Effect of vinconate, an indolonaphthyridine derivative, on metabolism and function of cerebral cholinergic neurons in rat

Neurothem lnt Vol 23. No 5, pp 399 405,1993 Printed m Great Britain

0197-0186/935600+000 Pergamon Press Ltd

EFFECT OF VINCONATE, AN INDOLONAPHTHYRIDINE DERIVATIVE, ON METABOLISM AND FUNCTION OF CEREBRAL CHOLINERGIC NEURONS IN RAT TOSHIAKI IINO, MASASHI KATSURA a n d KINYA KURIYAMA* Department of Pharmacology, Kyoto Prefectural Umversity of Medicine, Kawaramachi-HlrokojL Kamlgyo-Ku, Kyoto 602, Japan ( Recett,ed 7 Aprtl 1993 : accepted 6 May 1993 ) Abstract--Effects of(+)-methyl 3-ethyl-2,3,3a,4-tetrahydro-lH-indolo [3,2,1,-de] [1,5] naphthyridlne-6carboxylate hydrochloride (vmconate), an indolonaphthyridine derivatwe, on the metabolism and functmn of cerebral cholinergic neurons were investigated using male W~star rats. Single administration of vinconate (5, 50 and 200 mg/kg) decreased acetylchohne content in the stnatum but not those in the cerebral cortex and hlppocampus. The same treatment with vinconate (5, 50 and 200 mg/kg, p.o.) had no effect on the actwities of choline acetyltransferase and acetylchohnesterase in these brain areas Although the addmon of vmconate (10 7 10 4 M) had no effect on the high affimty uptake of [~H]choline into striatal shces, it mduced a concentration-dependent increase of a KCI(2× 10 2 M)-evoked endogenous acetylchohne release. The ad&tion of ( - )-sulpiride (10 ~ 10 ~ M l, a dopamme D~ receptor antagomst, also accentuated the KCI(2× 10 -~ M)-evoked endogenous acetylcholine release form striatal slices. Furthermore, it was found that this ( )-sulpinde (10 7 M)-induced increase of endogenous acetylchohne release was further augmented by the addmon of ~mconate (10 5 M). These results suggest that vinconate may enhance the release of endogenous acetylcholine wa the modulation of presynapt,c dopamme heteroreceptor m the smatum.

( + )-Methyl 3-ethyl-2,3,3a,4-tetrahydro- 1H-'indolo [3,2,l-de] [l,51 naphthyridine-6-carboxylate hydrochloride (vinconate) is a mdolonaphthyridine derivative and developed to enhance cerebral metabolism and function. Previous studms indicated that vinconate significantly prolonged the duration of consciousness and significantly delayed the appearance of electroencephalographic disturbances observed under hypoxic condJtions (Thiebauld et al., 1983). Oral administration of vinconate is also known to improve psychomotor activity, cognitive function, attention and concentration in elderly subjects (Saletu et al., 1984). Furthermore, vinconate is known to prevent ischemic neuronal damage in the brain of rats and Mongolian gerbils (Iino et al., 1992; Araki et al., 1989; Araki and Kogure, 1989). Recently, vinconate is reported to have an antmmnesic effect on the basal forebrain lesion- and medial septal lesion-induced amnesia by ameliorating the dysfunction in cholinergic neurons (Kinoshita et al., 1992a, b). In addition, it is also reported that vinconate improves

*To whom correspondence should be addressed 399

scopolamine-induced amnesia in mice (Saito et al., 1991). These reports suggest that vinconate may be effective for the treatment of cerebral disorders induced by hypoxic conditions such as cerebral ischemia and neuropsychiatric symptoms associated with senile dementm. Nerve terminals are known to possess presynaptlc receptors which are sensitive to either the same neurotransmitter (autoreceptor) released from nerve terminals or the different neurotransmitter (heteroreceptor). In the case of dopaminergic neurons, it is reported that dopamine release is regulated in an inhibitory manner by presynaptic dopamlne autoreceptor (Kamal et al., 1981; Starke et al., 1983; Diliberto et al., 1987) and are regulated in an accelerated manner by presynaptic muscarme heteroreceptor (Lehmann and Langer, 1982: Raiteri et al., 1984; Dlliberto et al., 1987). h is also reported that 5-hydroxytryptamine release is regulated in an inhlbltatory manner by presynaptic 5hydroxytryptamine autoreceptor (Cerrito and Raiteri, 1979: Gothert and Schlicker, 1983) and presynaptic ~-adrenergic heteroreceptor (Gothert et al., 1981 ; Raiteri et al., 1983) Cholinergic nerve terminals are also shown to possess both autoreceptor (James

TOSH1AKI hNO et al.

