Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat

Brain Research, 363 (1986) 128-134 Elsevier

128

BRE 11370

Frontal Decortication and Adaptive Changes in Striatal Cholinergic Neurons in the Rat SILVANA CONSOLO, MARIA SIEKLUCKA, FRANCESCO FIORENTINI, GIANLUIGI FORLONI and HERBERT LADINSKY

lstttuto di Rtcerche Farmacologtehe 'Mario Negrt', Mdan (Italy) (Accepted May 14th, 1985)

Key words decortlcation - - cortlcostriatal pathway - - mgrostrlatal pathway - - striatum - acetylchohne - - apomorphme - - choline - - bromocnptme - - neuroleptlc - - rat

Interruption of the cortlcostrlatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylchohne (ACh) synthesis by 30% in striatum after two postleslon weeks without affecting the content of ACh and choline, the specific binding of [3H]dexetimide to muscarlnlC receptors, the activity of choline acetyltransferase and the levels of noradrenahne, serotonin, dopamlne and 3,4-dihydroxyphenylacetlc acid The influence of this exotatory pathway on strlatal chohnergtc neuropharmacology was investigated It was found that the effect of a number of agonists (R-apomorphlne, bromocrlptlne, hsunde, quinpirole. JL-14389, 2-chloroadenoslne, oxotremorine and methadone), capable of depressing cholinerglc activity in the strmtum through receptor-mediated responses - - reflected as an increase in ACh content - - is operatwe only when the corticostrmtal pathway is intact By contrast, antagonists capable of decreasing ACh content, 1 e the typical neurolepucs plmozlde, halopendol and the atypical ones clozaplne, L-sulplnde, as well as the antl-muscarlmc agent scopolamine, were not influenced by the lesion The possibility that the lesion non-specifically damaged striatal cells on which the agomsts, but not the antagonists acted was excluded by results showing, firstly, that the increase in strmtal ACh elioted by the ACh precursor, choline, was not blocked by decorticatlon, and secondly, that the degeneration of the corticostnatal neurons did not prevent the ACh-increasmg effect of bromocnptme, a long-acting ergot alkaloid, when suffloent time was allowed for the drug to act It was furthermore possible to restore the inhibitory action of apomorphlne on chohnerglc neurons either by short-term chemical lesion of the nlgrostnatal dopaminerglc input or by the administration of chohne The results suggest that the deafferentmted chohnerglc neurons, being already Inhibited by the toss of the excitatory Input, cannot further be depressed by drugs that slow down their actiwty and their ACh turnover rate Finally, some comments on the relatmnshlp between the dopaminergic, cholinergic and excitatory inputs an the strlatum will be gwen

INTRODUCTION

m o r p h o l o g t c a l l y s~milar to the p r e s u m e d strmtal cholmergic interneuronslO

T h e entire c e r e b r a l c o r t e x p r o j e c t s into the stria-

Several lines of e v i d e n c e suggest that the corticos-

turn m a highly o r d e r e d a r r a n g e m e n t with the n e o cortex sending fibers to the caudoputamen39, an a r e a

triatal p a t h w a y uses g l u t a m a t e as p o t e n t i a l n e u r o transmitterg,15.24.29.36 an e x c i t a t o r y a m m o acid which

which stands out as having an e x t r e m e l y rich c o n t e n t

has b e e n s h o w n to m c r e a s e K + - e v o k e d A C h release

of A C h (acetylchollne) and r e l a t e d e n z y m e s c o m -

from s m a t a l slices m vitro t h r o u g h N M D A ( N - m e t h -

p a r e d with m a n y o t h e r parts of the brain. T h e n e o cortical p r o j e c t i o n s o r i g i n a t e f r o m two classes of

yl-D-aspartate)-type r e c e p t o r s and g l u t a m l c acidpreferring r e c e p t o r s possibly localized on the c h o h n -

cells' slowly c o n d u c t m g cells that p r o j e c t only to the

ergtc cell ~6. T h a t the corttcostrtatal p a t h w a y regu-

s t n a t u m and large, fast c o n d u c t m g o n e s that p r o j e c t

lates c h o h n e r g l c activity is f u r t h e r i n d i c a t e d by data

to the b r a m s t e m and gtve off collaterals to the strta-

showing that the synthesis rate of A C h 4°, as well as

turn B o t h of these cell types reside m layers V, VI and in the s u p r a g r a n u l a r layer and a p p e a r , on the ba-

