Increases in striatal acetylcholine by SKF-38393 are mediated through D1 dopamine receptors in striatum and not the frontal cortex

186

Brain Research, 627 (1993) 186-192 © 1993 Elsevier Science Pubhshers B V All rights reserved 0006-8993/93/$06 00

BRES 19380

Increases in striatal acetylcholine by SKF-38393 are mediated through D 1 dopamine receptors in striatum and not the frontal cortex Alessandro Zocchl *, Agu Pert Btologlcal Psychzatry Branch, Nanonal Instttute of Mental Health, Buddmg 10, Room 3N212, 9000 Rockt dle Ptke, Bethesda, MD 20892, USA

Key words Acetylchohne, SKF-38393, Stnatum, Frontal cortex, MIcrodmlysls

It has been proposed by some that the D 1 receptor effects are mediated through stnatal actions while others have suggested that they are determmed indirectly through the frontal cortex The experiments reported here represent a further attempt to resolve this controversy It was found that focal apphcatlons of the mactwe and active enantlomers of SKF-38393 (a D 1 dopamlne receptor agomst) to the rat strlatum via reverse dmlysls increased extracellular acetylchohne (ACh) m a stereoselectwe manner Infusions of SKF-38393 into the frontal cortex, on the other hand, were ineffectwe m altering stnatal ACh Furthermore, partial hemlsectlons caudal to the frontal cortex did not alter the ability of systemically admmlstrated SKF-38393 to increase stnatal ACh Taken together, these results suggest that at least some of the effects of D l receptor agonlsts on strmtal chohnerglc function are medmted through actions m the strmtum and not the frontal cortex

INTRODUCTION A large n u m b e r o f studies have s u p p o r t e d t h e conc e p t t h a t d o p a m m e ( D A ) m o d u l a t e s t h e function of s t n a t a l c h o h n e r g t c m t e r n e u r o n s 33'5~ E a r l y b t o c h e m l c a l e w d e n c e s u g g e s t e d t h a t D A exerts an m h l b t t o r y control over a c e t y l c h o h n e ( A C h ) r e l e a s e 2,7'H'2s'2836,44'45,48 M o r e r e c e n t studies have r e v e a l e d t h a t such m h t b l t o r y effects are medtated through D 2 DA receptors 3 4,8 1617,19,21,22,43,46,4950 which a r e p r e s u m a b l y loc a t e d d~rectly on t h e large a s p m y s t n a t a l chohnerg~c m t e r n e u r o n s 34'35'52 W h i l e D A mhlbtts c h o h n e r g t c function t h r o u g h D 2 r e c e p t o r s , r e c e n t l y ~t also has b e e n f o u n d to f a c t h t a t e A C h r e l e a s e t h r o u g h D~ D A r e c e p t o r s L9'~°'2°-22'42 T h e m e c h a m s m s t h r o u g h which D~ D A r e c e p t o r actwat~on e n h a n c e s c h o h n e r g l c function a r e not e n t i r e l y u n d e r s t o o d C o n s i d e r i n g t h e htgh c o n c e n t r a t i o n o f D1 r e c e p t o r s (espectally r e l a t w e to D 2 r e c e p t o r s ) m the rat s t r m t u m 54~ It ~s m o r e p a r s l m o m o u s to a s s u m e t h a t t h e D a D A r e c e p t o r effects on c h o h n e r g t c strmtal m t e r n e u r o n s a r e d e t e r m i n e d d~rectly t h r o u g h r e c e p t o r s intrinsic to t h e s t r l a t u m Ind e e d , focal a p p h c a t l o n of t h e D~ a g o m s t SKF-38393 t h r o u g h dmlys~s p r o b e s s i t u a t e d m t h e s t r m t u m has b e e n f o u n d to m c r e a s e A C h r e l e a s e ~ O t h e r investigators, however, have c o n c l u d e d t h a t t h e f a o h t a t o r y ef-

