Dopamine Receptors in the Neostriatum: Biochemical and

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Dopamine Receptors in the Neostriatum: Biochemical and Physiological Studies J. C. STOOF Free University, Department of Neurology, Medical Faculty, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands

Dopamine induces biochemical and p h y s i o l o g i c a l e f f e c t s i n the mammalian neostriatum. The occurrence of a D-1 dopamine receptor ( i n the classific a t i o n scheme o f Kebabian and Calne) accounts f o r the ability of dopamine to enhance cyclic AMP f o r mation. The occurrence o f a D-2 dopamine receptor accounts f o r the ability of dopamine to i n h i b i t c y c l i c AMP formation brought about by s t i m u l a t i o n of a D-1 dopamine r e c e p t o r . Dopamine receptors mediate the r e g u l a t i o n of (1) the r e l e a s e or t u r n over of a c e t y l c h o l i n e (postsynaptic dopamine r e ceptor) and (2) the release or turnover o f dopamine (presynaptic a u t o r e c e p t o r ) . Both receptors can be classified as D-2 dopamine r e c e p t o r s . I n d i cations f o r the occurrence of dopamine receptors a f f e c t i n g the r e l e a s e o r turnover of GABA, g l u t a mate, s e r o t o n i n and s e v e r a l neuropeptides are evaluated.

Despite the recent burst of i n t e r e s t i n the p e r i p h e r a l actions of dopamine, t h i s catecholamine i s s t i l l best known as a neurotransmitter i n the c e n t r a l nervous system. This chapter discusses the biochemical and p h y s i o l o g i c a l actions of dopamine i n the neostriatum and the s u b s t a n t i a n i g r a , the regions cont a i n i n g most of the dopamine i n the b r a i n . The goal of t h i s chapter i s to show that the concepts derived from the simple p e r i p h e r a l systems c o n t a i n i n g a s i n g l e category of dopamine r e ceptor 2, 3) can be a p p l i e d to the more complex CNS. T h i s chapter i s not intended to be an a l l i n c l u s i v e compendium o f every technique used to study c e n t r a l dopamine r e c e p t o r s . A l though dopamine receptors can be s t u d i e d i n b i n d i n g assays o r by b e h a v i o r a l p r o t o c o l s , I w i l l not focus a t t e n t i o n on e i t h e r o f these methodologies. Binding studies of dopamine receptors, a l though easy to perform, have y i e l d e d too many data, too many 0097-6156/83/0224-0117$08.50/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

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c a t e g o r i e s o f dopamine r e c e p t o r s a n d t o o many c o n t r o v e r s i e s (4^ s e e a l s o C a r o n , t h i s v o l u m e ) . I n p a r t , t h i s s i t u a t i o n may be a consequence o f t h e s e n s i t i v i t y o f b i n d i n g assays t o minor changes i n a s s a y c o n d i t i o n s C5). The i n t e r p r e t a t i o n o f b e h a v i o r a l s t u d i e s i s hampered by t h e c u r r e n t i g n o r a n c e o f t h e n e u r o a n a t o m y and n e u r o p h y s i o l o g y as t o how s t i m u l a t i o n o f a dopamine r e c e p tor i s t r a n s l a t e d i n t o an observable behavior. This chapter w i l l f o c u s a t t e n t i o n upon t h e dopamine r e c e p t o r s i n t h e n i g r o - n e o s t r i a t a l axis which e l i c i t e i t h e r biochemical o r p h y s i o l o g i c a l e v e n t s amenable t o i n v i t r o e x p e r i m e n t a l i n v e s t i g a t i o n . I n d i s c u s s i n g t h e p h a r m a c o l o g y o f e a c h s y s t e m , I w i l l u s e t h e two dopamine r e c e p t o r h y p o t h e s i s as t h e b a s i s f o r my c o n s i d e r a t i o n o f r e c e p t o r p h a r m a c o l o g y ( s e e Brown a n d Dawson-Hughes & K e b a b i a n e t a l . , t h i s volume). The