400

a n d C u b e d d u , 1984: 1987; T o e d e , 1989; W a t a n a b e a n d S h i m i z u , 1989) a n d h e t e r o r e c e p t o r ( K u b o t a et al., 1987: C h a n g , 1988: Cai et al., 1991) It is d e m o n strated that a c e t y l c h o h n e release in the s t r i a t u m is modulated by m u s c a r i n e M , a u t o r e c e p t o r in an i n h i b i t o r y m a n n e r (Dolezal and Wecker, 1990: Wcller, 1989). O t h e r i n v e s t i g a t o r s indicate that a c e t y l c h o h n e release is also m o d u l a t e d by p r e s y n a p t i c d o p a m i n e ( A l b e r c h et al.. 1985; A j i m a et a/., 1990; Bertorelh et al., 1992), N - m e t h y l - D - a s p a r t ate (Cai et al., 1991) a n d a d e n o s i n e r e c e p t o r s ( F r e d h o l m a n d D u n e r - E n g s t r o m , 1989). It has been well e s t a b l i s h e d that t h e r e is a close c o n n e c t i o n b e t w e e n cholinergic a n d d o p a m l n e r g i c n e u r o n s in the s t r i a t u m . S t o o f et al. (1992) also have r e p o r t e d that the release o f a c e t y l c h o l i n e in the stria t u m is especially m o d u l a t e d b y d o p a m i n e r g i c p r o j e c t i o n s a n d intrinsic c h o l i n e r g i c n e u r o n s . It has been r e p o r t e d that v l n c o n a t e induces the facilitation o f d o p a m i n e a n d 5 - h y d r o x y t r y p t a m i n e release in rat stria t u m ( K o d a et al., 1989a, b) a n d possesses affinities for m u s c a r l n e a n d d o p a m i n e r e c e p t o r s ( K o d a et al., 1989 ; K o d a , 1989a). H o w e v e r , t h e a c t i o n o f v i n c o n a t e on c e r e b r a l c h o h n e r g i c s y s t e m s is n o t clearly defined at cellular level Therel\~re, we have e x a m i n e d the effects o f vinc o n a t c o n the cerebral c o n t e n t o f a c e t y l c h o h n e , the activities o f a c e t y l c h o h n e s y n t h e s i z i n g a n d d e g r a d i n g e n z y m e s , a n d the striatal cholinergic n e u r o n a l functions. EXPERIMENTAL PROCEDURES 4 ntmu[,s

Male Wlstar rats weighing 200 300 g were purchased from Japan SLC, Inc (Hamamatsu, Japan). They were used for the experiments under breeding with laboratory chow (MF, Oriental Yeast Co., Ltd., Chiba, Japan) and tap water ad hhtlum. Drug lreUD?ttqlt Vinconate (Tokyo Tanabe Co., Ltd., Tokyo, Japan) was dissolved and diluted in distilled water. Vinconate and vehmle were orally administered to examine their effects on the cerebral content of acetylchohne and the activities of chohne acetyltransferase and acetylcholinesterase in a vol of I ml/100 g body wt. In the experiments of the addition of ~mconate to examine its effects on [3H]chollne uptake and acetylchohne release, vmconate was dissolved and diluted in dlstdled water and added to the incubation medium 5 mm before the addition of [3H]choline or the second KCI (2 × I 0 ~ M) stimulation according to the method of Katsura et al. ([991l Meu,~urement o[ aceo'lchohne content Rats were killed by a focused microwave ~rradiatmn on the head (5 kW, 1.1 s) 1 h after the oral administration of