* Corresponding author Fax (1) (301) 402-0052

fect o f D A on s t n a t a l A C h a r e m e d i a t e d t h r o u g h D~ r e c e p t o r s l o c a t e d e x t r a s t r m t a l l y D a m s m a et al 9 a n d D e B o e r et al 14 have failed to find a l t e r a t i o n s m s t n a t a l A C h r e l e a s e following focal a p p l i c a t i o n of eit h e r D~ agonlsts o r a n t a g o m s t s T h e f o r m e r g r o u p also r e p o r t e d t h a t strlatally a p p h e d MK-801 (a n o n - c o m p e titive N M D A a n t a g o n i s t ) inhibits D~ agontst i n d u c e d strlatal A C h r e l e a s e B a s e d on t h e s e findings, the authors p r o p o s e d t h a t D~ a g o m s t s m~ght i n c r e a s e strmtal A C h r e l e a s e indirectly t h r o u g h D~ D A r e c e p t o r s loc a t e d in t h e frontal cortex Such cortical D 1 agonlst acttons have b e e n p o s t u l a t e d to e n h a n c e t h e r e l e a s e of g l u t a m a t e from c o r t l c o - s t r l a t a l n e u r o n s which innerv a t e c h o h n e r g l c l n t e r n e u r o n s C o n s o l o et al 6, on t h e o t h e r hand, have f o u n d httle e v i d e n c e to s u p p o r t t h e c o n c e p t that D A exerts a facfl~tatory effect on s t n a t a l A C h r e l e a s e t h r o u g h the c o r t e x T h e s e investigators r e p o r t e d t h a t the D~ a n t a g o m s t , SCH-23390, a p p h e d to t h e frontal c o r t e x h a d no effect on strtatal A C h while d e c r e a s i n g it following s t n a t a l a p p h c a t l o n s T h e y c o n c l u d e d t h a t D~ r e c e p t o r s r e g u l a t i n g A C h r e l e a s e are l o c a t e d m the s t r t a t u m T h e p u r p o s e o f t h e s e studies was to f u r t h e r d e f i n e t h e sites of action of D~ agonlsts on A C h f u n c t i o n Mtcrodmlys~s t e c h n t q u e s were u s e d to m e a s u r e strmtal A C h levels m rats with t h e following t r e a t m e n t s (1)

187 perfuston of the strlatum by reverse dialysis with the active ( + ) and less active ( - ) enantlomer of the DA D 1 receptor agonist SKF-38393, (2) perfuslon of frontal cortex with (+)-SKF-38393 and (3) systemic injections of (+)-SKF-38393 following leslonlng of the neuronal connections between the frontal cortex and the striatum

MATERIALS AND METHODS Subjects and surgery Male Sprague-Dawley rats (Taconlc Farms) weighmg 290-350 g were used as subjects The ammals were indmduaily housed and malntamed for a week on a hght-dark cycle (hght on 07 00-19 00 h) with food and water available ad hb Testmg was always performed between 09 00-17 00 h Prior to surgery, animals were anaesthetized

Fig 1 Coronal sections stained with thlonm lllustratmg the extent of the partial forebram hemlsectlon (shaded area in a) and representatwe probe placements in the frontal cortex (b,c) and stnatum (d,e) Arrows delineate the extent of the &alysls membrane

188 with chloral hydrate (400 m g / k g i p ) Using standard stereotaxlc procedures, a C M A / 1 2 mlcrodmlysls probe guide with a stainless steel stylette (Carnegie Medlcm), was implanted vertically in the left strmtum (AP + 9 9 mm, L A T + 3 0 mm, DV + 5 0 m m relative to interaural zero with the incisor bar set at - 3 5 mm) O n e group of animals had an addmonal guide cannula implanted in the lpsdateral frontal cortex (AP + 1 2 7 mm, L A T + 0 7 mm, DV + 7 0 m m ) and one group had the cortlco-striatal pathway originating from the frontal cortex lpsllateral to the striatal guide cannula severed This was accomplished by lowering a rectangular surgical blade (width 3 3 mm) to the base of the brain 11 7 m m anterior to lnteraural zero The medml edge of the blade was ahgned with the mldhne of the brain (LAT 0 0) Animals were allowed to recover for at least 5 days following surgery

