172
Brain Re.~earc~, 5tl• (199(t) i72 i74 Elsevier
BRES 23967
Presynaptic regulation of d o . m i n e release in corpus striatum monitored in vitro in real time by fast cyclic voltammetry P. Palij 2, D.R. Bull 1, M.J. Sheehan t, J. Millar 3, J. Stamford z, Z.L. Kruk 2 and P.P.A. Humphrey l 1Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, ( U. K. ) and Departments of 2pharmacology and 3physiology, The London Hospital Medical College, London (U. K.)
(Accepted 7 November 1989) Key words: Dopamine autoreceptor; Dopamine uptake blocker; Quinpirole; Metoclopramide; Haloperidol; SKF 38393
Dopamine release was evoked by single electrical pulses in slices of rat corpus striatum, and measured by fast cyclic voltammetry in real time. The magnitude of the release varied in the expected way to agents which modify dopamine storage, release and re-uptake: The presence of functional dopamine D 2 autoreceptors was demonstrated by showing that the release was potently and completely inhibited by the selective agonists quinpirole and N,N-dipropyl-5,6-ADTN. The selective D1 agonist SKF 38393 was ineffective. The inhibition by quinpirole was competitively antagonised by haioperidol and metoclopramide with potencies which correspond closely to published values at postsynaptic striatal D 2 receptors. Thus, the D2 autoreceptors on striatal nerve terminals appear to be indistinguishable from those on the postsynaptic neurons. Dopamine-containing neurons of the nigrostriatal pathway possess terminal autoreceptors which can inhibit the release of neurotransmitter ~'18. Previous studies of these autoreceptors have generally involved isotopically labelled pools of neurotransmitter and have a poor time resolution. We have applied the technique of fast cyclic voltammetry, which has up to now been used only in vivo t2"14, to the measurement of endogenous dopamine released in striatal slices in vitro. This has made it possible to demonstrate the factors controlling the kinetics of dopamine release and re-uptake, and also to perform a quantitative pharmacological characterization of the autoreceptors. Slices of rat corpus striatum were placed in an incubation chamber 16 and superfused with artificial cerebrospinal fluid maintained at 32 °C. Voltammetric recordings were made using a conventional three-electrode system 12 in which the carbon-fibre working electrode ~ was placed in one of the translucent stria of the tissue 75/~m below the surface. A bipolar stimulating electrode was placed 200-400/~m ventromedial to the working electrode with its poles straddling the same band of tissue. With this arrangement, minimal electrical stimulation (a single 0.1 ms rectangular pulse, amplitude 20 V) produced a voltammetric signal which was identified (see below) as being solely due to the release of dopamine. The signal reached a maximum within the first or second 0.5 s sampling period after the stimulus, and
then declined exponentially with a half-life of about 1 s. When slices were stimulated in this way at 2-min intervals, the evoked release was consistent for 3-4 h. When calcium was iso-osmotically replaced by magnesium in the superfusion medium, or when tetrodotoxin (10 -6 M) was added, the voltammetric signal was abolished, indicating that it originated from axonal conduction of action potentials to nerve terminals. The response could be restored by superfusion with fresh medium. The released substance was shown to be dopamine alone by the following observations. Its oxidation and reduction current peaks, which occur at voltages which are characteristic of the substance being oxidized 11, were identical to those obtained in a solution of exogenous dopamine, but differed from those for norepinephrine, 5-hydroxytryptamine, epinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) or 5-hydroxyindoleacetic acid. The selective dopamine uptake blocker G B R 12909 (ref. 7, 3 × 10 -7 M) tripled the magnitude of the signal (Fig. la) and considerably prolonged its rate of decay to a half-life of 3 s. In contrast, the release was unaffected by a concentration of desipramine (5 x 10 -8 M) which selectively blocks the uptake of norepinephrine and 5-hydroxytryptamine (Fig. lb). The fast acting reserpinelike compound, Ro 4-1284 (ref. 17) abolished the electrochemical signal within 20 min of application (Fig. lc). Finally, the monoamine oxidase inhibitor nialamide (10 -6 M ) had no effect (Fig. ld), showing that oxidative
Correspondence: M.J. Sheehan, Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, Herts SG12 ODE U,K.
