4-Phenyltetrahydroisoquinoline, but not nomifensine or cocaine, inhibits methamphetamine-induced dopamine release

European Journal ¢ff"Pharmacology, 24(I(1993) 51-56 ,~) 1993 Elsevier Science Publishers B.V. All rights reserved (XJ14-2999/93/$06.110

EJP 53225

4-Phenyltetrahydroisoquinoline, but not nomifensine or cocaine, inhib methamphetamine-induced dopamine release M i c h i h i r o T a t e y a m a , T a k u N a g a o , S h i g e r u O h t a ~', M a s a a k i H i r o b e " a n d H i d e k i O n o l)epartment ~ff"7?z~icoh#,3"and Pharrnacolols:v, " Department of Bioorganic and Medicinal ('hemistry, Faculo' ~f Pharmaceutical Sciences, Unitersity o]" Tokyo. Hongo 7-3-I, Bunkyo-ku Tokyo 113, Japan

Received 25 March 1993, accepted 25 May 1993

The inhibitory effect of 4-phenyltetrahydroisoquinoline (4-PTIQ) on methamphetamine-induced dopaminc release in th~ nucleus accumbens was investigated using a brain microdialysis method. Mcthamphctamine (10 ~' M) infusion throu~ microdialysis probe induced the release of dopamine. Although the uptake inhibitors, cocaine (3 × 10 ¢' M) and nomifet7 (1(} ¢' M), failed to block dopamine release, 4-PTIQ (10 ~' M) inhibited the dopaminc-releasing effect of mcthamphetan 4-PTIQ did not affect the elevation of the cxtraccllular dopaminc level induced by high concentrations of nomifcnsine (10- : and cocaine (3 × 10 -~ M). 4-PTIQ was the weakest inhibitor of [3H]dopaminc uptake by rat striatal synaplosomes. These re: suggest that 4-PTIQ is a selective antagonist against the dopamine-rcleasing effect of mcthamphetamine in the nut accumbens. Microdialysis, 4-PTIQ (4-phcnyltctrahydroisoquinoline); Cocaine; Nomifcnsinc; Methamphetamine; Dopaminc; Nucleus accumbens

1. Introduction Amphetamine and methamphetamine produce locomotion and stercotypy in animals (Kelly and lverscn, 1976; Lewander, 1977). The increase in locomotor activity and the production of stereotypy are considered to be mediated by an increase in the concentration of dopamine in the nucleus accumbcns and an increase of dopaminc concentration in the striatum, respectively (Sharp et al., 1989; Kuczenski and Segel, 1989). The increased dopamine level induced by amphetamine is caused mainly by dopamine release and partly by inhibition of its uptake and of monoamine oxidase (Miller et al., 1980; Seyfried, 1983; Parker and Cubeddu, 1988; B6nisch and Trendelenburg, 1988). We have reported that 4-phenyl-l,2,3,4-tetrahydroisoquinoline (4-PTIQ), an analog of nomifensine, inhibited the noradrenaline-releasing effect of mcthamphetamine in the rat spinal cord (Ono et al., 1990, 1991; Satoh et al., 1992). In the supraspinal central neuron system, 4-PTIQ co-injected with methamphetamine into the nucleus accumbcns inhibited the

Correspondence to: H. Ono, Department of Toxicologyand Pharmacology. Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo7-3-1. Bunkyo-ku, Tokyo l l3, Japan.

mcthamphetamine-induccd increase in locomotor tivity (Tateyama ct al., 1993). In the present study, the inhibitory effect of 4-Pq nomifcnsine and cocaine on the dopamine-relea effect of methamphetamine in the nucleus accumt was investigated. The minimum concentration methamphetamine required to increase dopamine used in order to investigate the effects of the drug: the dopamine-releasing effect of methamphetarn The effects of 4-PTIQ on the elevation of the cxtr~ lular dopamine level induced by nomifensine and caine were also studied.