Expertmental procedures On the day of the experiment the stylette was removed and a concentric mlcrodmlysis probe with a 3 m m tip ( C M A / 1 2 , M W cutoff 20 kDa, A C h in vitro recovery, 40%) was inserted into the striatal guide cannula Polyethylene tubing connected the inflow port of the probe to a 1 ml glass syringe situated In a micromfuslon p u m p ( C M A / 1 0 0 ) The animal was placed in a Plexaglas cyhnder (29 4 cm d i a m e t e r × 2 9 4 cm height) and a counter balance arm w]th an attached liquid swivel (Instech Lab ) was used m order to allow it free movement without twisting the tubing The strmtal probe was perfused with artlficml cerebrospmal fluid (aCSF) comprising of NaC1 147 mM, KCI 4 mM, CaCl 2 2 28 m M and 1 jzM neostlgmine bromide (Sigma Chemical) The perfusion flow rate was 0 5 / z l / m m and samples were collected every 20 mln into polyethylene tubing After reaching a stable baseline (the last three A C h samples not differing from each other by more than 10%) experimental manipulations were lmtlated In the imtlal study, tetrodotoxin (TTX) dissolved in aCSF (1 p.mol/l) was introduced into the strmtum for 60 min by reverse dmlysts following basal A C h stablllzat]on In the second study ammals with dmlysls probes in the striatum were perfused for 20 m m with aCSF containing 100 /~mol/1 of either (+)-SKF-38393 or ( - ) - S K F - 3 8 3 9 3 Five 20-mm samples were collected after each treatment and injected directly into the analytical system to evaluate A C h levels Animals with probes situated m the frontal cortex in a d d m o n to the lpsflateral striatum were perfused with 100/~mol/I of (+)-SKF-38393 through the cortical probes after reaching a stable stnatal A C h basehne The cortical application of (+)-SKF-38393 lasted for 20 m m Strlatal samples were collected and analyzed as described above Animals with forebrain hemlsectlons as well as unlesloned controls, were injected mtrapentoneally with l0 m g / k g of (+)-SKF-38393 following A C h basehne stabdlzatlon Striatal samples were collected every 20 mln for a period of 100 mln after the rejections and assayed as described above After each experiment, probe location was verified with standard histological techniques Animals in which the probe placement was lnapproprmte were discarded Data are expressed as percentage of the mean of the last three pre-treatment samples and statistical significance was assessed with one factor or two factor A N O V A with repeated measures and a D u n n e t t ' s t-test or lndw]dual post hoc comparisons as appropriate

Acetylchohne analysis The analytical system consisted of an H P L C with electrochemical detection and an a c e t y l c h o h n e / c h o h n e assay kit (BAS #MF-8910) Mobile phase (35 m M Na2PO4, pH adjusted to 8 5 with H3PO4, 0 05% antibacterial (Kathon BAS)) was pumped at a flow rate of 0 6 m l / m m and replaced with a fresh preparatton every 3 days Potential was set at + 500 mV on a platinum working electrode vs a A g / A g C I reference electrode

RESULTS Photomicrographs of coronal sections stained w~th thionm illustrating representative probe placements

120'

ACh

100' Q Q0 I

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80'

i 40

,o

I

o

.x

,'o

I

time

Fig 2 Effects of stnatal T T X (1 tzM) perfuslon on basal extracellular A C h levels *, P < 0 05 and * * , P < 0 01 for comparisons against baseline controls n = 4

and the partial forebraln hemlsectton are presented in Fig 1 Fig l a illustrates the extent of the parttal hemisect~on whtch was used to sever frontal cortex connections with strlatum It was not possible to present representative reconstructions of the les~on itself due to difficulties m keepmg the cutting plane parallel to the hemisectlon throughout ~ts full extent All of the animals represented in data analysis had appropriate probe placement similar to those shown in Fig 1 Perfusion of the strlatum with 1 t~mol/l of T T X for one hour following baseline stablltzatlon produced a pronounced decrease m basal extracellular levels of ACh The effect was apparent during the first 20-mm sample and increased dramatically over the next two sampling periods (Fig 2) A N O V A revealed a slgmficant treatment effect ( F = 17 898, df 6/18, P < 0 000,1, n = 4) and the Dunnett's t-test indicated that ACh levels at each time interval following the introduction of T T X were significantly different from the basehne control Fig 3 illustrates the effects of perfuslon with either the actwe ( + ) or less active ( - ) enantlomer of SKF38393 on stnatal ACh Apphcation of the actwe enantiomer directly to the strlatum at a concentration of 100 ~ m o l / 1 produced an elevation in extracellular ACh which increased progresswely over the three sampiing periods following termination of exposure Surprisingly, ACh levels had not returned to baseline 80 m m following the termination of treatment The less active enantlomer did not have an immediate effect on striatal ACh but did appear to result in a delayed response which was evident at 60 and 80 min following termination of treatment A two-way repeated measures A N O V A of ACh levels following termination of

189 4.