the s o d i u m - d e p e n d e n t high-affimty u p t a k e of choline ( S D H A C U ) 35, are r e d u c e d in the striatum f o l l o w i n g

sis of e l e c t r o n m~croscoplc e v i d e n c e 13, to m a k e syn-

l o n g - t e r m d e c o r t t c a u o n , t h e s e results are s u p p o r t e d by less direct e v i d e n c e s h o w i n g that the d e g e n e r a t i o n

aptlc contact with the a s p m y d e n d r i t e s of n e u r o n s

Correspondence S Consolo. IstltUtO dl Ricerche Farmacologiche 'Marlo Negrf, Via Erltrea 62, Milan, Italy 20157 0006-8993/86/$03 50 © 1986 Elsevier Science Publishers B V (Biomedical Division)

129 of cholinergic neurons produced in the striatum by kainic acid, a conformationally restricted analog of glutamic acid, is dependent upon an intact corticostriatal pathway 28. Research outlined in the present study gives the first evidence that cholinergic neurons become refractory to the neuropharmacological action of a number of drugs capable of depressing cholinergic actwity as a consequence of corticostriatal degeneration. MATERIALS AND METHODS Female CD-COBS rats, body weight 175-200 g, were purchased from Charles River (Calco, Italy). The rats were killed by focused microwave irradiation to the head (1.3 kW, 2.45 GHz, 4 s) and then ACh and choline contents of striatum were measured by the radioenzymatic method of Saelens et al. 33 as modified by Ladinsky et al. 19. The ACh synthesis rat,, was determined by the method of Racagnl et al. 31 after the i.v. infusion of [3H]choline, the ACh precursor 38. Choline-o-acetyltransferase activity was measured by the method of Fonnum 10 and acetylchollnesterase activity was determined by the method of McCaman et al. 27. Saturation curves of [3H]dexetlmlde binding (0.02-1.5 nM) were determined as described by Laduron et al. 23. Stereospecific binding was defined as that displaceable by 20/~M (-)-dexetlmide but not that by 20pM (+)-dexetimide and averaged 90% of total binding. Sriatal noradrenaline, dopamine and serotonin contents were measured by electrochemical detection coupled with high-pressure liquid chromatography 14,30. Unilateral degeneration of the mgrostrlatal dopaminerglc pathway was induced by the infusion of 6hydroxydopamme-HCl (6-OHDA) dissolved in saline contaming ascorbic aod (1 mg/ml) at a rate of 1/~l/mln for 4 mln into the ventral tegmental area made according to the coordinates taken from the K6mg and Klippel atlas of the rat brain 17, AP = 3.5, L = 1.1, H = 2. Frontal decortication by undercutting the cortex was performed in etherized rats: the animals were positioned in a stereotaxic apparatus and the skull was opened by a 6 mm lateral cut made along the frontal-temporal suture starting 2 mm below bregma. A horizontal undercut of the right hemisphere was then made with a glass knife fashioned

from a coverslip. In sham-operated animals, the skull was opened but no lesion was made. The experiments were performed 14 days after the lesion. The uptake of [3H]glutamic acid was estimated by the method of Dwac et al. 7. The following drugs, routes, schedules and solvents were used: pimozide (gift from Janssen Pharmaceutica, Beerse, Belgium), 1 mg/kg, i.p., 240 min, dissolved in 0.1 M tartaric acid; haloperidol (gift from Lusofarmaco, Milan), 0.25 mg/kg, i.p., 30 rain dissolved in 5 mM HC1; L-sulplride (gift from Ravizza, Milan), 100 mg/kg, i.p., 180 mln, dissolved in 0.12 N acetic acid in saline; clozapine (gift from Sandoz, Basel), 20 mg/kg, l.p., 240 min, dissolved in 90 mM HC1; bromocriptine (gift from Sandoz, Basel), 4 mg/kg, i.p., dissolved in 20% ethanol, hemichohnlum-3, 20 pg/10 pl, 1.c.v., 30 min and 2-chloroadenosine 20/~g/5 ~l, i.c.v., 30 min, dissolved in sterilized saline; the following drugs were all dissolved in saline and administered i.p: JL-14389 (methylamlno-5-tetrahydro-4,5,6,7-benzothlazole monochlorohydrate; gift from Jaques Logeais, Issy-Les-Moulinealx, France), 1.5 mg/kg, 60 mln; methadone, 10 mg/kg, s.c., 60 mln; R-apomorphine (gift from Sandoz, Basel) 1.5 mg/kg and 0.8 mg/kg, i.p., 30 min; hsurlde (gift from Hoechst, Berlin), 0.2 mg/kg, 30 mln; quinpirole (LY-171555, gift from Lilly Research Laboratories, Indianapolis U.S.A.), 0.09 mg/kg, 30 min; oxotremorine sesquifumarate, 1 mg/kg, 20 mln; choline chloride, 100 mg/kg, 10 mln and 250 mg/kg, 30 mm; scopolamine, 1 mg/kg, 30 mln; CM-54903 (gift from Sanofi, Montpellier, France), 40 mg/kg, 30 rain. Control animals were treated with equivalent volumes of approprmte solvents. The data were analyzed statistically by ANOVA (2 × 2) factorial analysis and Tukey's test for unconfounded means. RESULTS Transection of the cortlcostriatal pathway by undercutting the cortex produced neurochemical changes in the striatum. [3H]glutamlc acid uptake was decreased by 55% (from 5.73 _+ 0.17 to 2 63 +_ 0 13 nmol glutamic acid/min/mg protein, n = 6, P < 0 01) m the strlata lpsllateral to the lesion as compared with the striata of sham-operated rats indicating extensive damage to the corticostriatal glutama-