N i g r o - N e o s t r i a t a l D o p a m i n e r g i c Neurons

Some 3500 d o p a m i n e r g i c n e u r o n s l o c a t e d i n t h e zona c o m p a c t a of t h e s u b s t a n t i a n i g r a i n n e r v a t e the e n t i r e neostriatum ( 6 , 7 ) . W i t h i n t h e n e o s t r i a t u m , t h e axons o f t h e s e n e u r o n s f o r m a n e x t r e m e l y dense t e r m i n a l a r b o r i z a t i o n t h a t c a n be v i s u a l i z e d w i t h f l u o r e s c e n c e h i s t o c h e m i s t r y and i m m u n o c y t o c h e m i c a l t e c h n i q u e s (8^, 9). T h i s t e r m i n a l a r b o r i z a t i o n c o n t a i n s approximately 1 b i l l i o n d o p a m i n e r g i c v a r i c o s i t i e s a n d forms a b o u t 2 0 % o f a l l t h e v a r i c o s i t i e s (10) p r e s e n t i n t h e n e o s t r i a t u m . P o s t s y n a p t i c Dopamine R e c e p t o r s The m a j o r i t y o f n e u r o n s i n t h e n e o s t r i a t u m a r e i n t e r n e u r o n s . The n e o s t r i a t u m r e c e i v e s afférents f r o m d i v e r s e a r e a s l i k e the thalamus, t h e d o r s a l raphe n u c l e i , the c e r e b r a l c o r t e x and t h e s u b s t a n t i a n i g r a . E f f e r e n t s f r o m t h e n e o s t r i a t u m i n n e r v a t e t h e g l o b u s p a l l i d u s and t h e s u b s t a n t i a n i g r a ( 1 1 ) . The n e o s t r i a t u m c o n t a i n s many n e u r o t r a n s m i t t e r s a n d p u t a t i v e n e u r o t r a n s m i t t e r s i n c l u d i n g : a c e t y l c h o l i n e , d o p a m i n e , γ-aminobutyric a c i d , g l u t a m a t e , s e r o t o n i n and t h e p e p t i d e s c h o l e c y s t o k i n i n , enkephalin and s u b s t a n c e Ρ (12, 1 3 ) . T h e o r e t i c a l l y , t h e d o p a m i n e r g i c n e u r o n s c o u l d communicate v i a d o p a m i n e r g i c s y n a p s e s and p o s t s y n a p t i c dopamine r e c e p t o r s w i t h n e u r o n s c o n t a i n i n g e a c h o f t h e s e n e u r o t r a n s m i t t e r s . C o n s e q u e n t l y , changes i n e i t h e r t h e r e l e a s e o r t h e t u r n o v e r o f any o f t h e s e n e u r o t r a n s m i t t e r s c o u l d p r o v i d e e v i d e n c e o f a c t i v i t y a t a p o s t s y n a p t i c dopamine receptor. A P o s t s y n a p t i c Dopamine R e c e p t o r R e g u l a t i n g or T u r n o v e r o f A c e t y l c h o l i n e

the Release

A c e t y l c h o l i n e i s a m a j o r n e u r o t r a n s m i t t e r i n t h e neo s t r i a t u m . W i t h i n the neostriatum, both the content of a c e t y l c h o l i n e and t h e s p e c i f i c a c t i v i t y o f c h o l i n e a c e t y l t r a n s f e r a s e ,