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Fig 3 Effects on stnatal A C h following strlatal perfuslons with ( + ) and ( - ) - S K F - 3 8 3 9 3 (100/~M) *, P < 0 05 for comparisons of A C h levels following ( + )-SKF-38393 with A C h levels following ( - )-SKF38393 * * , P < 0 05 for comparisons against the b a s e h n e control n = 4 for both groups

treatment revealed a sigmflcant treatment effect ( F = 6 18, df 1/6, P < 005), a slgnificant effect of time ( F = 22 381, df 4 / 2 4 , P < 0 000,1) as well as a slgmficant treatment × time mteractlon ( F = 15 036, df 4 / 2 4 , P < 0 000,1) Indwldual post-hoc compartsons indicated significant difference between the two treatment groups 20 and 40 m m following the termination of drug application The Dunnett's t-test revealed that A C h levels were significantly different from the basehne control in all samples following (+)-SKF-38393 and at the 80- and 100-mln samphng interval following ( - ) SKF-38393 Fig 4 dustrates the effects of cortical (+)-SKF-38393 perfuslon on striatal ACh Apphcatlon of 1 0 0 / x m o l / l to the frontal cortex did not alter A C h levels in the

Fig 5 Effects of mtraperitoneally administered (+)-SKF-38393 on stnatal A C h following partial hemlsections caudal to the frontal cortex *, P < 0 05 and * * , P < 0 01 for comparisons against the baseline controls n = 4 for both groups

strlatum A one way A N O V A did not reveal a significant treatment effect ( F = 2 095, df 5/20, P > 0 05) Fig 5 illustrates the effect of systemically administered (+)-SKF-38393 (10 m g / k g , i p ) on strlatal ACh in les~oned and intact rats An increase in strlatal ACh was seen in both groups following systemically administered (+)-SKF-38393 A two-way repeated measures A N O V A did not reveal a significant treatment effect or a treatment × time interaction The effect of time did prove to be significant, however ( F = 2546, df 4/24, P < 0 05) The Dunnett's t-test revealed significant increase in ACh levels during the 20- and 40-mln samphng periods for the control rats and a significant elevation m ACh during the 40-mln sampling pertod for the lesioned animals DISCUSSION

160

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[] (+)-SKF-38393 1001~M In frontal cortex

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time Fig 4 Strlatal A C h levels following perfusions of (+)-SKF-38393 to the frontal cortex by reverse dialysis n = 5

One major concern in mlcrodlalysls studtes is the origin and functional relevance of the analyte in question, especially m studies where samphng is initiated relatively soon following probe insertion into tissue In our studies guide cannulae were Implanted at least 5 days before experimentation This procedure has the advantage of mlmmlzmg the contribution of post-surgical stress which may be an important mteractive factor in studies using other methodologies During the test day, only 3 m m of tissue was damaged in the dorsoventral plane by a 0 5 m m diameter probe Although all experiments were conducted on the day of probe insertion, it was clear that the basal ACh following stabilization was of neuronal origin, since infusion of T T X 53, a voltage-dependent Na + channel blocker, into