vmconate, and the cerebral cortex, hlppocampus and strlatum were dissected out according to the method of Glowinski and lversen (1966). For the measurement of acetylcholine, acetylchohne was extracted from the tissue samples according to the method of Potter et al. (1983) and lgarashl et al, (1984). In brief, the samples were weighed and homogenized in 2 ml of [ N formic acid : acetone (l 5.85). Then, the homogenate was centrifuged at 1700g for 20 rain at 4 C The supernatant was washed with dietbyl ether and finally lyophlhzed at - 2 0 C After resuspendlng the lyophilized sample in distilled water, it was mixed with a solution contaming KI-solutlon and 10 ~ M tetraethylammomum chloride before centrifuging at [000 g for 3 rain tit room temperature In order to remove excessive mdme, the pellet was dissolved In acetomtrile and anion exchange resin (200 400 mesh, AG I-X8 chloride form, BIO-RAD) was added. The ~odlne-free supernatant was dried under a N, stream and subjected to acetylcholine determination Meaaurement o f the acttvitte.s o f acetylchohne synthemzmq and de,qradiny enzl'mes The actlwty of choline acetyltransferase was assayed by the formation of [~4C]acetylchohne from [l -~4C]acetyl CoA and choline according to the method of Fonnum (1975). The activity ofacetylcholinesterase was assayed by the formation of 5-thlo-2-nitro-benzolc acid from acetylthlochohne accordlng to the method of Ellman et ul ( 1961 ) Measurement o/ [ ~H]cholow uptake and cndo,qenous acetvh'hohne relea~e Rats were killed by decapitation and strlatal hssues were dissected out. Freshly prepared strmtal tissues were sectioned with a mJcroshcer (DTN-1000, Dosaka EM Co L i d , Kyoto, Japan) at 200 #m thickness Each striatal slice was placed in a small plastic vessel eqmpped with a nylon mesh at the bottom (Kurlyama et al., 1984) The slices were prelncubated at 37'C for 20 min in 5 ml/shce of oxgenated Krebs Ringer bicarbonate buffer (pH 7.4) containing 10 ~ M NaC1, 4 , 8 x l 0 ~M KC1, 1 2 x 1 0 ~MMgSO47H~O, 2 . 7 x I 0 ~M CaCI~ 2H~O, 2.5 x l0 -~M NaHCO~ and 10 ~ M D-glucose. After the premcubation, the slice was incubated for 30 mm in 1 ml of the incubation buffer containing 10 ~ M [3H]choline. The reaction was terminated by adding 5 ml of the icecold buffer, and the slice was rinsed twine with 3 ml of the same buffer. The radioactivity in the slice, which was homogenized with 0 2 ml of distilled water, was measured with a liquid scintillation spectrometer (model 3379, Packard) using triton-toluene sclntlllant (05°,'0 2.5-d~phenyloxazone (PPO), 0.03% 1,4-dl-(2-(5-phenyl)oxazolyl)-benzene (POPOP) and 33% Triton X-100 in toluene). To measure the release of endogenous acetylchohne, the vessel containing striatal slices (4 5 shces/assay) was incubated at 37 C for 5 rain in 2 ml of the incubation buffer After the spontaneous acetylchohne release became constant, the slices were transferred successively to vials containing I ml of 10 ' M physostlgmlne m the mcubatmn buffer at 1 rain Intervals. The slices were shmulated twice at 5 and 20 rain by the addition of 2 x I0 -" M KCI to determine the KCl-evoked acetylchohne release. Each incubation buffer used for the measurement of acetylchohne release was treated w~th 5 x 10 : M perchlonc acid to machvate degrading enzymes and 5 x 10 ~ M KHCO~ to neutrahze the mcubahon buffer. The data for the release of endogenous acetylchohne was expressed as the raho of S: (second KCl-evoked acetylcholine

401

Cerebral cholinergic neurons and wnconate release)/S~ (first KCl-evoked acetylcholine release). The content of protein m each sample was determined by the method of Lowry et al. 119511, with bowne serum albumin as a standard.

Acetyh'hohne de'termination To examine cerebral acetylchohne content, the extract of cerebral nssue homogenate or the incubated buffer was analyzed b~ a high performance liquid chromatograph (HPLC) eqmpped with a precolumn (AC-ODS, Etcom, Kyoto, Japan), an immobilized enzyme column (AC-Enzympak, Elcom, Kyoto, Japan), and an electrochemical detector (ECD-100, Elcom, Kyoto, Japan) operating at a flow rate of 1.4 ml/mln. The mobde phase consisted of 10 ~M phosphate buffer soluhon (pH 8.0) containing 8 × 10 4 M of sodium ldecansulfonate and 6 × 10 4 M of tetramethylammonium chloride The detector potential was maintained at 450 mV against an Ag/AgCI reference electrode (Potter et al, 1983, Fujzmon and Yamamoto, 1987). Reuqen t Reagents used were sodmm l-decansulfonate (Tokyo Kasei Kogyo Co., Tokyo, Japan): tetramethylammonmm chloride (Nacalm Tesque, Kyoto, Japan) ; physostigmme sulfate (Kanto Che)rucal Co., Inc., Tokyo, Japan): S(--)-sulplnde (Sigma Chemical Co , St Lores, U.S.A ), [1 HC]acet~l CoA 11.85 GBq,mmoll and [2,4-~H]chohne (592.0 GBq/mmol, Ne~, England Nuclear, Boston, U.S.A ) Other reagents used m th~s study were of the highest grade .~'INIISIIC¢I[ blll¢l[r.wa

Results were expressed as the mean + SE. Yhe stansncal stgmficance was assessed by the analysis of variance followed by Dunnett's test and Scheffe's test.

Effect o f t'inconate on chohne acetyltrans[erase and acetyh'holinesterase aetivtties The oral a d m i m s t r a t i o n of w n c o n a t e (5, 50 and 200 mg/kg) had no cffect on choline acetyltransferase and acetylcholinesterase activities in the cerebral cortex, h l p p o c a m p u s and striatum (Table 2).