In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


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the enzyme s y n t h e s i z i n g a c e t y l c h o l i n e , are extremely high (14) . Most of the n e o s t r i a t a l a c e t y l c h o l i n e occurs w i t h i n i n t e r neurons; only a small amount of n e o s t r i a t a l a c e t y l c h o l i n e can be associated with a f f e r e n t neurons o r i g i n a t i n g i n the center median-parafascicular complex of the thalamus (11). The dopaminergic n i g r o - n e o s t r i a t a l neurons make synaptic contacts with the c h o l i n e r g i c interneurons (Γ5, F i g u r e 1). The content of a c e t y l c h o l i n e i n the neostriatum i s increased by dopamine receptor agonists and decreased by dopamine receptor antagonists 0 6 , _1_7, J_8) . Apomorphine and L-DOPA i n h i b i t the i n vivo r e l e a s e of a c e t y l c h o l i n e from cat neostriatum; t h i s e f f e c t i s blocked by n e u r o l e p t i c s ( 19) . RU 24926 (chemical s t r u c t u r e depicted i n F i g u r e 2), a s e l e c t i v e D-2 agonist, i n creases the content of n e o s t r i a t a l a c e t y l c h o l i n e (20). Together, these data from i n v i v o experiments are c o n s i s t e n t with the hypothesis t h a t s t i m u l a t i o n of a D-2 receptor upon the c h o l i n e r g i c interneurons increases the content o f n e o s t r i a t a l a c e t y l c h o l i n e by b l o c k i n g i t s r e l e a s e . In vivo experiments studying e i t h e r the content or the r e l e a s e of n e o s t r i a t a l a c e t y l c h o l i n e are time consuming, tech n i c a l l y d i f f i c u l t and not always easy to i n t e r p r e t . Conversely, i n v i t r o studies o f a c e t y l c h o l i n e r e l e a s e with a s u p e r f u s i o n technique are less time consuming, t e c h n i c a l l y e a s i e r to perform and e a s i e r to i n t e r p r e t . With t h i s i n v i t r o technique, s l i c e s of neostriatum are incubated with r a d i o l a b e l e d c h o l i n e , a precursor of a c e t y l c h o l i n e , i n order to l a b e l the pool of newly synthe s i z e d a c e t y l c h o l i n e . The t i s s u e i s t r a n s f e r r e d to a s u p e r f u s i o n apparatus and the calciurn-dependent r e l e a s e of r a d i o l a b e l e d a c e t y l c h o l i n e i s evoked e l e c t r i c a l l y , with v e r a t r i d i n e or with elevated potassium concentrations (21). The s u p e r f u s i o n tech nique i s a simple procedure f o r i n v e s t i g a t i n g the r e l e a s e of a c e t y l c h o l i n e (or other n e u r o t r a n s m i t t e r s ) . However, there are some l i m i t a t i o n s to the technique. For example: dopaminergic agonists e l i c i t no more than a 50% to 60% i n h i b i t i o n of a c e t y l c h o l i n e r e l e a s e from r a t neostriatum (e.g. F i g u r e 3). I t i s not c l e a r i f this implies that 40% of the c h o l i n e r g i c interneurons i n r a t neostriatum do not possess dopamine r e c e p t o r s . A l t e r n a t i v e l y , because d i f f e r e n t species ( r a t versus c a t or r a b b i t ) and d i f f e r e n t techniques (potassium-evoked r e l e a s e versus e l e c t r i c a l l y stimulated r e l e a s e ) give q u a n t i t a t i v e l y d i f f e r e n t r e s u l t s (22-27), i t remains p o s s i b l e that there are t e c h n i c a l l i m i t a t i o n s to the p r e c i s i o n of t h i s technique. A more d e t a i l e d d e s c r i p t i o n of t h i s method i s presented elsewhere (26, 27). The r e s u l t s obtained from in v i t r o s up erf us i o n experiments are i n accord w i t h the c o n c l u s i o n that the c h o l i n e r g i c i n t e r neurons possess a D-2 dopamine r e c e p t o r . Dopamine i n h i b i t s the r e l e a s e of [3H]-acetylcholine from n e o s t r i a t a l t i s s u e ; however, concentrations greater than 1 μ Μ are required to achieve maximal i n h i b i t i o n . Because dopamine i s removed from the e x t r a c e l l u l a r space by the dopaminergic nerve terminals, i t i s d i f f i c u l t to



120

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Figure 1. Degenerating nerve ending (^>) in guinea pig neostriatum following 6-OH-dopamine administration making asymmetrical synaptic contact with dendritic spine positively staining for cholineacetyltransferase Bar indicates 0.125 μτη. (Reproduced with permission from Ref. 15. Copyright 1976, Elsevier Biomedical Press.)