2. Materials and methods 2.1. Surgery and microdialysis procedure

Male Wistar rats (Nippon Rat Co. 220-260 g) anesthetized with sodium pentobarbital (40 m g / k g i A guide cannula (stainless steel, 8 mm long, 0.7 internal diameter, 1.2 mm external diameter) was planted unilaterally at the coordinates A 1.8, L 1.4 according to the atlas of Paxinos and Watson (1 c with the tip placed 1 mm above the nucleus ace bens. The guide cannula was then fixed to the ,, with dental cement and an anchored screw. A

52 surgery, kanamycin (10 mg, intramuscularly) and pcnicillin (10 mg, intramuscularly) were administered. The experiment was performed after 5 - 7 days. A dialysis probe (membrane length = 1 mm, Eicom, Japan) was inserted into the left nucleus accumbcns through the guide cannula. The rat was then placed in a plastic box (3(1× 30 × 3(1 cm). The probe was connected to a microdialysis system and perfused with artificial cerebrospinal fluid (CSF) (mM: 138 NaCI, 5.0 KCI, 1.(1 CaCI 2, 1.(1 MgCI 2, 1.0 N a H 2 P O 4, 11.0 Nat-ICOn, pH 7.4). After more than 10(1 min, when the release of dopamine and its metabolites had stabilized, the experiment was started. For elevation of the dopamine level, the stimulants mcthamphetaminc, nomifensine and cocaine werc infused for 4(1 min. 4 - H ' I Q , nomifensinc and cocaine werc prcinfused 20 min beforehand, and then co-infused with the stimulants,

2.2. Assay Artificial CSF was delivcrcd at a rate of 2 / s l / m i n by an infusion p u m p (EP60, Eicom, Japan) through a Teflon-coated tube, and the perfusate was collccted into an autoinjector (AS-10, Eicom, J a p a n ) w h i c h automatically injected the perfusate into an H P L C system every 2(I min. Dopamine in the dialysate was separated on a reverse-phase column (150 × 4.6 mm) (5Ct~-AR, Nacalai, Tokyo) maintained at 25°C. The mobile phase (86 mM citric acid, 86 mM sodium acetate, 13% methanol, 112 mg/1 1-octasulfonate, 5 /xM E D T A 2 sodium) was delivered by a p u m p (EPI0, Eicom, Japan) set at a flow rate of 1 m l / m i n . Dopaminc, homovanilic acid ( H V A ) and 3,4-dihydroxyphenylacetic acid ( I ) O P A C ) were quantified using an electrochemical detector (ECDI00, Eicom, Japan) with a glassy carbon electrode maintained at +700 mV.

2.3. Histology At the end of the experiments, the rats were killed by injection of sodium pentobarbita[. The brains were removed and fixed in a solution of 1(1% formalin for 2 - 4 days, followed by soaking in gum-sucrose solution for a further day, then freezing and sectioning on a freezing microtome. The site of the probe tip was located and animals in which the dialysate sites were incorrect were discarded from the results.

2.4. [~ll]Dopamine uptake &hibition The uptake of [3H]dopamine by striatal synaptosomes was studied by a modification of the procedure of Koide and Uyemura (1980). Striatal tissue obtained from male Wistar rats was homogenized in 4(1 volumes of ice-cold (1.3 M sucrose in a glass homogenizer with a

Teflon pestle. The homogenate was centrifuged at ] × g for 10 rain and the supcrnatant was centrifuge 17000 × g for 20 rain. The pellet was resuspende 50 volumes of 0.3 M sucrose (2-3 mg p r o t e i n / m l ) then used immediately as striatal synaptosome pr~ ration. The incubation medium contained (mM): I~ 100, glucose 11, KCI 4, ascorbic acid (I.11, sod phosphate 40 buffer (pH 7.4). Fifty microliter~ synaptosomal suspension was added to 400 #1 of incubation medium containing various concentrat of the drugs, and the mixture was prcincubated fi rain. [~H]Dopamine 50 p,l (final concentration 1. 10 '~ M) was added and incubated at 37 or 0°C fi rain. Incubation was terminated by rapid filtratkn the mixturc through po[ycthyleneimine-coatcd W man G F / B glass-fiber filters. Each of thc filters washed three times with 4 ml of ice-cold incuba medium. Radioactivity on the filtcr was d e t e r m i n e 5 ml of scintillation cocktail (New England Nucl Aquasol-2) using a liquid scintillation counter (L 700, Aloka, Tokyo). Active uptake was calculatec subtracting the 0°C control value from the 37°C va

2.5. Drugs The drugs used wcrc S ( + ) - m e t h a m p h c t a m i n e drochloride (Dainippon), cocaine hydrochloride (5 kyo), nomifensine maleate (Hoechst) and mazir (Sandoz). 4-Phenyl-l,2,3,4-tetrahydroisoquinoline drochloride was synthesized, and its purity was rr than 99.7%. All drugs were dissolved in artificial (

2.6. Statistics Individual time-point values were calculated percentage of the last two basal values before c infusion and are expressed as means + S.E.M. Stat cal comparisons among different treatments were m by Student's t-test or analysis of variance ( A N O ~ followed by Bonfcrroni's multiple t-test.