190 the strlatum was effective in producing a significant inhibition of extracellular ACh Findings from studies which have evaluated the role of D~ D A receptors m regulating ACh actwlty are somewhat equwocal Some investigators have been unable to observe effects of D l agomsts on K +2 or electrically 1921'28'434749 evoked release of ACh in stnatal slices, while others have reported a potentiation z1'22 Surprisingly, however, m the latter studies, D~ antagonists appeared to induce a similar response 2~ 22 While D 1 agomsts, m general, have failed to alter strlatal ACh levels 7'43, D~ antagonists have been found to increase ACh content 7 1743, signifying an inhibitory action on chohnergIc activity and suggesting as well that D 1 modulation of ACh function is tonically active More recent mlcrodlalysls studies have provided stronger evidence for D~ regulation of ACh function Systemic admlmstration of D~ agonlsts, for example, have been found to increase strlatal ACh release which ~s antagonized by D~ but not D 2 antagonists 843 Our studies also indicate that systemically administrated SKF-38393 increases extracellular ACh in the strmtum (Fig 4) In one previous study focal applications of SKF38393 to the strmtum increased ACh m a dose-dependent fashion while high (but not low) doses of a D 1 antagonist had opposite effects ~ Interestingly, D 2 agonlsts and antagonists however had little effect on extracellular strlatal ACh in the same study As already noted, however, others have faded to find alterations In stnatal ACh following focal applications of D 1 agonlsts or antagonists 9'14 The reasons for these disparities are not entirely clear but may be related to the types and doses of D~ receptor specific drugs used in the above studies In this study we utilized the active and less active enantlomers of SKF-383933° to determine if D 1 receptor activation produces a pharmacologically relevant alteration in ACh release following direct stnatal perfuslons The use of enantiomers may be a better approach to establish the pharmacological specifioty of SKF-38393 following strlatal application than attempting to block with SCH-23390 This antagonist has often been found to also enhance ACh release alone and to potentiate evoked release 12122 following direct tissue applications possibly by some non-specific actions or by its ability to act partially as a D e antagonist 394° D l D A receptors have been classically defined by their ability to activate D A stimulated adenylate cyclase 29 In this regard, ( +)-SKF-38393 has been found to be an effectwe actwator of D A - d e p e n d e n t adenylate cyclase while ( - ) - S K F - 3 8 3 9 3 is entirely meffectwe 3° Focal apphcat~ons of the active enantlomer to the striatum in these studies produced a significant and long lasting

elevation in strlatal ACh The inactwe enantiomer was significantly less active In elevating ACh although it did appear to Induce a rather delayed response which was evident 60 mln following the termination of apphcatlon Such delayed actions by both enantiomers could represent effects of unknown nature not mediated through activation of adenylate cyclase Based on the ability of strlatally applied MK-801 to antagonize the faclhtatory effects of D~ agonlsts on ACh release, D a m s m a et al 9 proposed that D 1 receptors activation produces increases in chohnerglc activity indirectly through the frontal cortex by actwatlng cortlcostriatal glutammerglc pathways The results from these studies do not support this proposition Direct application of SKF-38393 to the frontal cortex through reverse dialysis failed to exert any effect on ACh in the strlatum lpsllateral to the infusion Likewise, knife cuts caudal to the frontal cortex failed to alter increases in striatal ACh release induced by systemically admlmstrated SKF-38393 These results are consistent with the observation that focal applications of SCH-23390 to the frontal cortex also are without effect on striatal ACh 6 The conclusions from this study, however, appear to be based on the assumption that the dopamlnerglc input to the frontal cortex is tonically active Although D 1 agonlsts appear to enhance ACh function, at least In part, through actions intrinsic to the strlatum, the p r e o s e mechanisms are still unclear D I agonists could exert their effects on chohnerglc mterneurons either directly or indirectly through other Interneurons or through strIatal efferents One assumption expressed by several investigators is that stnatal chollnerglc lnterneurons possess only D e D A receptors 4'6 This assumption is based on a report by W e m e r et al 52 who found only D 2 m R N A m the large asplny striatal lnterneurons which were presumed to be chohnerglc Subsequent studies, however, have detected D~ receptor m R N A as well as DARPP-32 m R N A (a marker for D 1 receptors) on the large-sized strlatal neurons 24'34 Although D~ receptors are not expressed to the same degree as D 2 receptors on these cells24,3435 it is still conceivable that D 1 agomsts could modulate their function directly Alternatively, D~ agonIsts could mediate their effects on strlatal chollnerglc neurons indirectly either through non-chohnerglc lnterneurons or through striatal efferents The large-sized aspmy cells, some of which are chohnerglc, represent only 5% of the total neurons found in the strlatum 2~ ~ The rest are m e d m m sized asplny cells which are either projection neurons or mterneurons containing somatostatln, GABA, neuropeptlde Y and a variety of other markers 2° A significant proportion of these cells express either D~ or D2

191 r e c e p t o r s 24'34'35'52 D 1 r e c e p t o r s a p p e a r to be lo c a li zed p r e d o m i n a n t l y on s u b s t a n c e - P c o n t a i n i n g strlatal efferents

whde

D2

receptors

are

found

on

prepro-

e n k e p h a h n - A n e u r o n s 34 It is hkely that a c e r t a i n prop o r t i o n o f t h e m e d i u m - s i z e d m t e r n e u r o n s also express D 1 and D 2 receptors