STOOF

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Ç3H7

S K & F 38393

Figure 2. Chemical structures of LY 141865, RU 24926, and SKF 38393.


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120

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_100 ρ

> ο

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ο

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R U 24926

1 •

LY 141865

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S K F 38393

J_ 10-

8

10-

7

JL

10-

5

DRUG CONCENTRATION (M) +

Figure 3. D-2 receptor agonists, RU 24926 and LY 141865, inhibit the K stimulated release of [ Η]-acetylcholine from blocks of rat neostriatum. (Repro duced with permission from Ref. 96. Copyright, Elsevier Biomedical Press.) 3



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r e l i a b l y estimate the concentration of dopamine causing maximal i n h i b i t i o n . Apomorphine and a m i n o t e t r a l i n d e r i v a t i v e s i n h i b i t i n a dose-dependent manner the release o f [3H]-acetylcholine from n e o s t r i a t a l t i s s u e (22-27) . The s e l e c t i v e D-2 agonists, LY 141865 and RU 24926 (28, 29 ; chemical s t r u c t u r e s depicted i n Figure 2) i n h i b i t the r e l e a s e o f [3H]-acetyl c h o l i n e from neos t r i a t a l t i s s u e s l i c e s (Figure 3). The maximal e f f e c t o f e i t h e r drug i s an approximate 50% r e d u c t i o n o f the f r a c t i o n a l rate o f r e l e a s e of [3H]-acetylcholine. LY 141865 i s half-maximally a c t i v e a t a c o n c e n t r a t i o n of 70 nM; t h i s i s very s i m i l a r to i t s potency upon the D-2 receptor i n the intermediate lobe o f the r a t p i t u i t a r y gland (28). RU 24926 i s half-maximally a c t i v e a t a c o n c e n t r a t i o n of 7 nM; t h i s i s very s i m i l a r to i t s potency upon the D-2 dopamine r e c e p t o r on the mammotrophs of the anter i o r p i t u i t a r y gland (29). Likewise ( - ) - s u l p i r i d e , a s e l e c t i v e D-2 antagonist (3, 30, 31), reverses the i n h i b i t i o n of L3H]-acetylcholine r e l e a s e induced by e i t h e r LY 141865 or RU 24926 (Figure 4 ) . Furthermore, SKF 38393, a s e l e c t i v e D-l agonist (32, 33, 34; chemical s t r u c t u r e depicted i n Figure 2 ) , does not i n h i b i t (and a t high concentrations s l i g h t l y stimul a t e s ) the r e l e a s e of [3H]-acetylcholine (Figure 3). Other n e u r o l e p t i c drugs antagonize the i n h i b i t o r y e f f e c t o f dopamine and dopaminergic agonists on the r e l e a s e o f [3H]- a c e t y l c h o l i n e (22, 26, 27). The i n v i t r o e f f e c t s of dopaminergic agonists and antagonists upon the r e l e a s e o f [3Hj-acetylcholine r e i n f o r c e the c o n c l u s i o n drawn from i n vivo studies that a D-2 receptor regul a t e s the r e l e a s e of n e o s t r i a t a l a c e t y l c h o l i n e . Despite the t e c h n i c a l or methodological l i m i t a t i o n s of experiments determining the release of a c e t y l c h o l i n e from the neostriatum, this experimental parameter i s an extremely v a l u able model f o r studying a postsynaptic CNS dopamine receptor. A c e t y l c h o l i n e release i s one of the few p h y s i o l o g i c a l parameters regulated by a dopamine receptor that can be q u a n t i f i e d w i t h i n v i t r o techniques. Furthermore, dopaminergic r e g u l a t i o n of a c e t y l c h o l i n e release i s a matter of some p r a c t i c a l i n t e r e s t . For example, Parkinson's disease i s a n e o s t r i a t a l dopamine d e f i ciency syndrome (35). The loss of n e o s t r i a t a l dopamine d i s r u p t s the balance between the n e o s t r i a t a l dopaminergic and c h o l i n e r g i c systems that i s thought to regulate normal a c t i v i t y i n the neos t r i a t u m (36) . The dopaminergic agonists p r e s e n t l y used i n the treatment of Parkinsonism (37, 38) may achieve some of t h e i r therapeutic e f f e c t by d i r e c t l y s t i m u l a t i n g dopamine receptors ; however some o f t h e i r therapeutic e f f e c t may be a consequence of s t i m u l a t i n g the dopamine receptor upon the c h o l i n e r g i c i n t e r neuron and thereby r e s t o r i n g the balance between the dopamine r g i c and c h o l i n e r g i c systems i n the neostriatum. P r i o r to the advent o f L-DOPA therapy f o r Parkinsonism, c h o l i n e r g i c antagonists were widely used to a l l e v i a t e the symptoms o f t h i s disease (39).