3. Results

3.1. lnJIuence ofmethamphetamine on dopamh~e reh Methamphetamine (10 -6 M) infusion for 4(1 evoked a 500-650% increase in the level of d o p a m and the increase declined after cessation of infu, (figs. 1, 2). This concentration of 1 0 6 M was minimum necessary to cause a reproducible and cor tent increase in dopaminc release. The levels dopamine metabolites, D O P A C and HVA, were changed by m e t h a m p h e t a m i n e (10 -¢' M) (data shown).

not shown). Although 4-PTIQ (3 × 10 - 7 M) did reduce methamphetamine-induced dopamine rele 4-PTIQ (10 -6 , 3 x 10 ~' M) reduced the incrca dopamine release significantly (fig. 1). Howe nomifcnsine (10 -~' M) or cocaine (3 x 10 ~' M) fa to attenuate the mcthamphetamine-induced releas~ dopamine (fig. 2A, B).

1000-

v

c~

~ ~

soo

"D

0

'

'

1()0

3.3. Effect of 4-PTIQ on eleration of extraeelh dopamine let'el induced by nomifensine and cocaine

200

Time (rain) Fig. 1. Effects of 4-PTIQ on dopaminc release induced in the nucleus accumbens by mcthamphctaminc 1,10-~' M. open circle7 infusion (white horizontal bar). Infusion of 4-PTIQ (3x 10-7 M. closed triangle; 10 -~' M, closed circle; 3x 10 ~' M, closed square) (black horizontal bar) was started 20 min before mcthamphetaminc

Infusion of the uptake inhibitors nomifcnsine (1 M) and cocaine (3 x 10-5 M) for 40 min increased extracellular dopamine level to about 500% (fig. 3A The start of their effects was slightly slower than of methamphetamine; the maximum increases

infusion and co-infusion was carried out for 41') rain. The effect of 4-PTIQ ( 3 × 10-~' M) on basal dopaminc release is represented as closed squares and a doned line. A dotted line and open squares show a time course change of basal dopamine. Each curve represents data from four rats with time points expressed as means+S.E.M, Statistical significance of differences between the m c t h a m -

dopamine were observed at 20 min after cessatiol infusion o f d r u g s . T h e s e concentrations of u p t a k e hibitors were the minimum necessary to produc constant increase in dopamine. 4-PTIQ (3 x 10 -~' did not affect the elevation of dopaminc level cat:

phetamine-infuscd group and 4-PTIQ co-infused groups was calculated by Bonfcrroni's multiple t-test. * P < (7.1)5, **: P < 1'7.1,)1.

by nomifensine or cocaine (fig. 3A,B).

3.4. 7he inhibitory effect of nomifensine at high corn tration on methamphetamine-induced dopamine rele~

3.2. Effects of drugs on dopamine release induced by methamphetamine

Infusion of methamphetamine (10- 5 M) markq increased the extracellular level of dopamine to at 3700% (fig. 4). Nomifensine (10 -5 M) also incre~ the level of dopamine by itself (fig. 3A). At this c centration of 1 0 .s M, nomifensine reduced dopamine release induced by mcthamphetamine (1 M).

4-PTIQ 3 x 10 -~' M, nomifensine 10 ~' M and cocaine 3 x 10 -6 M were the maximum concentrations at which they did not affect the basal release of dopamine (figs. 1, 2). In the preliminary experiments, 4-PTIQ (10 -5 M), nomifensine (3 X 10 -" M) and cocaine (10 -5 M) increased the extracellular level of dopamine (data

A)

-o

B) 1000 -

1000

soo

soo

o

o

0

100 Time (min)

200

0

1IX) Time (rain)

2IX)

Fig. 2. Effect of nomifensine 1,A) and cocaine (B) on dopamine release induced in the nucleus accumbens by methamphctamine (10 <' M, circle) infusion (white horizontal bar). (A) Infusion of nomifensine (1(7 ~' M, closed circle) (black horizontal bar) was started 20 rain bq methamphetamine infusion and co-infusion was carried out for 40 rain. The effect of nomifcnsinc (10 ~' M) on basal dopamine relea represented as closed squares and a dotted line. (B) Infusion of cocaine (3 × 10 ~ M, closed circle) (black horizontal bar) was started 2(} before methamphetamine infusion and co-infusion was carried out for 40 min. The effect of cocaine ( 3 x l0 ~' M) on basal dopamine relez represented as closed squares and a dotted line. A floned line and open squares show a time course change of basal dopamine (A,B). Each ( represents data from four rats with time points expressed as means _+S.E.M.