Effect o[ rinconate on [ ~H]choline uptake In vitro additton of vinconate (10 ~'-10 4 M) had no effect on the high affimty uptake of [3H]choline into striatal slices (data not shown). Effect o/rineonate and ( - )-sulpirtde on endogenous aceo'lchol#w release The KCI(2 x 10 ~ M)-cvoked release of e n d o g e n o u s acetylcholine under control condition (no addition of drugs) was 0.81 + 0 . 0 4 (as the ratio of S:,'S~). The addition of w n c o n a t c (10 : - 1 0 4 M) o r ( - )-sulpiride (10 ~ 10 i, M), a d o p a m i n e D: receptor antagonist, significantly increased the KCI (2 x 10 -~ M)-cvokcd release o f e n d o g e n o u s acetylchohne IYom striatal slices in a c o n c e n t r a t i o n - d e p e n d e n t m a n n e r (Figs 1 and 2) without altering the basal release (data not shown). F u r t h e r m o r e . the ( - ) - s u l p l r i d e (10 7 M)induced increase o f KCl-evoked release o f endogenous acetylcholine was significantly a u g m e n t e d by the addition o f I0 s M vinconate (Fig. 3). DISCUSSION

RESULTS

El[eet o/t'incanate on cerebral acetyh'holme content Acetylcholine content in the striatum showed a tendency o f reduction following the oral a d m i n istration of vinconate (5, 50 and 200 mg/kg), a m o n g which the dose of 200 m g / k g gave a statistically s~gnificant decrease as c o m p a r e d with the control value (Table I). In contrast, no changes were observed m the acetylchollne contents of the cerebral cortex a n d h i p p o c a m p u s under the same experimental conditlons Table 1 Elfect of ~mgle a d m m l s t r a n o n o f v l n c o n a t e on acetylcholme (ACh) content m rat brain A C h content (nmol,'g wet vet) m g kg, p o

Control Vmconatc 5 511 200

Cerebral Cortex

Hlppocampus

Stnatum

3573+3113 3673+456 3651+442 3403+6112

3674-+513 3487_+387 3468+228 3994+602

7940_+1314 5837_+1 36 5937_+7511 4529_+404*

Eat.h value represents the mean ± SE obtained froiTl 5 animals Vmconate [mg/kg) was admmJ,',tered orally * P < 0 01, compared with the control value ( O u n n e t t ' s test)

In this study, we have found that single administration of vinconate induces a reduction o f acetylchohne content m the striatum but not those m the Table 2 Effect of single administration o f vmconatc on choline acetyltransferase (CAT) and acetylcholmesterase (AChE)achvme~ m rat brain C A T ( n m o l 'mg protein h) Cereht a/torte Control Vmconate 5 50 200 Hlppo~ ampu Control Vmconate 5 50 200 ~lrttlllO?l C ontrol Vmconate 5 50 200

AChE(pmol mg protem'h)

16 40 +_0 25 18 48_+0.23 17 4 2 + 0 57 16 84 + 0 42

5 60 -+ 0 6 12+_0 6 I13+0 6115 + 0

1_.2 09 07 09

14.01 + 0 14 38 +_0 15 68_+0 14 3 5 + 0

24 45 25 42

5 4 5 5

09 16 08 06

39 3 6 + 0 39 (17+ I 40 21 + I 4236+I

73 69 10 91

10 1 4 ± 0 l0 9 7 4 + 0 19 9 6 2 + 0 08 10 14-+047

01 + 0 80 + 0 26+0 16.0

Each value represents the mean + SE obtained from 5 a m m a n Vmconate (mg/kg) wa,, administered orally

402

TOSHIAKI lIYO et al. 2.0 !

.4"

2.0

--

~e

,Oo

--t--

•

1.0

! a=,-.

<

o

Control

7

6

5

<

4

Vinconate (-log M) Fig 1. Effect of wnconate on KCI (2× l0 -" M)-evoked release of endogenous acetylchohne from rat striatal slices. Each column represents the mean + SE from 5 -10 separate experiments The data for the release of endogenous acetylchollne was expressed as the ratio of $2 (second KCIevoked acetylchohne release)/St (first KCl-evoked acetylchohne release). *P < 0.05, **P < 0.01, compared with control value (no addition of vmconate) (Scheffe's test)

2.0--

4

1.0 -

/ Control

8

7

0 Vmconate (-log M) -Sulptride (-log M) -Fig.3. Effect of vmconate on ( )-sulpirlde-mduced lncreaso of KCI(2 x 10 2 M)-evoked release of endogenous acetylchohne from rat striatal slices. Each column represents the mean_+ SE from 3 9 separate experiments. The release of endogenous acetylcholine was expressed as shown m the footnote of Fig. 1. **P < 0.01, compared with control value (no addition of vinconate and ( - )-sulplrlde) : # P < 0 05, compared with ( - )-sulplnde alone (Scheffe's test)