In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983. 3

3

μ

Figure 4. Reversal by (-)-sulpiride of either the RU 24926 (left) 0.1 Μ or the LY 141865 (right) (1.0 iM)-inhibited release of [ H]-acetylcholine (K*-stimulated) from blocks of rat neostri atum. The release of [ H]-acetylcholine was determined without drugs (Q) or with one of the D-2 receptor agonists in the presence of (-)-sulpiride(O). (Reproduced with permission from Ref. 96. Copyright, Elsevier Biomedical Press.)

SULPIRIDE (M)


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Neostriatum the Release

Both GABA and glutamic a c i d decarboxylase (GAD) , a marker enzyme f o r GABA-containing nerve terminals, occur i n the neostriatum, globus p a l l i d u s and s u b s t a n t i a n i g r a (12) . The somata o f GABA-containing neurons occur predominantly i n the globus p a l l i d u s : these neurons p r o j e c t to the zona r e t i c u l a t a of the s u b s t a n t i a n i g r a ; t h e i r recurrent c o l l a t e r a l s p r o j e c t to the neostriatum.GABA-containing interneurons and g l i a a l s o occur i n the neostriatum (40-43). In vivo s t u d i e s i n d i c a t e that dopamine may i n f l u e n c e the GABA-containing c e l l s i n the neostriatum and s u b s t a n t i a n i g r a . Thus, apomorphine increases the content o f n e o s t r i a t a l GABA (44) ; conversely, h a l o p e r i d o l decreases the content (45) and turnover (46) of n e o s t r i a t a l GABA. Chronic (8 weeks) treatment with e i t h e r h a l o p e r i d o l or chlorpromazine increases n e o s t r i a t a l GAD a c t i v i t y but does not a l t e r the content o f GABA w i t h i n the neostriatum. D e s t r u c t i o n of the n i g r o - n e o s t r i a t a l dopaminergic neurons also increases n e o s t r i a t a l GAD a c t i v i t y (47). I n e x p e r i ments using a push-pull canula, e i t h e r apomorphine or dopamine i n h i b i t s the r e l e a s e o f endogenous n e o s t r i a t a l GA.BA (48) . In the s u b s t a n t i a n i g r a , h a l o p e r i d o l decreases the content of GABA (45) , while e i t h e r apomorphine o r dopamine i n h i b i t the r e l e a s e of endogenous GABA (49). The e f f e c t s o f dopaminergic drugs upon the s y n t h e s i s , storage and r e l e a s e o f GABA are i n accord w i t h the p o s s i b i l i t y that a dopamine receptor might regulate the a c t i v i t y o f GABAc o n t a i n i n g neurons. However, this p o s s i b i l i t y can be accepted w i t h only l i m i t e d enthusiasm. Extremely high doses of dopamine r g i c drugs are r e q u i r e d to e l i c i t e f f e c t s i n the n e o s t r i a t a l GABA system. Although apomorphine a t a dose o f 0.05 mg/kg w i l l s t i m u l a t e dopamine receptors (50), apomorphine must be used a t a dose of 20 mg/kg to induce a 25% increase i n n e o s t r i a t a l GABA (44). Likewise, h a l o p e r i d o l must be used a t 10 mg/kg to induce a 37% decrease i n the content of n e o s t r i a t a l GABA (45) . Such a massive dosis of h a l o p e r i d o l r e s u l t s i n b r a i n concentrations so high that h a l o p e r i d o l can block not only dopamine receptors b u t a l s o a-1 and a-2 adrenoceptors, H-1 and H-2 histamine receptors and s e r o t o n i n receptors (5 1) . Therefore, i t appears o p t i m i s t i c to conclude from such i n vivo experiments t h a t the observed e f f e c t s of dopaminergic drugs upon the n e o s t r i a t a l GABA system r e s u l t from an i n t e r a c t i o n with a s p e c i f i c dopamine r e c e p t o r . This negative c o n c l u s i o n i s i n accord with the data o f Pycock e t a l . (52) who could not demonstrate that s u b t l e manipulations o f c e n t r a l dopaminergic systems a l t e r e d the c o n c e n t r a t i o n o f GABA. The p o s s i b i l i t y that dopamine regulates n e o s t r i a t a l GABAe r g i c f u n c t i o n receives no support from i n v i t r o s u p e r f u s i o n experiments determining the release o f [3H]-GABA from s l i c e s o f r a t neostriatum (53) . The D-2 receptor agonist RU 24926 i s