130 tergic i n p u t . [ 3 H ] d e x e t i m i d e b i n d i n g in t h e s t r i a t u m

m o v a l of t h e t o n i c p o s i t i v e i n p u t . W h y this d o e s n o t

of lesioned animals did not reveal changes either m

o c c u r is u n c l e a r at p r e s e n t , b u t ~t is r e a s o n a b l e t o as-

t h e d e n s i t y o r in t h e Kd o f m u s c a r i n i c r e c e p t o r s as

sume from the data that compensatory mechamsms

c o m p a r e d to c o n t r o l v a l u e s (Bma x = 2.30 + 10 p m o l / g

are actwated which maintain the cholinergic neurons

w e t wt; K d = 0.34 n M ) , m e a s u r e d o n t h e 3rd, 14th

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

a n d 120th p o s t l e s i o n d a y , i n d i c a t i n g t h a t m u s c a r i m c

s t a t e . I n fact, u n d e r c u t t i n g t h e c o r t e x s i g n i f i c a n t l y al-

receptors are not localized on fibers of the corticos-

t e r e d t h e d y n a m i c s o f t h e c h o l i n e r g i c n e u r o n s as re-

triatal pathway. Cortical deafferentiation resulted m

f l e c t e d b y t h e 3 0 % r e d u c t i o n in t h e s y n t h e s i s r a t e o f

a

17%

reduction

in

acetylchohnesterase

activity

A C h ( f r o m 10.7 + 0.8 in t h e s h a m - o p e r a t e d r a t s to

( f r o m 2.07 + 0.04 t o 1.72 + 0 . 0 6 ~ m o l A C h h y d r o l y -

7 5 + 0.3 p m o l A C h s y n t h e s i z e d / m i n / m g w e t w t . ;

z e d / h / g p r o t e i n ; P < 0.05, n = 4) 14 d a y s p o s t l e s l o n .

n = 6; P < 0 01) m t h e s t r l a t a o f d e c o r t i c a t e d rats.

A t t h e s a m e t i m e , t h e a c t w i t y of c h o l i n e a c e t y l t r a n s -

T h i s r e s u l t ~s in a c c o r d a n c e w i t h t h e p r e v i o u s w o r k o f

f e r a s e (1.9 n m o l A C h s y n t h e s l z e d / m l n / m g p r o t e i n )

W o o d et al 40 in w h i c h d e c o r t i c a t i o n w a s p r o d u c e d b y

as well as t h e c o n t e n t o f n o r a d r e n a l i n e (102.2 + 6.4

a b l a t i o n o f t h e f r o n t a l c o r t e x . M o r e o v e r , it was f o u n d

ng/g), s e r o t o n i n (166.5 + 9.8 n g / g ) , d o p a m i n e (10.7

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

+ 0 . 4 / ~ g / g ) , c h o l i n e (23.0 + 1.0 n m o l / g ) a n d A C h

p l e t e s t r l a t a l A C h , w h i c h h a s b e e n u s e d as a n i n d e x

(68.7 + 1.7 n m o l / g ) w e r e n o t a l t e r e d in t h e d e a f f e r -

of c h o h n e r g i c n e u r o t r a n s m i t t e r u t i h z a t i o n 8 , w a s sig-

entiated striata.