173 m e t a b o l i t e s did not contribute to the o b s e r v e d signal (cf. ref. 12). Previous studies have suggested that the a u t o r e c e p t o r s on the terminals of d o p a m i n e neurones in the striatum are of the D z type, as defined by K e b a b i a n and Calne 9. In the p r e s e n t study, the selective D 1 agonist, S K F 38393 (ref. 15; 10 -7 to 5 × 10 -5 M) did not alter the e v o k e d release of d o p a m i n e . H o w e v e r , the highly selective D 2 agonists quinpirole 2° and N , N - d i p r o p y l - 5 , 6 - A D T N 13 were able to abolish the signal in a c o n c e n t r a t i o n - r e l a t e d m a n n e r , p r o d u c i n g 50% inhibition at concentrations of 26 + 5 n M and 186 + 26 n M (means + S . E . M . , n = 6 and 10) respectively. A d d i t i o n of the selective D 2 antagonist h a l o p e r i d o l (10 -6 M) to the m e d i u m antagonised the inhibition caused by both of these agonists, w h e r e a s the selective D 1 antagonist, Sch 23390 (ref. 8; 10 -6 M) did not. In o r d e r to m e a s u r e the absolute potency of two D 2 antagonists, h a l o p e r i d o l and m e t o c l o p r a m i d e , Schild plots e were constructed. C o n c e n t r a t i o n - r e s p o n s e curves were d e t e r m i n e d for inhibition of d o p a m i n e release by quinpirole, first in the absence of antagonist and then, after a washout p e r i o d and 30 min incubation with antagonist, in its presence. F o r m e t o c l o p r a m i d e , a pA 2 value of 7.57, with a slope factor of 1.30, was calculated
(Fig. 2). H a l o p e r i d o l gave a calculated p A 2 value of 9.33 and a slope factor of 0.74 ( d a t a not shown). Neither antagonist caused any d e t e c t a b l e increase in the basal release of d o p a m i n e , implying that u n d e r the conditions of these e x p e r i m e n t s there was little or no tonic stimulation of inhibitory a u t o r e c e p t o r s . This is clearly not so when m o r e p r o l o n g e d releasing stimuli are used 4'6. The antagonist potency values r e p o r t e d above correspond closely to those r e p o r t e d for b l o c k a d e of a p o m o r phine-induced [3H]dopamine release from rabbit striaturn 19. No c o m p a r a b l e d a t a are available for the rat, but in binding studies using rat striatal m e m b r a n e s , potency values were r e p o r t e d which also agree with the present study 3n°. T h e slopes of the Schild plots in our own experiments were not, however, equal to unity, and more d a t a would be n e e d e d to confirm that haloperidol and m e t o c l o p r a m i d e were behaving competitively. In s u m m a r y , this study has shown the presence of D2 autoreceptors on striatal nerve terminals in a functional
100 (D
8O E 8.
60
O "E}
% GBR12909
Desipramine
j= ~ ] 300 ~
a
/-~
~ ] ~100 b
40
g 20
.E C
0 g
-9
g 50
C 3x10-6M
C 5x10-SM
RO 4-1284 lOO
-8 - ~7 -6 -~5 Log [quinpirole] (M)
Nialamide
c2, O
I
1oo O J
I
50
50
E
0
r~ --
C
~
5x10-7M
~
0
C
10-6M
Fig. 1. Effects of agents affecting the storage, uptake and metabolism of biogenic amines on the voltammetric signal detected during electrical stimulation of striatal slices, a, GBR 12909, a dopamine uptake blocker; b, desipramine, a noradrenaline and 5-hydroxytryptamine uptake blocker; c, Ro 4-1284, a depleter of monoamines; d, nialamide, a monoamine oxidase inhibitor. Values are the mean + S.E.M. of 3 experiments and are expressed as a percentage of time-matched control responses (bar labelled C) obtained in separate control experiments. * P < 0.05, ** P < 0.005 compared to control.