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i n e f f e c t i v e i n modulating the potassium-stimulated r e l e a s e o f [3H]-GABA a t concentrations maximally i n h i b i t i n g a c e t y l c h o l i n e r e l e a s e (Figure 3). Also the D-l receptor agonist SKF 38393 does not cause a s i g n i f i c a n t change i n the release o f [J3H_-GABA from n e o s t r i a t a l t i s s u e . Therefore, the reported e f f e c t s o f 100 μ Μ apomorphine (48, 49, 54) must be explained as a consequence o f an i n t e r a c t i o n w i t h an e n t i t y other than a D-1 o r a D-2 dopamine receptor. As noted e a r l i e r , GABA appears to be a neurotransmitter i n the s u b s t a n t i a n i g r a . F o l l o w i n g chronic blockade o f dopamine receptors w i t h h a l o p e r i d o l , the turnover r a t e o f n i g r a l GABA i s depressed; acute h a l o p e r i d o l i s without e f f e c t (47). The e f f e c t s of dopamine upon the r e l e a s e o f Q3H]-GABA from the s u b s t a n t i a n i g r a are c o n t r o v e r s i a l . Reubi e t a l . (55) r e p o r t that dopamine, a t high concentrations, stimulates the r e l e a s e of [3H]-GABA from the n i g r a i n v i t r o . D i b u t y r y l cAMP mimicks t h i s e f f e c t o f dopa mine, thereby r a i s i n g the p o s s i b i l i t y that a D-l receptor medi ates t h i s e f f e c t . However, A r b i l l a e t a l . (56) could not r e produce these observations and concluded that dopamine does not modulate the spontaneous or stimulus-evoked r e l e a s e o f GABA i n the s u b s t a n t i a n i g r a . Therefore, i t seems premature to accept the p o s s i b i l i t y that dopamine a f f e c t s GABAergic f u n c t i o n i n the s u b s t a n t i a n i g r a v i a receptors l o c a t e d on GABAergic neurons. A Postsynaptic Dopamine Receptor Regulating Turnover o f Glutamate?