*

I-"F-1

<

I

6

(-) -Sulpiride (-log M)

Fig 2 Effect of (-)-sulplride on KCI(2× l0 2 M)-evoked release of endogenous acetylcholine from rat striatal slices. Each column represents the mean__+SE from 3 9 separate experiments. The release of endogenous aeetylchohne was expressed as shown m the footnote of Fig 1. *P < 0.05, • *P < 0.01, compared with control value (no addition of vlneon~te) IScheffe's test).

cortex a n d h i p p o c a m p u s . U n d e r the same experimental conditions, vinconate did n o t induce any changes in the activities o f choline acetyltransferase a n d acetylcholinesterase in these brain areas. These results suggest that the v i n c o n a t e - i n d u c e d decrease of acetylcholine m a y not be due to the changes in enzyme activities involved in the synthesis a n d d e g r a d a t i o n of acetylcholine. T h e high affinity uptake o f choline, k n o w n as the rate limiting step o f acetylcholine synthesis, was also not affected by the addition o f vinconate. Therefore, the alteration in th~s u p t a k e process seems also unlikely to be involved in the cause of

vinconate induced acetylcholine decline in the striatum. Acetylcholine release from brain shces has been usually determined by the efllux of [3H]acetylcholine formed from prelabeled [3H]choline (James a n d C u b e d d u , 1984: D r u k a r c h et al., 1989). However, we determined acetylcholine release by H P L C procedure using electrochemical detection, since it was indicated that the property a n d m e c h a n i s m o f e n d o g e n o u s acetytcholine release from brain slices was different from t h a t of preloaded [3H]acetylcholine (Weiler, 1989). The addition o f v i n c o n a t e (10 7-10 4 M) significantly e n h a n c e d 2 x 10-: M KCI (a s u b m a x i m a l concentration for acetylcholine release)-evoked endogenous acetylcholine release from striatal slices in a conc e n t r a t i o n - d e p e n d e n t manner. These results suggest that vlnconate may facilitate the function of cholinergic n e u r o n s t h r o u g h the a u g m e n t a t i o n of acetylcholine release in the striatum. Cholinergic nerve terminals are reported to possess both a u t o r e c e p t o r (James and C u b e d d u , 1984: 1987: Toede, 1989; W a t a n a b e and Shimizu, 1989) and heteroreceptor ( K u b o t a et al., 1987, Chang, 1988: Cai et ul., 1991). It has been d e m o n s t r a t e d that acet~lcholine release in the strlatum is modulated by muscarine Me a u t o r e c e p t o r in an inhibitory m a n n e r (Dolezal a n d Wecker, 1990: Weller, 1989). A l t h o u g h vinconate is s h o w n to have an affinity for muscarine receptor, the action of vinconate via the muscarine receptor is k n o w n to be agonistic rather than antag-

Cerebral chohnerglc neurons and wnconate onlstlc (Koda et al., 1989a). The IC~.. values of wnconate for [~H]qulnuclidinyl benzilate and ['H]splperone binding were also reported to be 5 x 10 4 and 2.5 x 10 ~' M, respectively (Koda et al., 1989a : Koda, 1989). These reports suggest that vinconate may not enhance acetylcholine release via the inhibition of the presynaptic muscarine autoreceptor. Other investigators have indicated that acetylcholine release is modulated by presynaptic dopamine (Alberch et al., 1985 ; Ajima et al., 1990 ; Bertorelli et al., 1992), N-methyl-D-aspartate (Cai et al., 1991 ) and adenosine receptors (Fredholm and DunerEngstrom, 1985). Stoof et al. (1992) have reported that the release of acetylcholine m the strlatum is especially modulated by dopammergic projections and intrinsic cholinerglc neurons. In fact, it has been shown that the stimulation of dopamine D, receptor in the striatum inhibits acetylcholine release (Helmreich et al., 1982, S t o o f a n d Kebabian, 1982), whereas that of dopamine D~ receptor (which is coupled to adenylate cyclase In a facilitatory manner) does not inhibit acetylcholine release In addition, it has been demonstrated by in r i r o microdialysis that ace@choline release from the rat striatum is inhibited by dopamme D_, receptor agonist added to the perfusion medium (de Boer et al., 1990: Damsma et al., 1990). Furthermore, the lack of correlation between dopamine D~ receptor mediated control of striatal acetylchohne release and the changes in the activity of adenylate cyclase system (Stoof and Kebabian, 1982) has been demonstrated. D o p a m i n e D2 receptor has been also shown to be involved in the regulation of K + channel functmn. It has been indicated that the stimulation of dopamine D~ receptor leads to the opening of K ~ channels (i.e. K + efflux), which results in a hyperpolarization of the cell membrane (Israel et al., 1987: Lacey et al., 1987) and the inhibition of the evoked release of acetylcholine (Drukarch et al., 1989). Taking the above reports into consideration, it is hkely that d o p a m m e D_, heteroreceptor, which resides at cholinergic terminals, is involved in the regulation of the release of acetylcholine in the striatum. Furthermore, it seems likely that these dopamine D~ receptors may be coupled to a K+-channel (via a Go-protein?) which operates Independently from the changes in cyclic A M P formatmn, although some of dopamme D2 receptors in the striatum is known to be coupled to adenylate cyclase in an inhibitory manner (via a Gl-protein). Interestingly, we have found in this study that I - )-sulpirlde, a dopamine D2 receptor antagonist, increases 2 x 10 -" M KCl-evoked release of endogenous acetylchohne in a concentration-