n i f i c a n t l y r e d u c e d a f t e r d e c o r t i c a t i o n ( T a b l e I): t h e

D e c o r t l c a t i o n m i g h t h a v e b e e n e x p e c t e d to p r o d u c e a n i n c r e a s e in A C h c o n t e n t as a r e s u l t o f t h e re-

choline

uptake

inhibitors,

hemicholinium-3,

and

CM-54903, a non-polar analog of dimethylamino-

TABLE I The effect of various classes o f drugs on strtatal acetylchohne content m frontally-decorucated rats The data are means + S E M (n = 6-12) Doses and times hemlcohnmm-3, 20/~g I c v 30 mm, CM-54903, 40 mg/kg, l p 30 mm, R-apomorphme, 1 5 mg/kg, i p , 30 mm, bromocnptme, 4 mg/kg, 1 p., 90 mm; llsunde, 200 ktg/kg, ~ p , 30 mm, (-)qumplrole, 90/~g/kg, i p , 30 mm; JL-14839, 1 5 mg/kg, s c , 60 mln, oxotremorme, 0 5 mg/kg, ~ p , 20 mm; 2-chloroadenosme, 20 ,ug, i c v , 30 mm, methadone, 10 mg/kg, s c , 60 mln; chohne chloride, 250 mg/kg, l p , 30 mm, plmozlde, 1 mg/kg, L p , 240 mm, halopendol, 0 25 mg/kg, x p , 30 mln, clozaplne, 20 mg/kg, 1 p , 60 min; L-sulpmde, 100 mg/kg, i p , 180 mm, scopolamine, 0 5 mg/kg, 1 p , 30 mln Drug

Ch-uptake mhlbttors Hemlchohnlum CM-54903 ACh-mereaslng drugs R-apomorphme Bromocnptme LlSurlde (-)Qumplrole JL-14839 Oxotremorme 2-Chloroadenosme Methadone Cholinechlonde ACh-deereasmg drugs Plmozlde Halopendol Clozapme L-Sulplnde Scopolamine

Strtatal A Ch (nmol/g) Sham

Decorttcated

Drug

Drug + decorttcated

F mteractton

65 4 _+ 2 4 66 5 + 1 9

61 4 _+ 3 2 66 7_+ 1 7

28 4 + 1 2* 42 3 + 1 1"

34 1 __+_1 0* 48 8_+ 1 3*

1/20 5 0"** 1/44. 4 1"**

64 4 _+ 1 0 689_+1 7 65 1 + 1 8 64 8 + 2 1 636_+ 1 1 68.5 + 2 1 65 1 _+ 2 1 663_+1 1 65 1 + 2 8

64 0_+ 1 8 694+21 664_+14 63 7 _+ 1 3 670_+39 67 9 + 2 7 65 3 + 2 6 669_+ 1 8 630_+22

80 1 + 1 2* 802+23" 865_+2 1" 88.9 + 2 2* 8 6 0 + 1 8* 90 8-+ 2 7* 78 2 + 1 3* 8 2 3 + 1 5* 847+30"

67 7_+ 2 1 720_+24 699_+ 1 5 74 8 + 3 0 72 1 + 1 5 74 4 + 2 3 66 8 + 2 2 692+24 854_+26"

1/47-12 8* 1/26 45"** 1/38 30 2* 1/28 8 4* 1/18 65"* 1/44 11 7* 1/23 7 3* 1/40 69"* NS

6 6 3 + 14 71 1_+39 66 5 _+_1 4 668_+14 674+30

622+32 678_+5 2 62 9 _+ 1 8 642+32 654_+3 1

4 4 7 + 1 9* 39 1 + 2 7 " 37 5 + 1 9* 494+29" 425+43"

3 7 8 + 1 6* 405_+ 1 6* 37 8 _+ 1 6* 479_+20" 469+28"

NS N S N S NS NS

* P < 0 01, ** P < 0 02, *** P < 0 05, Tukey's test and ANOVA (2×2) factorial analysis