the Release o r

The neostriatum receives a massive neuronal input from the i p s i l a t e r a l c e r e b r a l cortex (57). These f i b e r s d i s t r i b u t e , i n an organized way, to a l l parts o f the neostriatum. The h e a v i e s t p r o j e c t i o n comes from the sensorimotor c o r t e x . Spencer (58) i n i t i a l l y suggested that ( p a r t of) these c o r t i c o s t r i a t a l f i b e r s u t i l i z e glutamate as a neurotransmitter. Evidence i m p l i c a t i n g glutamate as the major neurotransmitter used by these f i b e r s i s gradually accumulating (43). C o r t i c a l a b l a t i o n has been found to r e s u l t i n 40-50% r e d u c t i o n of high a f f i n i t y uptake o f l a b e l e d glutamate i n n e o s t r i a t a l t i s s u e (59, 60) . S t r i a t a l neurons are e x c i t e d by e i t h e r d i r e c t c o r t i c a l s t i m u l a t i o n o r by i o n t o p h o r e t i c a p p l i c a t i o n of glutamate; these e f f e c t s are blocked by L-glutamate d i e t h y l e s t e r , a glutamate antagonist (58). E l e c t r i c a l s t i m u l a t i o n of the f r o n t a l c o r t e x induces s p e c i f i c r e l e a s e of l a b e l e d glutamic a c i d from r a t neostriatum (61). Furthermore, endogenous glutamate i s r e l e a s e d , i n a calcium-dependent manner, by elevated concentrations o f potassium ions (62). Dopamine receptors may occur on the terminals of the glutamatergic afférents to the neostriatum (63). F o l l o w i n g c o r t i c a l a b l a t i o n , the number o f |J3H]-haloperidol b i n d i n g s i t e s i n the s t r i a t u m i s reduced by 32% (63) . I n an i n v i t r o superf u s i o n system, dopamine, apomorphine, amino t e t r a l i n d e r i v a t i v e s o r bromocriptine i n h i b i t the d e p o l a r i z a t i o n - i n d u c e d r e l e a s e o f



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[3H]-gluta ma te (64, 65). However, very high concentrations of these drugs are needed to e l i c i t t h i s i n h i b i t o r y e f f e c t . In one of these studies d i b u t y r y l cAMP d i d not mimic the e f f e c t s of the dopaminergic agonists (65) ; t h e r e f o r e , i t i s very u n l i k e l y that a D-l r e c e p t o r mediates t h i s modulation of glutamate r e l e a s e . In a recent study (53), n e i t h e r the D-l a g o n i s t SKF 38 39 3, nor the D-2 agonist RU 24926, a l t e r e d the d e p o l a r i z a t i o n - i n d u c e d r e l e a s e of [3H]-glutamate (even when tested a t concentrations maximally a c t i v e on t h e i r r e s p e c t i v e r e c e p t o r s ) . Thus, i t appears that neither a D-l nor a D-2 receptor modulates the r e l e a s e of glutamate. A Postsynaptic Dopamine Receptor Regulating the Release or Turnover of Serotonin? Serotonin-containing neurons p r o j e c t from the raphe n u c l e i to the neostriatum (66) . L e s i o n i n g techniques show that t h i s p r o j e c t i o n o r i g i n a t e s only i n the d o r s a l raphe n u c l e i (67, 68) . In a d d i t i o n , a major s e r o t o n i n e r g i c pathway from the medial and d o r s a l raphe n u c l e i (69) p r o j e c t s to the s u b s t a n t i a n i g r a . In preparing t h i s review, I d i d not encounter any reports suggest ing that the turnover or r e l e a s e of s e r o t o n i n i n the neostriatum i s d i r e c t l y i n f l u e n c e d by drugs s t i m u l a t i n g or b l o c k i n g dopamine r e c e p t o r s . Furthermore, according to Hassler (43) and Pasik (70), there are not many axo-axonal contacts i n the neostriatum. This makes the occurrence of d i r e c t s y n a p t i c contacts between dopaminergic and s e r o t o n i n e r g i c nerve terminals u n l i k e l y * Obviously, i t i s s t i l l p o s s i b l e that both neuronal systems communicate v i a mechanisms other than s y n a p t i c c o n t a c t s . A few studies describe i n t e r a c t i o n s between the dopamin e r g i c and the s e r o t o n i n e r g i c systems i n the s u b s t a n t i a n i g r a , thereby suggesting a r o l e f o r n i g r a l dopamine r e c e p t o r s . Dopamine (0.1 μ Μ ) i n h i b i t s the r e l e a s e o f [3H]-serotonin (71), while apomorphine (50 μ Μ ) stimulates the r e l e a s e o f [3H]-serot o n i n (72). These apparently c o n f l i c t i n g observations preclude any d e f i n i t i v e conclusions being drawn about the involvement of dopamine receptors i n r e g u l a t i n g the turnover or r e l e a s e of s e r o t o n i n i n the s u b s t a n t i a n i g r a . A Postsynaptic Dopamine Receptor Regulating the Release or Turnover of Peptide Neurotransmitters? The neostriatum contains many of the peptides which are c u r r e n t l y fashionable research e n t i t i e s ( f o r a review see 73). In t h i s s e c t i o n , I w i l l mention the peptides which have been implicated as being under dopaminergic c o n t r o l . Substance Ρ was among the f i r s t peptides d i s c o v e r e d i n the n i g r o - n e o s t r i a t a l a x i s . This peptide occurs i n both interneurons and i n neurons p r o j e c t i n g to the s u b s t a n t i a n i g r a (74) . Several pieces o f c i r c u m s t a n t i a l evidence p o i n t to a dopaminergic e f f e c t upon