|
I
I
I
-8 -7 -6 Log [metocloprarnide] (M) Fig. 2. Top: mean cumulative concentration-response curves for the inhibition of electrically evoked dopamine release by quinpirole, and antagonism of this effect by metoclopramide. Values are the mean percentage inhibition + S.E.M. of 6 preparations, first in the absence of antagonist (filled circles) and then in the presence of metoclopramide 10 7 M (open circles, n = 2), 3 x 10 7 M (squares, n = 2) o r 10 -6 M (triangles, n = 2). Bottom: Schild plot derived from the above data. The intercept on the x-axis is the pA2 value, i.e. the negative logarithm of the concentration of antagonist which would produce a 2-fold shift of the quinpirole concentrationresponse curve, and was equal to 7.57.
174 tissue p r e p a r a t i o n , and has d e m o n s t r a t e d in a direct m a n n e r some aspects of the presynaptic control of d o p a m i n e release which have previously been d e d u c e d only by indirect means. The in vitro m e t h o d allowed the brain a r e a to be chosen u n d e r visual guidance, and drugs could be a p p l i e d u n d e r equilibrium conditions and without the p r o b l e m of limited access through the b l o o d - b r a i n barrier. Quantitative pharmacological char-
acterization of the a u t o r e c e p t o r s showed them to be apparently identical to the postsynaptic receptors detected in binding studies. This novel combination of brain slice technology with fast cyclic v o l t a m m e t r y now makes possible a direct comparison of autoreceptors in the corpus striatum and the nucleus accumbens, and potentially also in o t h e r dopamine-rich brain regions.
1 Armstrong-James, M. and Millar, J., Carbon fibre microelectrodes, J. Neurosci. Methods, 1 (1979) 279-287. 2 Arunlakshana, O. and Schild, H.O., Some quantitative uses of drug antagonists, Br. J. Pharmacol., 14 (1959) 44-58. 3 Barone, D., Assandri, A., Galliani, G., Glasser, A. and Tarzia, G., Characterization of [3H]zetidoline binding to rat striatal membranes, J. Pharm. Pharmacol., 37 (1984) 180-187. 4 Cubeddu, L.X. and Hoffman, I.S., Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors, J. Neurochem., 41 (1983) 94-101. 5 Farnebo, L.O. and Hamberger, B., Drug-induced changes in the release of [3H]-monoamines from field-stimulated rat brain slices, Acta Physiol. Scand., Suppl., 371 (1971) 35-44. 6 Herdon, H. and Nahorski, S.R., Comparison between radiolabelled and endogenous dopamine release from rat striatal slices: effects of electrical field stimulation and regulation by D2autoreceptors, Naunyn-Schmiedeberg's Arch. Pharmacol., 335 (1987) 238-242. 7 Heikkila, R.E. and Manzino, L., Behavioural properties of GBR 12909 and GBR 19098, specific inhibitors of dopamine uptake, Eur. J. Pharmacol., 103 (1984) 241-248. 8 Iorio, L.C., Barnett, A., Leitz, EH., Houser, V.P. and Korduba, C.A., Sch 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems, J. Pharmacol. Exp. Ther., 226 (1983) 462-468. 9 Kebabian, J.W. and Calne, D.B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 10 Leysen, J.E., Multiple dopamine receptors: relevance of in vitro binding data for subclassification of binding sites. In: Catecholamines: Basic and Peripheral Mechanisms, Liss, New York, 1984, pp. 225-235. 11 Marsden, C.A., Brazell, M.P. and Maidment, N.T., An introduction to in vivo electrochemistry. In: C.A. Marsden (Ed.), Measurement of Neurotransmitter Release in Vivo, Wiley, Chi-
chester, 1984, pp. 127-151. 12 Marsden, C.A., Joseph, M.H., Kruk, Z.L., Maidment, N,T., O'Neill, R.D., Schenk, J.O. and Stamford, J.A., In vivo voltammetry - present electrodes and methods, Neuroscience, 25 (1988) 389-400. 13 McDermed, J.D., McKenzie, G.M. and Phillips, A.P., Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists, J. Med. Chem., 18 (1975) 362-367. 14 Millar, J., Stamford, J.A., Kruk, Z.L. and Wightman, R.M., Electrochemical, pharmacological and electrophysiological evidence of rapid dopamine release and removal in rat caudate nucleus following electrical stimulation of the median forebrain bundle, Eur. J. Pharmacol., 109 (1985) 341-348. 15 Pendleton, R.G., Samler, L., Kaiser, C. and Ridley, P.T., Studies on renal dopamine receptors with a new agonist, Eur. J. PharmacoL, 51 (1978) 19-28. 