131 ethanol capable of crossing the b l o o d - b r a i n barrier30,

TABLE III

induced depletion in A C h content of 57% and 36% in s h a m - o p e r a t e d rats, respectively, whereas in the decort~cated rats these reductions a m o u n t e d to 44% and 27%. T h e a p p r o x i m a t e l y 25% decrease in A C h utilization in the decorticated rats verified by either of the two drugs is in r e m a r k a b l y g o o d a g r e e m e n t with the observed slowed turnover rate. Chromc, unilateral frontal decortication prevented completely the large increase in striatal A C h content induced by the administration of several classes of drugs, comprising the typical d o p a m m e r g i c agonists R - a p o m o r p h i n e and JL-14839 (manuscript in p r e p a r a t i o n ) , the ergot alkaloids b r o m o c r i p t i n e and lisuride; the D 2 r e c e p t o r agonist qulnpirole; the muscarlmc agonist o x o t r e m o r i n e ; the purinerglc drug 2-chloroadenosine and the opiate m e t h a d o n e (Table I). Instead, the increase in strlatal A C h induced by choline, the A C h precursor, was not mitigated by the lesion. On the other hand, the m a r k e d reductions m striatal A C h content induced by the typical neuroleptlc d o p a m i n e r e c e p t o r antagonists pimozlde or haloperidol and the atypical neuroleptics clozapine and L-sulpinde, in addition to the antlmuscarlmc agent scopolamine were not influenced by the lesion (Table I) The d e c o r t l c a t i o n - m d u c e d blockade of R - a p o m o r p h i n e appears to be at varmnce with the data of Scatton et al.34 who found that the striatal A C h - a c c u m u l a t m g action of the d o p a m m e r g l c agon1st was not p r e v e n t e d m decorticated rats. A l t h o u g h ~t is difficult to explain this discrepancy, an i m p o r t a n t difference in m e t h o d o l o g y must be p o i n t e d out, i.e. these workers m e a s u r e d A C h m strlata taken from decapitated, rather than from m~crowaved, rats.

Dopammergtc deafferenttatton or systemtc chohne admmistratlon restores striatal acetylcholine accumulating acttvity of apomorphine m decortwated rats

TABLE II Ttme-course of the effect of bromocrtptme on stnatal acetylchohne content tn sham-operated and frontal decorttcated rats

The data are means + S E M (n = 6-12) Bromocnptlne was administered at the dose of 4 mg/kg, i p Ttme after bromocrtptme (mm)

Strtatal A Ch (nmol/g) Sham

Lesioned

Controls 60 120 180 240

66 0 _ 1 4 82.6 _+ 1 4* 8 6 7 _ 16" 895+19" 82.2 + 1 3*

66.4 + 2.4 66 4 + 1 2 697+14 734+30 82.8 + 2 4*

* P < 0 01 vs respective vehicle group, Dunnett's test

Data represent means and S.E.M (n) The rats were kdled 15 days postdecorttcatlon and 48 h after 6-OHDA infusion; Rapomorphme, 0.8 mg/kg, l p , 30min; choline chloride, 100 mg/kg, l.p, 40 mm. Treatment

Sham-operated Decortlcated Decortlcated + 6-OHDA lesion Decorticated + choline

Strtatal A Ch (nmol/g) Sahne

R-apomorphtne

68.7 + 1 6 (11) 66.2 + 1.6 (12)

87 0 + 2 3* (10) 70.7 + 2.6 (10)

618+26(12)

808+1.8"(11)

74 2 + 1.8 (10)

88.9 __+3.1" (10)

* P < 0.01 vs respective sahne-treated group as determined by Tukey's test for unconfounded means

The deafferentiated cholinergic neurons, when allowed sufficient time, are capable of responding to a depressant stimulus. In fact, a time-course of the effect of bromocriptlne, 4 mg/kg, i.p., showed that degeneration of the corticostriatal neurons p r e v e n t e d the ACh-increasing effect of this drug up to 180 min but not at 240 min (Table II). A t this later time, bromocriptine, which was chosen for its long actionS, produced a 25% increase in A C h content in the lesioned animals which was equivalent to that elicited by the drug in s h a m - o p e r a t e d rats. This e x p e r i m e n t is indicative of the possibdity that the lesion impaired the sensitivity state of the cholinergic neurons u p o n which the effects of the drugs a p p e a r to be d e p e n d ent. In this respect, we were also able to d e m o n s t r a t e that the inhibitory effect of R - a p o m o r p h i n e on cholinergic neurons could be r e s t o r e d in decorticated rats by two different means (Table III): (1) by a short-term (48 h) lesion of the nlgrostriatal dopammergic input; and (2) by p r e t r e a t m e n t with choline (100 mg/kg, 1.p., 10 min). DISCUSSION A n important feature brought out by this study is that neuropharmacological responses in the striatum a p p e a r to be the result of an interaction between several m a j o r n e u r o t r a n s m i t t e r systems. A l t h o u g h one