54 A)

B) 1000 -

1000 -

500

500,

A

o~

¢~ C

0 "0

o

o

'

o

Tlme(min)

Time(min)

Fig. 3. Effect of 4-PTIQ (3:< 10 -~' M, closed symbol) on elevation of cxtraccllular dopamine level evoked in the nucleus accumben nomifensine (10 s M, open square) (A) or cocaine (3 × 10 s M, open circle) (B) infusion. Infusion of 4-PTIQ (black horizontal bar) was sta 20 rain before nomifensinc or cocaine (white horizontal bar) and co-infusion was carried out for 41,1rain. Each curve represents data from rats with time points expressed as means ± S.E.M.

g

4000.

4. D i s c u s s i o n

3000.

T h e increase in extraccllular d o p a m i n c c o n c e n tion evoked by a m p h e t a m i n e s has b e e n considere~ bc caused mainly by d o p a m i n c release a n d partl} inhibition of d o p a m i n e uptake and m o n o a m i n c oxic (Miller et al., 1980; Parker and C u b e d d u , 1988; B6n: a n d T r c n d e l e n b u r g , 1988). T h e d o p a m i n e release d u c c d by a m p h e t a m i n e is thought to occur througl" a m i n e u p t a k e carrier, a n d to be u n r e l a t e d to exocyt ( N i d d a m e t a [ . , 1985; H u r d and U n g e r s t e d t , 1989 C a r b o n i et al., 1989). N o m i f c n s i n c (10 ~ M) and t a i n t (3 × 111-5 M) i n c r e a s e d the cxtracelh

=0 2000-

1000-o

0'

0

100

200

Tlme(min)

Fig. 4. Effect of nomifcnsine (lt) 5 M, closed circle) on dopaminc release induced in the nucleus accumbcns by methamphetamine (10 s M, open circle). Infusion of nomifcnsine (black horizontal bar) was started 211 rain before methamphetaminc infusion (white horizontal bar) and co-infusion was carricd out for 411 min. Each curve represents data from three rats with time points expressed as means _~S.E.M. Statistical comparison between two groups was made by means of Student's t-test. *P ~, ().115.

d o p a m i n e level (fig. 3A,B). U p t a k e inhibitors ca~ evoke an increase in d o p a m i n e u n d e r Ca 2 ÷-free COl tions, as was shown by brain microdialysis ( H u r d U n g e r s t e d t , 1989a; C a r b o n i et al., 1989). Furtherm, the effect of uptake inhibitors is impulse-flow-del:

TABLE 1 I(;~,(~ values of drugs for [3]t]dopamine uptake inhibition in the rat striatum, The values arc the means and S.E.M. from three experiments performed in duplicate. I(-'s, was calculated with a probit m e t h o d ,

d e n t ( C a r b o n i et al., 1989). These findings indicate i the increase in d o p a m i n e i n d u c e d by uptake inhibi is due to i n h i b i t i o n of cxocytotically released doparr uptake. In the p r e s e n t experiments, the IC50 values n o m i f e n s i n c , cocaine and m e t h a m p h c t a m i n e were x 10 ~, 3.6 × 10 -7 and 1.7 x 10-7 M, respectively blc 1), a n d the c o n c e n t r a t i o n s necessary to evoke al: a 6 to 7-fold increase in d o p a m i n e were 10 ~ 3 × 1 a n d 10 -~' M, respectively (figs. 1 and 3). tiowever, c o n c e n t r a t i o n ratios b e t w e e n n o m i f e n s i n c and coc~ ( 1 : 3 ) were similar for the uptake inhibition and creasc in d o p a m i n e . A l t h o u g h m e t h a m p h e t a n showed a weaker uptake inhibition than n o m i f c n s it was 10 times more p o t e n t for increasing the levc d o p a m i n e . T h e s e results indicate that the increas~

Drugs 4-PTIQ Cocaine Methamphetamine Nomifensine Mazindol

d o p a m i n e i n d u c e d by m e t h a m p h c t a m i n c is due t d o p a m i n e - r e l e a s i n g effect. T h e drug c o n c e n t r a t i o n s tested on the d o p a m i n e leasing effect of m c t h a m p h c t a m i n e were the maxin o n e s which did not affect the basal d o p a m i n e con~ tration. At thesc c o n c e n t r a t i o n s , cocaine and nomi