16 Richards, C.D. and Tegg, W.J.B., A superfusion chamber suitable for maintaining mammalian brain tissue slices for electrical recording, Br. J. Pharmacol., 59 (1977) 526P. 17 Shore, P.A., On the role of storage granules in the functional utilization of newly synthesized dopamine, J. Neural Trans., 39 (1976) 131-138. 18 Starke, K., Presynaptic receptors, Annu. Rev. Pharmacol. Toxicol., 2l (1981) 7-30. 19 Starke, K., Spath, L., Lang, J.D. and Adelung, C., Further functional in vitro comparison of pre- and post-synaptic dopamine receptors in the rabbit caudate nucleus, Naunyn-Schrniedeberg's Arch. Pharmacol., 323 (1983) 298-306. 20 Titus, R.D., Kornfeld, E.C., Jones, N.D., Clemens, J.A., Smalstig, E.B., Fuller, R.W., Hahn, R.A., Hynes, M.D., Mason, N.R., Wong, D.T. and Foreman, M.M., Resolution and absolute configuration of an ergoline related dopamine agonist, trans-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH (or 2H)-pyrazolo[3,4-g]quinoline, J. Med. Chem., 26 (1983) 1112-1116.
Brain Re.~earc~, 5tl• (199(t) i72 i74 Elsevier
BRES 23967
Presynaptic regulation of d o . m i n e release in corpus striatum monitored in vitro in real time by fast cyclic voltammetry P. Palij 2, D.R. Bull 1, M.J. Sheehan t, J. Millar 3, J. Stamford z, Z.L. Kruk 2 and P.P.A. Humphrey l 1Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, ( U. K. ) and Departments of 2pharmacology and 3physiology, The London Hospital Medical College, London (U. K.)
(Accepted 7 November 1989) Key words: Dopamine autoreceptor; Dopamine uptake blocker; Quinpirole; Metoclopramide; Haloperidol; SKF 38393
Dopamine release was evoked by single electrical pulses in slices of rat corpus striatum, and measured by fast cyclic voltammetry in real time. The magnitude of the release varied in the expected way to agents which modify dopamine storage, release and re-uptake: The presence of functional dopamine D 2 autoreceptors was demonstrated by showing that the release was potently and completely inhibited by the selective agonists quinpirole and N,N-dipropyl-5,6-ADTN. The selective D1 agonist SKF 38393 was ineffective. The inhibition by quinpirole was competitively antagonised by haioperidol and metoclopramide with potencies which correspond closely to published values at postsynaptic striatal D 2 receptors. Thus, the D2 autoreceptors on striatal nerve terminals appear to be indistinguishable from those on the postsynaptic neurons. Dopamine-containing neurons of the nigrostriatal pathway possess terminal autoreceptors which can inhibit the release of neurotransmitter ~'18. Previous studies of these autoreceptors have generally involved isotopically labelled pools of neurotransmitter and have a poor time resolution. We have applied the technique of fast cyclic voltammetry, which has up to now been used only in vivo t2"14, to the measurement of endogenous dopamine released in striatal slices in vitro. This has made it possible to demonstrate the factors controlling the kinetics of dopamine release and re-uptake, and also to perform a quantitative pharmacological characterization of the autoreceptors. Slices of rat corpus striatum were placed in an incubation chamber 16 and superfused with artificial cerebrospinal fluid maintained at 32 °C. Voltammetric recordings were made using a conventional three-electrode system 12 in which the carbon-fibre working electrode ~ was placed in one of the translucent stria of the tissue 75/~m below the surface. A bipolar stimulating electrode was placed 200-400/~m ventromedial to the working electrode with its poles straddling the same band of tissue. With this arrangement, minimal electrical stimulation (a single 0.1 ms rectangular pulse, amplitude 20 V) produced a voltammetric signal which was identified (see below) as being solely due to the release of dopamine. The signal reached a maximum within the first or second 0.5 s sampling period after the stimulus, and