132 transmitter system may be the specific target of a drug, others too, are essential for the successful completion of the drug's action. This is illustrated by our results providing the first evidence that the effect of a number of agonists capable of depressing cholinergic activity through receptor-mediated responses 2, 3,5,6,12,18.20.21 IS operative only when the corticostrlatal pathway is intact It is conceivable that the chohnergic neurons, being already inhibited by the loss of the excitatory input, cannot further be depressed by drugs that slow down their activity and their A C h turnover rate, whereas these neurons are still responsive to agents that activate them 4. This type of mechanism best explains how such different neuropharmacological classes of drugs may share the property of being blocked by decortlcatlon. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists, acted can be excluded by the following results: firstly, the increase In striatal A C h elicited by choline was not blocked by the decortlcation; and secondly, it was proved that when the insensitive neurons of the deafferentlated striata were exposed to the action of bromocriptine for a longer period of time, they were capable of responding to its stimulus Based on these data, it is proposed that the lesion altered the sensitivity state of the cholinergic neurons upon which the effects of the drugs are dependent. When it became apparent from these experiments that the cholinergic lnterneurons were potentially functional, we endeavored to restore the inhibitory effect of apomorphine on these neurons. It was indeed found that the prior administration of choline made it possible for the dopaminergic agonist to express its full inhibitory effect on the chohnergic neuron. Treatment with the ACh-precursor is somehow able to overcome the decreased synthesis rate of ACh and the reduced S D H A C U activity of the cortlcally-deafferentiated strlata. In addition, it was found that the 48 h chemical degeneration of the nlgrostriatal dopaminerglc input restored the action of apomorphme in the decorticated rats. This phenomenon cannot be the result of dopamine receptor supersensitivity onset in this short time span I8,37, since apomorphlne did not induce a greater increase in A C h content in the 6 - O H D A lesioned rats as compared with the sham-operated animals. Ongoing studies are aimed at determining whether choline ad-

ministration or the deafferentiation of the dopamlnergic input can restore the striatal ACh-accumulating action of the drugs, other than the dopaminergic ones, in decortlcated rats It is conceivable, as indeed many findings indicate, that the activity of the cholinerglc neurons in strlatum is maintained m a functional equilibrium state by a balance of dual influences: the excitatory corticostrlatal input which has been reported to exert its action at the dendritic level of the chohnergic interneutons 26, and the mgroneostrlatal dopaminerglc afferents well known to possess an Inhibitory influence on the chollnerglc system. Moreover, cholinerglc agonists are able to directly regulate the release of dopaminell 25.32 by a mechanism that apparently does not involve axo-axonlc relationships but rather a dendroaxonic communlcatory process 1 In this manner, monoaminerglc, chohnergic and excitatory neurons interact with each other in the strlatum so as to maintain a dynamic equilibrium. Changes in the activity of one component of such a circuit results in compensatory changes by the other components to restore a normal balance As a consequence, not only do the chohnerglc neurons become refractory to a further depressive activity, but dopamlnerglc tone, too, is lowered as suggested by data obtained in a collaborative study (ref 22; Ruscom et al , manuscript in preparation) that the neuropharmacologlcal action of apomorphlne in decreasing the striatal dopamine metabolites, 3-methoxytyramlne, 3,4-&hydroxyphenylacetic acid and homovanlllic acid, was also strongly inhibited In decortlcated rats. Whatever the intimate mechanisms underlying this phenomenon may be. further studies are needed to determine how behavioral responses to the drugs are affected by the decorttcation and whether other neurotransmitters might possibly participate in this neuronal circuitry. However, the relationship of the excitatory cortlcostriatal pathway with the chohnerglc and dopamlnerglc systems in the striatum reported here may be of relevance to the mode of action of drugs that alleviate the symptoms of neurological and psychiatric disorders, and may further suggest new inroads to therapy ACKNOWLEDGEMENTS Dr Maria Sleklucka was a Visiting Scientist from the Department of Pharmacology, Institute of Pa-

133 thology, University of Lublin Medical School, Lub-

partially supported by a National Research Council

lin, P o l a n d . T h e a u t h o r s a p p r e c i a t e t h e e x c e l l e n t p a r -

(CNR-Gruppo

t i c i p a t i o n o f D r . G i l b e r t o F i s o n e a n d M r . P a o l o Ci-

t r a c t 83.02411.04.

Nazionale

di F a r m a c o l o g i a ) ,

Con-

cioni in s o m e o f t h e s e e x p e r i m e n t s . T h i s w o r k w a s

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