAC l e v e l s after
khe l a s t
injection
(J mg/kg,
daily
injection
treatment
24 h r s , elevated
ruption,
oF a c h r o n i c
For JS d a y s )
DOPAC l e v e l s
As a f t e r
was p r e s e n t
returned
treatment
up the 4 t h day a f t e r only
treatment
, While after
Followlng a chronic
ned to c o n t r o l v a l u e
in the SN a t d i F F e r e n t
to control
haloperidol
the a c u t e t r e a t m e n t chronic
haloperidol haloperidol value within
they remained maxlmally withdrawal
no change
and r e t u r -
haloperidoi
inter-
in DOPAC l e v e l s
treatment,
SUBSTANTIA [~
a single
a t the 5th day a f t e r
in the VTA a f t e r
with
times
NIGRA
CHRONIC SALINE CHRONIC
HALOPERIDOL
200 0
L.
0 U
U 9K
tOO
L
o
o
2
;P4
48
72
t20
h r a f t e r HAL
F i g 2. DOPAC l e v e l s in the s u b s t a n t i a n i g e a a t v a r i o u s t i m e s a f t e r the l a s t i n j e c t i o n o f a c h r o n i c t r e a t m e n t w i t h h a l o p e r i d o l (1 mg/k9 i , p , d a i l y f o r 15 d a y s ) and a f t e r the a c u t e i n j e c t i o n oF 1 mg/kg h a l o p e r i d o l in r a t s c h r o n i c a l l y t r e a t e d w i t h s a l i n e . Each v a l u e i s the mean + S.E= oF 5 d e t e r m i n a t i o n s . DOPAC l e v e l s in the VTA were n o t mod i f i e d e i t h e r by a c u t e o r c h r o n i c h a l o p e r i d o l , * P ¢ 0 , 0 0 1 in r e s p e c t oF sai ine t r e a t e d r a t s =
Pharmacological Research Communications, VoL 12, No. 7, 1980
687
IU scuss I ON, The p r e s e n t r e s u l t s i n f l u e n c e s DOPAC l e v e l s to haloperidol cteristics
show t h a t h a l o p e r i d o l
differentially
in the SN and VTA. Two d i s t i n c t
suggest d i f f e r e n t
o f the n i g r o s t r i a t a l
increase on DOPAC l e v e l s
regulatory
and F u n c t i o n a l
and m e s o c o r t i c a l
in the SN a f t e r
ted on axonal nating
chara-
DA systems. The
acute h a i o p e r i d o l
be due to the blockade o f DA a u t o r e c e p t o r s p r e s e n t (Nagy e t a l ,
responses
might
in t h i s
area
1978) or o f the D A - s e n s l t i v e a d e n y l a t e c y c l a s e t e r m i n a l s o f neurons i n n e r v a t i n g
in the striatum ( Gale et e l ,
1976t Spano e t e l ,
loca-
the SN and o r i g i -
1977; Kebabian and Saavedra,
1977).
In co,,trast to the SN, no evidence has been provided as yet For the existence in the VTA of DA autoreceptors, nor o f DAsensitive adenylate cyclase (Premont et e l ,
1976).Moreover,
there
is no evidence For a Feedback loop From the l imbic or c o r t i c a l areas to the VTA. Thus, none of those elements on which h a l o p e r i dot might operate when modifying DOPAO content seems to be present in the VTA. The p e r s i s t e n t increase in SN DOPAC content: a f t e r
inter-
ruption of chronic haloperidol treatment might indicate a stable modification in DA synthesis and cannot be correlated with the
presence o f h a l o p e r i d o l
in the b r a i n ,
even up to the 4 t h day a f t e r
haloperidol
drug i s c o m p l e t e l y el i m i n a t e d , t h e s i s might r e f l e c t
since the
increase p e r s i s t s
withdrawal,
The p e r s i s t e n t
an enhanced s t i m u l a t i o n
when the
change in DA syno f a u t o r e c e p t o r s clue
to an increased r e l e a s e o f DA From d e n d r i t e s ,
T h i s mechanism might
contribute to the development o f tolerance to the e f f e c t s o f haloperidol
in the n i g r o s t r i a t a l system, On the contrary, the absence
o f changes in DA metabolism in the VTA a f t e r chronic haloperidol treatment m i g h t explain the lack of tolerance to the e f f e c t s of
haioperidoi
on DA s y n t h e s i s
in the m e s o c o r t l c a l
DA system,
688
Pharmacological Hesearch Communications, VoL 12, No. 7, 1980
REFERENCES Argiolas A, and Fadda F,, Experientia 34, 739-741 (1978), Carisson A,, in Pre- and p o s t - s y n a p t i c Receptors, ads E, Usclin end W,E, Bunney,jr, Marcel Dekkert New York, pp, 45-63 (1975). Dalhstrom A. and Fuxe K,, Acta PFysiol. Scand, 6.22, suppl. 232,
t-55 (1964). Fadda F,, Argiolas A., Stefenini E. and Gessa G.L,, Life Sci. 21, 411-418 (1977), Gale K., Guidotti A. and Costa E., Science 195, 503-505 (1977). Groves P.M,, Wilson C,J., Youn9 S,J, and Rebec G.V., Science 190,
522-529 (1975), Julou t , , Scatton B, and Glowlnski J., in Advances in Biochemical Psychopharmacology, eds E, Costa and G,L, Gessa, Vol 16, Raven Press, New York, pp, 617-624 (1977). Kebabian J,W. and Saavedra J,M., Science 193, 683-685 (1976). Lindvall 0,, Bjorklund A. and Divac I , , Brain Res. [42, [-24
(1978). Nagy J,T,, Lee P,, Seaman P. and Fibiger H.Clp Nature 274, 278-
281 (1978). Nieoullon A,, Cheramy A. and Glowinski J., Nature 266, 375-377
(1977). Premont J , , T h i e r r y A.M., Tassin J , P , , Glowinski J . , Blanc G, and Bockaert J,, FEBS Letters 68, 99-104 (1976), Spano P.F., Trabucchi M. and Di Chiara G., Science 196,13431345 (1977). Tassin J , P , , Stinus L., Simon H., Blanc O,, T h i e r r y A,M,, [e Meal M,, Cardo B, and Glowinski J . , Brain Res. 141,,, 267-281 (1978). Westerink B.H.C, and Karl J,, Brain Res. 113, 429-434 (1976).