then declined exponentially with a half-life of about 1 s. When slices were stimulated in this way at 2-min intervals, the evoked release was consistent for 3-4 h. When calcium was iso-osmotically replaced by magnesium in the superfusion medium, or when tetrodotoxin (10 -6 M) was added, the voltammetric signal was abolished, indicating that it originated from axonal conduction of action potentials to nerve terminals. The response could be restored by superfusion with fresh medium. The released substance was shown to be dopamine alone by the following observations. Its oxidation and reduction current peaks, which occur at voltages which are characteristic of the substance being oxidized 11, were identical to those obtained in a solution of exogenous dopamine, but differed from those for norepinephrine, 5-hydroxytryptamine, epinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) or 5-hydroxyindoleacetic acid. The selective dopamine uptake blocker G B R 12909 (ref. 7, 3 × 10 -7 M) tripled the magnitude of the signal (Fig. la) and considerably prolonged its rate of decay to a half-life of 3 s. In contrast, the release was unaffected by a concentration of desipramine (5 x 10 -8 M) which selectively blocks the uptake of norepinephrine and 5-hydroxytryptamine (Fig. lb). The fast acting reserpinelike compound, Ro 4-1284 (ref. 17) abolished the electrochemical signal within 20 min of application (Fig. lc). Finally, the monoamine oxidase inhibitor nialamide (10 -6 M ) had no effect (Fig. ld), showing that oxidative
Correspondence: M.J. Sheehan, Department of Neuropharmacology, Glaxo Group Research Ltd., Ware, Herts SG12 ODE U,K.
173 m e t a b o l i t e s did not contribute to the o b s e r v e d signal (cf. ref. 12). Previous studies have suggested that the a u t o r e c e p t o r s on the terminals of d o p a m i n e neurones in the striatum are of the D z type, as defined by K e b a b i a n and Calne 9. In the p r e s e n t study, the selective D 1 agonist, S K F 38393 (ref. 15; 10 -7 to 5 × 10 -5 M) did not alter the e v o k e d release of d o p a m i n e . H o w e v e r , the highly selective D 2 agonists quinpirole 2° and N , N - d i p r o p y l - 5 , 6 - A D T N 13 were able to abolish the signal in a c o n c e n t r a t i o n - r e l a t e d m a n n e r , p r o d u c i n g 50% inhibition at concentrations of 26 + 5 n M and 186 + 26 n M (means + S . E . M . , n = 6 and 10) respectively. A d d i t i o n of the selective D 2 antagonist h a l o p e r i d o l (10 -6 M) to the m e d i u m antagonised the inhibition caused by both of these agonists, w h e r e a s the selective D 1 antagonist, Sch 23390 (ref. 8; 10 -6 M) did not. In o r d e r to m e a s u r e the absolute potency of two D 2 antagonists, h a l o p e r i d o l and m e t o c l o p r a m i d e , Schild plots e were constructed. C o n c e n t r a t i o n - r e s p o n s e curves were d e t e r m i n e d for inhibition of d o p a m i n e release by quinpirole, first in the absence of antagonist and then, after a washout p e r i o d and 30 min incubation with antagonist, in its presence. F o r m e t o c l o p r a m i d e , a pA 2 value of 7.57, with a slope factor of 1.30, was calculated
(Fig. 2). H a l o p e r i d o l gave a calculated p A 2 value of 9.33 and a slope factor of 0.74 ( d a t a not shown). Neither antagonist caused any d e t e c t a b l e increase in the basal release of d o p a m i n e , implying that u n d e r the conditions of these e x p e r i m e n t s there was little or no tonic stimulation of inhibitory a u t o r e c e p t o r s . This is clearly not so when m o r e p r o l o n g e d releasing stimuli are used 4'6. The antagonist potency values r e p o r t e d above correspond closely to those r e p o r t e d for b l o c k a d e of a p o m o r phine-induced [3H]dopamine release from rabbit striaturn 19. No c o m p a r a b l e d a t a are available for the rat, but in binding studies using rat striatal m e m b r a n e s , potency values were r e p o r t e d which also agree with the present study 3n°. T h e slopes of the Schild plots in our own experiments were not, however, equal to unity, and more d a t a would be n e e d e d to confirm that haloperidol and m e t o c l o p r a m i d e were behaving competitively. In s u m m a r y , this study has shown the presence of D2 autoreceptors on striatal nerve terminals in a functional
100 (D
8O E 8.