403

dependent manner, although dopamine itself inhibits the evoked acetylcholine release. Since it was demonstrated that the binding of [3H]spiperone, a dopamine D_~antagonist, to striatal membrane fraction was displaced by vinconate (IC50 = 2.5 x 10 ~ M) (Koda, 1989), we have attempted to examine whether or not the vinconate induced-increase of the evoked release of acetylcholine involves presynaptlc dopamine D, receptor. ( - ) - S u l p l r i d e (at a submaximal concentratlon) induced-increase of the evoked release of acetylcholine was further augmented by the addition ofvinconate. These results suggest that vinconate may facilitate the release of acetylchollne via the blockade of presynaptic dopamme D2 receptor in the striatum. Although an enhancing effect of vinconate on acetylcholine release was examined in this study using striatal slices, the same effect of vinconate was demonstrated m z iro using mlcrodialysls (Kinoshlta et al., personal communication). In conclusion, we have demonstrated that vinconate, a indolonaphthyridine derivative, may facilitate the striatal cholinergic function by increasing the release of acetylchohne, probably via the blockade of presynaptic dopamine D, receptor. This action seems to be one of the important characteristics of vinconate

REFERENCES

A lima A., Yamagucht T. and Kato T. (1990) Modulation of acetylchohne release by D~, D, dopamme receptors in rat striatum under freely moving conditions. Brain Res 518, 193 198. Alberch J., Marsal J. and Solsona C. (1985) Modulation of the endogenous acetylchohne release from rat strlatal slices. Bram Re,~. 346, 353 356. Araki T. and Kogure K. (1989) Prevention of delayed neuronal death m gerbil hlppocampus by a nobel vmca alkaloid den~atwe (Vinconate) Moh'c Chem. Neuropathol 11,33 43 Arakl T., Nlshloka K., Yukl S. and Kogure K (1989) Vmconate pre,mnts ischemic neuronal damage in the rat hlppocampus Acta Neurol. Scand. 81, 173 176. Bertorelh R., Zambelh M., DI Chlara D and Consolo S (1992) Dopamine depletion preferentially impairs D~-over D2-receptor regulation of strlatal tn eiro acet)lchohne release. J. Neurochem. 59, 353 357 de Boer P., Damsma G., F1Nger H C., Timmerman W, De Vnes J. B. and Westerink B. H. C. (1990) Dopamlnerglccholinerglc interactions in the stnatum thc critical significance of calcium concentrations in brain mlcrodlalysls. Naunyn-Schmledeberg's Archs Pharmac. 342, 528 534. Cal N -S., Kiss B. and Erbo S. L. (1991) Heterogeneity of N-methyl-o-aspartate receptors regulating the release of dopamlne and acetylchollne from strlatal shces .I. Neurochem. 57, 2148 2151 Cernto F and Ralteri M. (1979) Serotonm release is modu-