It ts possible t h e r e f o r e that D 1

agontsts co u l d ex ert t h e i r f a c th ta to r y actions on strlatal c h o h n e r g l c f u n c t i o n indirectly t h r o u g h e~ther strlatal e f f e r e n t s or t h r o u g h n o n - c h o l l n e r g l c m t e r n e u r o n s T h e s t r m t u m a p p e a r s to r e c e i v e a la r g e excitatory p r o j e c t i o n f r o m t h e c o r t e x w h i c h consists p r im a r il y o f g l u t a m l n e r g t c fibers 15 T h e g l u t a m l n e r g l c fibers a lo n g with ntgrostrtatal D A axon t e r m i n a l s m a k e synapt~c c o n t a c t with d e n d r i t i c spines o f t h e m e d m m - s ~ z e d strtatal n e u r o n s 18'3s D A a n d g l u t a m a t e t h e r e f o r e a p p e a r to i n t e r a c t in m o d u l a t i n g th e actwlty o f t h e s e cells E l e c t r o p h y s i o l o g t c a l e v i d e n c e suggests that D 1 agonlsts exert an lnh~bltory i n f l u e n c e on strmtal n e u r o n s w h i ch r e c e tve i n p u t f r o m t h e s u b s t a n t m nlgra 32 D 1 a g o m s t s also a p p e a r to mh~blt a p o p u l a t i o n o f p r e s u m e d D A i n n e r v a t e d n e u r o n s in t h e n u c l e u s a c c u m b e n s 54 T h e m h l b l t o r y effects o f D t agonlsts m a y be d e t e r m m e d t h r o u g h t h e ' t h i r d m e s s e n g e r ' D A R P P - 3 2 f o u n d excluswely in n e u r o n s with D 1 r e c e p t o r s D 1 r e c e p t o r activation is t h o u g h t to lnh~btt th e excitatory effects o f glutam a t e by l n c r e a s m g t h e state o f p h o s p h o r y l a t l o n o f D A R P P - 3 2 wh i ch acts as a p r o t e i n p h o s p h a t a s e mhtbltor 2627 If t h e spmy m e d i u m - s i z e d or large a s p m y G A B A l n t e r n e u r o n s r e c e i v i n g glutamaterg~c m p u t normally inhibit chollnerg~c m t e r n e u r o n s ,

It is possible

that D 1 r e c e p t o r s a c t w a t t o n Increases strlatal c h o h n e r glc activity t h r o u g h dlslnhtbltlOn

It lS i n t e r e s t i n g to

n o t e t h a t D 1 r e c e p t o r s a p p e a r to be m o r e p r o m m e n t on t he m e d i u m - s i z e d spiny n e u r o n s t h a n on t h e large asplny n e u r o n s

A significant p r o p o r t i o n ( 8 0 % ) o f t h e

large a s p m y ( p r e s u m a b l y c h o h n e r g l c ) n e u r o n s , on t h e o t h e r hand, posses D z r e c e p t o r s 35 It lS m o r e hkely t h a t the inhibitory a c t m n s o f D 2 agonlsts a r e m e d i a t e d directly t h r o u g h D 2 D A r e c e p t o r s l o c a h z e d on c h o l m erg~c m t e r n e u r o n s A l t h o u g h D1 actions in th e frontal c o r t e x do n o t s e e m to p a r t i c i p a t e m m o d u l a t i n g strtatal c h o h n e r g l c activity, it ~s sttU possible that D l r e c e p t o r s m o t h e r cortical (e g , c m g u l a t e ) or subcorttcal r e g i o n s m a y be revolved A l t h o u g h t h e p r e c ts e m e c h a m s m r e m a i n to be e l u o d a t e d , tt is a p p a r e n t that s o m e o f t h e actions o f D~ agonlsts o n striatal A C h are d e t e r m m e d t h r o u g h mtrlnstc effects

Acknowledgements We would like to acknowledge Mr Tim Sulhvan for his invaluable technical assistance and Drs Enrico Museo, D Nlgel Thomas and Krystyna M Woznlak for their careful reading of the manuscript

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