60
O "E}
% GBR12909
Desipramine
j= ~ ] 300 ~
a
/-~
~ ] ~100 b
40
g 20
.E C
0 g
-9
g 50
C 3x10-6M
C 5x10-SM
RO 4-1284 lOO
-8 - ~7 -6 -~5 Log [quinpirole] (M)
Nialamide
c2, O
I
1oo O J
I
50
50
E
0
r~ --
C
~
5x10-7M
~
0
C
10-6M
Fig. 1. Effects of agents affecting the storage, uptake and metabolism of biogenic amines on the voltammetric signal detected during electrical stimulation of striatal slices, a, GBR 12909, a dopamine uptake blocker; b, desipramine, a noradrenaline and 5-hydroxytryptamine uptake blocker; c, Ro 4-1284, a depleter of monoamines; d, nialamide, a monoamine oxidase inhibitor. Values are the mean + S.E.M. of 3 experiments and are expressed as a percentage of time-matched control responses (bar labelled C) obtained in separate control experiments. * P < 0.05, ** P < 0.005 compared to control.
|
I
I
I
-8 -7 -6 Log [metocloprarnide] (M) Fig. 2. Top: mean cumulative concentration-response curves for the inhibition of electrically evoked dopamine release by quinpirole, and antagonism of this effect by metoclopramide. Values are the mean percentage inhibition + S.E.M. of 6 preparations, first in the absence of antagonist (filled circles) and then in the presence of metoclopramide 10 7 M (open circles, n = 2), 3 x 10 7 M (squares, n = 2) o r 10 -6 M (triangles, n = 2). Bottom: Schild plot derived from the above data. The intercept on the x-axis is the pA2 value, i.e. the negative logarithm of the concentration of antagonist which would produce a 2-fold shift of the quinpirole concentrationresponse curve, and was equal to 7.57.
174 tissue p r e p a r a t i o n , and has d e m o n s t r a t e d in a direct m a n n e r some aspects of the presynaptic control of d o p a m i n e release which have previously been d e d u c e d only by indirect means. The in vitro m e t h o d allowed the brain a r e a to be chosen u n d e r visual guidance, and drugs could be a p p l i e d u n d e r equilibrium conditions and without the p r o b l e m of limited access through the b l o o d - b r a i n barrier. Quantitative pharmacological char-
acterization of the a u t o r e c e p t o r s showed them to be apparently identical to the postsynaptic receptors detected in binding studies. This novel combination of brain slice technology with fast cyclic v o l t a m m e t r y now makes possible a direct comparison of autoreceptors in the corpus striatum and the nucleus accumbens, and potentially also in o t h e r dopamine-rich brain regions.