404

TOSHIAKI hNO et al

lated by presynaptic autoreceptors. Eur. J. Pharmac. 57, 427 430 C h a n g H. T ([988) Dopamme-acetylcholine interaction in the rat strlatum: a dual-labeling immunocytochemical study. Brain Res. Bull. 21; 295 304. D a m s m a G., De Boer P., Westerink B H. C and Flblger H. C (19901 Dopammerglc regulation of stnatal cholinergic interneurons : an in vwo mlcrodlalysis study. Naunyn-Schmiedeherg's Archs Pharmac 342, 523 527. Dlhberto P A., Garret L. J., James M K and Cubeddu L. X. (19871 Ionic mechanism of dopaminergic and muscarlnic auto- and heteroreceptor activation in superfuged strtatal slices : role ofextracellular chloride. J. Phurmac. exp Ther. 240, 795 801 Dolezal V and Wecker L. (19901 Muscarmic receptor blockade increases basal acetylcholine release from strlatal slices. J. Pharmac. exp. Ther 252, 739 743. Drukarch B., Schepens E., Schofl'elmeer A N M. and Stoof J, C. (19891 Stimulation of D-2 d o p a m m e receptors decreases the evoked m vitro releasc of [~H]acetylchohne from rat neostriatum, role o f K + and Ca 2+. J Neztrochem. 52, 1680 1685. Ellman G. L., Courtney K D., Andres V. Jr. and Featherstone R. M. ( 1961 ) A new and rapid colorlmetrlc deterruination of acetylchohnesterase activity Blochem. Pharmac. 7, 88 95 F o l m u m F. (19751 A rapid radiochemlcal method for the determination of choline acetyltransferase J. Neurochem. 24, 407 409 Fredholm B B. and Duner-Engstrom M. (19891 Propentfylhne and a hydroxy metabolite augment A~-receptor mediated cyclic A M P accumulation and attenuate A~receptor mediated inhibition of acetylchohne release in the rat hlppocampus. Pharmac. Tovtcol 65, 347 351. Fujimorl K. and Y a m a m o t o K. (1987) Determination of acetylchohne and choline in perchlorate extracts of brain tissue using liquid chromatography-electrochemistry with an immobilized-enzyme reactor. J. Chromatoyr 414, 167 173. Glowlnskl J. and lversen L. L. (1966) Regional studies of catecholamlnes in rat brain-I : the disposition of [~H]noreplnephrine, [~H]dopamine and [3H]dopa in various regions of the brain J. Neurochem. 13, 655 669. Gothert M and Schlicker E. (1983) Autoreceptor-medmted inhibition of [~Hl-5-hydroxytyramine release from rat brain cortex slices by analogues of 5-hydroxytyramme. LtleSci 32, 1183 1191. Gothert M., Huth H. and Schhcker E. (19811 Charactarization of the receptor subtype involved in alphaadrenoceptor-medmted modulation of serotonin release I'ronl rat brain cortex slices. Naunl'n Schmtedeher¢l~' ,4rchs Phurmac. 317, 199 203. Helmrelch I., Relmann W., Herttlng G. and Starke K. ( 19821 Are presynaptlc dopamine autoreceptors and postsynaphc dopamine receptors in the rabbit caudate nucleus pharmacologically different. Neuroscwnce 7, 1557 1566 lgarashJ Y., Sasahara T. and M a r u y a m a Y. (1984)A simple method for determination of choline (Cr) and acetylchohne (ACh) in rat brain regions using high-per[brmance liquid chromatography with electrochemical detection (HPLC-ECD), Foha Pharmac. Japan 84, 529 536 (abstract in English) h n o T , Katsura M. and Kuriyama K. (1992) Protective effect of vinconate on lschemla-lnduced neuronal damage m the rat hippocampus. Eur. J. Pharmac. 224, 117 124.