3.5. [3H]Dopamine uptake inhibition IC~ 0 values for each of the drugs arc shown in table 1 . 4 - P T I Q showed an u p t a k e i n h i b i t i o n similar to that by cocaine, but weaker than that caused by n o m i f e n sine.

lCbc)(nM) 575 +_34.6 361-L-_20.9 172± 12.9 97+ 15.3 54 + 5.8

sine f a i l e d to r e d u c e t h e m e t h a m p h e t a m i n c - i n d u c e d i n c r e a s e in c x t r a c e l l u l a r d o p a m i n e level (fig. 2 A , B ) . It has b e e n r e p o r t e d t h a t u p t a k e i n h i b i t o r s b l o c k t h e amine-releasing effect of amphetamines (Hurd U n g e r s t e d t , 1989b; B u t c h e r ct al., 1988). in t h e s e pcrimcnts, however, subcutaneously administered t a k e i n h i b i t o r s i n d u c e d a s u b s t a n t i a l i n c r e a s e in c x t r a c e l l u l a r level o f d o p a m i n c

and exupthe

in the s t r i a t u m o f rats

and blocked the amine-releasing effect of amphetaminc. Thus the blocking effects of amine uptake inhibtors on amphetamine-induced dopamine release h a v e b e e n c o n s i d e r e d to be d u c to b l o c k i n g o f u p t a k e c a r r i e r f u n c t i o n . A l s o , in t h e p r e s e n t study, n o m i f c n sine (10 - s M), w h i c h i n c r e a s e d the c x t r a c c l l u l a r d o p a m i n c level, r e d u c e d m c t h a m p h c t a m i n e - i n d u c e d d o p a m i n c r e l e a s e (fig. 4). T h i s result s u g g e s t s t h a t t h e d o p a m i n e r e l e a s e e v o k e d by m e t h a m p h c t a m i n c is m e d i a t c d by an u p t a k e c a r r i e r , a n d t h a t n o m i f e n s i n c , 10 ¢' M, a n d c o c a i n e , 3 × 10 " M, w e r e not s u f f i c i e n t tO b l o c k t h e e f f e c t o f m e t h a m p h e t a m i n e . In t h e p r e s e n t study, 4 - P T I Q (3 x 10 ¢~ M), n o m i f c n s i n e (111 -~' M ) a n d c o c a i n e (3 × 10 ~' M ) aff c c t e d basal d o p a m i n e r e l e a s e slightly. H o w e v e r , t h e w e a k e s t d o p a m i n c u p t a k e i n h i b i t o r , 4 - P T I Q (10 ¢' a n d 3 X 1 0 - " M), i n h i b i t e d t h e d o p a m i n c - r e l c a s i n g e f f e c t of methamphctmainc. T h e s e r e s u l t s s u g g e s t that 4PTIQ inhibits the dopamine-rcleasing properties of mcthamphctamine of the modcl, ported Cho,

in a m a n n e r

other than inhibition

a m i n e u p t a k e c a r r i e r . In an e x c h a n g e - d i f f u s i o n a m p h e t a m i n e has b c c n c o n s i d e r e d to be t r a n s into the c y t o p l a s m i c c o m p a r t m e n t ( F i s c h e r a n d 1979; B 6 n i s c h , 1984), w h e r e it s t i m u l a t e s

dopaminc

release from storage vesicles (Raiteri and

Levi, 1987; B 6 n i s c h , 1984). A h i g h e r c o n c e n t r a t i o n o f 4 - P T I Q (10 - s M ) e v o k e d an i n c r e a s e o f d o p a m i n e by itself ( d a t a not s h o w n ) . It is p r o p o s e d t h a t 4 - P T I Q m i g h t be t r a n s p o r t e d by an u p t a k e c a r r i e r a n d a n t a g o nize m c t h a m p h c t a m i n e d u r i n g t h e i n n e r t r a n s p o r t p r o cess, o r b l o c k t h e r e l e a s e o f d o p a m i n e f r o m v e s i c l e s i n t o t h e c y t o p l a s m by s o - c a l l e d p a r t i a l a g o n i s t i c a c t i o n , in s u m m a r y , 4 - P T I Q , but n o t n o m i f e n s i n e o r cocaine, inhibited the dopamine-releasing effect of methamphetamine

in t h e n u c l e u s a c c u m b e n s o f rats.

Acknowledgements This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan. Wc are grateful to lioechst for a supply of nomifensinc maleate.

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