1 Armstrong-James, M. and Millar, J., Carbon fibre microelectrodes, J. Neurosci. Methods, 1 (1979) 279-287. 2 Arunlakshana, O. and Schild, H.O., Some quantitative uses of drug antagonists, Br. J. Pharmacol., 14 (1959) 44-58. 3 Barone, D., Assandri, A., Galliani, G., Glasser, A. and Tarzia, G., Characterization of [3H]zetidoline binding to rat striatal membranes, J. Pharm. Pharmacol., 37 (1984) 180-187. 4 Cubeddu, L.X. and Hoffman, I.S., Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors, J. Neurochem., 41 (1983) 94-101. 5 Farnebo, L.O. and Hamberger, B., Drug-induced changes in the release of [3H]-monoamines from field-stimulated rat brain slices, Acta Physiol. Scand., Suppl., 371 (1971) 35-44. 6 Herdon, H. and Nahorski, S.R., Comparison between radiolabelled and endogenous dopamine release from rat striatal slices: effects of electrical field stimulation and regulation by D2autoreceptors, Naunyn-Schmiedeberg's Arch. Pharmacol., 335 (1987) 238-242. 7 Heikkila, R.E. and Manzino, L., Behavioural properties of GBR 12909 and GBR 19098, specific inhibitors of dopamine uptake, Eur. J. Pharmacol., 103 (1984) 241-248. 8 Iorio, L.C., Barnett, A., Leitz, EH., Houser, V.P. and Korduba, C.A., Sch 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems, J. Pharmacol. Exp. Ther., 226 (1983) 462-468. 9 Kebabian, J.W. and Calne, D.B., Multiple receptors for dopamine, Nature (Lond.), 277 (1979) 93-96. 10 Leysen, J.E., Multiple dopamine receptors: relevance of in vitro binding data for subclassification of binding sites. In: Catecholamines: Basic and Peripheral Mechanisms, Liss, New York, 1984, pp. 225-235. 11 Marsden, C.A., Brazell, M.P. and Maidment, N.T., An introduction to in vivo electrochemistry. In: C.A. Marsden (Ed.), Measurement of Neurotransmitter Release in Vivo, Wiley, Chi-
chester, 1984, pp. 127-151. 12 Marsden, C.A., Joseph, M.H., Kruk, Z.L., Maidment, N,T., O'Neill, R.D., Schenk, J.O. and Stamford, J.A., In vivo voltammetry - present electrodes and methods, Neuroscience, 25 (1988) 389-400. 13 McDermed, J.D., McKenzie, G.M. and Phillips, A.P., Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists, J. Med. Chem., 18 (1975) 362-367. 14 Millar, J., Stamford, J.A., Kruk, Z.L. and Wightman, R.M., Electrochemical, pharmacological and electrophysiological evidence of rapid dopamine release and removal in rat caudate nucleus following electrical stimulation of the median forebrain bundle, Eur. J. Pharmacol., 109 (1985) 341-348. 15 Pendleton, R.G., Samler, L., Kaiser, C. and Ridley, P.T., Studies on renal dopamine receptors with a new agonist, Eur. J. PharmacoL, 51 (1978) 19-28. 16 Richards, C.D. and Tegg, W.J.B., A superfusion chamber suitable for maintaining mammalian brain tissue slices for electrical recording, Br. J. Pharmacol., 59 (1977) 526P. 17 Shore, P.A., On the role of storage granules in the functional utilization of newly synthesized dopamine, J. Neural Trans., 39 (1976) 131-138. 18 Starke, K., Presynaptic receptors, Annu. Rev. Pharmacol. Toxicol., 2l (1981) 7-30. 19 Starke, K., Spath, L., Lang, J.D. and Adelung, C., Further functional in vitro comparison of pre- and post-synaptic dopamine receptors in the rabbit caudate nucleus, Naunyn-Schrniedeberg's Arch. Pharmacol., 323 (1983) 298-306. 20 Titus, R.D., Kornfeld, E.C., Jones, N.D., Clemens, J.A., Smalstig, E.B., Fuller, R.W., Hahn, R.A., Hynes, M.D., Mason, N.R., Wong, D.T. and Foreman, M.M., Resolution and absolute configuration of an ergoline related dopamine agonist, trans-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-lH (or 2H)-pyrazolo[3,4-g]quinoline, J. Med. Chem., 26 (1983) 1112-1116.