Israel J. M , Kirk C and Vincent J. D. (1987) Electrophysiological responses to dopamine of rat hypophyslal cells in lactotroph-enriched primary cultures. J Physwl. 390, 1 22. James M. K. and Cubeddu L. X (19841 Frequency-dependent muscarmic receptor modulation of acetylcholine and dopamine release from rabbit striatum. J. Pharmac. exp. Ther. 229, 98 104. James M K. and Cubeddu L X. (19871 Pharmacologic characterization and functional role of muscarinic autoreceptors m the rabbit striatum. J. Pharmac exp. Ther. 240, 203 215. Kamal L. A., Arbllla S. and Langer S. Z (19811 Presynaptic modulation of the release of dopamtne from the rabbit caudate nucleus' differences between electrical stimulation, amphetamine and tyramine. J. Pharmac. exp. Ther. 216, 592 598. Katsura M., Hashlmoto T. and Kuriyama K. (19911 Effect of 1,3-di-n-butyl-7-(2-oxopropyl)-xanthine (denbufylline) on metabolism and function of cerebral chohnergic neurons. Japan. J Pharmac. 55, 233 240. Kinoshlta H., K a m e y a m a T., Hasegawa T. and Nabeshlma T (1992a) Effects of vmconate, a novel vlnca alkaloid, on spatial learning deficits induced by the basal forebrain lesion in rats. Pharmac. btochem. Behav 42, 19 23. Kmoshita H., K a m e y a m a T , Hasegawa T. and Nabeshlma T. (1992b) Effect of vmconate on spatial learning impairments induced by medial septal lesions in rats. Life Set 51,267 273 Koda H. (1989) Neurochemlcal studies on central effect of vlncamlne alkaloid. J. Kyoto Pref L:nw Med. 98, 69 102 (abstract m English). Koda H., Hashimoto T. and Kurlyama K. (1989a) MuscarlnlC receptor-mediated regulation of OM-853-induced dopamine release in strlatum of rat Eur. J Pharmac. 162, 501 508. Koda H., Hashimoto T., Katsura M and Kurlyama K. (1989b) Effect of( + )-methyl 3-ethyl-2, 3, 3a, 4-tetrahydro1H-lndolo [3,2, l-de] [1,5] naphthyrldine-6-carboxylate hydrochloride (OM-853), a new vlncamlnc analogue, on the metabolism and function of cerebral serotonerglc neurons. Japan. J. Pharmac. 49, 413 421 Kubota Y., lgarashl S., Shimada S., Klto S , Eckenstem F. and T o h y a m a M. (19871 Neostrlatal chohnergtc neurons receive direct synaptic inputs from dopamlnergic axons Brain Re~. 413, 179 184 Kurlyama K., Kanmori K , Taguchl J. and Yoneda Y. ( 19841 Stress-induced enhancement of suppression of [~H]GABA release from stnatal slices by presynaptlc autoreceptor. J. Neurochenl. 42, 943 950. Lacey M. G., Mercun N. B and North R. A. (19871 Dopamine acts on D-2 receptors to increase potassium conductance in neurones of the rat substantla nlgra zona compacta J. Phys'ml. 392, 397 416. L e h m a n n J. and Langer S. Z (19821 Muscarlntc receptors on dopamlne terminals in the cat caudate nucleus, neuromodulation of [3H]dopamlne release m vitro by endogenous acetylcholine. Brain Res 248, 61 69. Lowry O. H , Rosebrough N. J , Farr A. L. and Randall R. J. (19511 Protein measurement with the folin phenol reagent. J biol. Chem 193, 265 275 Potter P. E , Merk J. L and NeffN. H (19831Acetylchohne and choline in neuronal tissue measured by H P L C with electrochemical detection. J Neurochent 41, 188 194

Cerebral chohnerglc neurons and wnconatc R m t e n M., M a u r a G. and Versace P. (1983) Functional evidence for two stereochemlcally different alpha-2 adrenoceptors regulating central norepinephrine and serotonm release. J. Pharmac. exp. Ther. 224, 679 684. Raiten M., keardi R. and Marchl M (1984) Heterogeneity of presynapt~c muscarimc receptors regulating neurotransmitter release m the rat brain J. Pharmac. exp. Ther 228, 21)9 214. Smto T , K u n b a r a H. and Tadokoro S (1991) Behaworal cffects of OM-853, a cerebral metabohc enhancer, on ambulatory actJwt?, passive and active avoidance responses m Inlce. Japan J Pharma~ 55, (Suppl 1), 209 Saletu B , Grunbergcr J , Lmzmayer L. and Wlttek R. (1984) Classlfictmon and determination of a new antlhypoxldotic drug, vmconate, by p h a r m a c o - E E G and psychometry 4rch~" Geront Gertatr. 3, 127 146. Starke K., Spath L , Lang J D. and Adelung C (1983) Further funcllonal b+ t ttro compartson of pre- and postsynaptic d o p a m m e receptors in the rabbit caudate nucleus .Nau/1vll Sclll~Jl('deberq.s ,4t('h,s Pharmac 323, 298 306 Stoof J C and Kebabmn J. W. (1982) Independent it/tttro regulation by the D-2 d o p a m m e receptor of d o p a m m e

405

stimulated cychc A M P efllux and K ~ -stimulated release of acetylcholine from rat neostriatum. Brain Res. 250, 263-270 Stool J C , Drukarch B, de Boer P and Westermk B H C. (1992) ht ritro and m t'it'o acetylchohne release from rat stnatal as a functional para&gm of s~gnal transducuon via a D-2 dopamlne receptor. Neuro~hem h~t 20, 201 205. Thlebauld C., Van Mullen J., Lmtermans J. and Sprumont P (1983) Testing a h y p o b a n c chamber drugs claimed to improve brain function. Lancet 2, 225 226 Toede K. (1989) Effect of scopolamine on extracellular acetylchohne and chohne levels and on spontaneous motor actlvJty m freely moving rats measured by brain &alysis. Pharmac Biochem. Behuv. 33, 109 113. Watanabe H. and Schlmlzu H (1989) Effect ofanuchohnerglc drugs on striatal acetylchohne release and motor acnwty m freely moving rats studied by brain mlcrodmlysls Japan J. Pharmac 51, 75 82. Wciler M H. (1989) Muscarimc modulation of endogenous acetylcholine release m rat neostrmtal slices. J Pharma~ exp. Ther. 250, 617 623