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substance P. Chronic treatment with h a l o p e r i d o l reduces the c o n c e n t r a t i o n of substance Ρ i n the s u b s t a n t i a n i g r a (75) . However, treatment with apomorphine a l s o lowers n i g r a l substance Ρ c o n c e n t r a t i o n ; h a l o p e r i d o l blocks t h i s e f f e c t (76). Likewise, amphetamine causes a dose-dependent r e d u c t i o n i n substance P - l i k e immunoreactive m a t e r i a l w i t h i n the neostriatum (but not i n the s u b s t a n t i a n i g r a ) ; h a l o p e r i d o l blocks t h i s e f f e c t (77) . The neostriatum has a high content of enkephalin and these e n k e p h a l i n - l i k e peptides occur i n n e o s t r i a t a l interneurons (78). Chronic treatment with h a l o p e r i d o l increases both the content and the r e l e a s e of n e o s t r i a t a l enkephalin (79) . However, i n v i t r o s t u d i e s f a i l to demonstrate any dopaminergic r e g u l a t i o n of enkephalin r e l e a s e (79). C h o l e c y s t o k i n i n (CCK)-like immunoreactive m a t e r i a l occurs i n the CNS and the caudate has the h i g h e s t c o n c e n t r a t i o n of any b r a i n r e g i o n (13, 80). However, dopaminergic r e g u l a t i o n of neo s t r i a t a l CCK r e l e a s e has not been i n v e s t i g a t e d (81). I n t e r e s t i n g l y , CCK-like p e p t i d e ( s ) c o e x i s t with dopamine i n c e r t a i n dopaminergic neurons (73) . This r a i s e s the p o s s i b i l i t y that CCK might r e g u l a t e dopaminergic a c t i v i t y with a novel, but at present unknown, mechanism. In summary, i t i s d i f f i c u l t to g e n e r a l i z e about dopamin e r g i c c o n t r o l of p e p t i d e r g i c f u n c t i o n i n the neostriatum. This circumstance i s a consequence of the ignorance of the physio l o g i c a l functions regulated by the peptides and the l i m i t e d number of i n v e s t i g a t i o n s d i r e c t e d towards n e o s t r i a t a l p e p t i d e s . A Postsynaptic Dopamine Receptor Regulating C y c l i c AMP

Formation

A postsynaptic dopamine receptor i n the neostriatum can be c h a r a c t e r i z e d w i t h biochemical procedures. The b a s i s f o r t h i s c h a r a c t e r i z a t i o n i s the a b i l i t y of dopamine to s t i m u l a t e adenylate c y c l a s e a c t i v i t y i n c e l l - f r e e homogenates of neo s t r i a t a l t i s s u e . E a r l i e r i n this volume, Brown and Dawson-Hughes d i s c u s s the p r o p e r t i e s of this receρtor-enzyme system i n the bovine p a r a t h y r o i d gland and summarize the evidence that a dopamine-stimulated formation of c y c l i c AMP t r i g g e r s the r e l e a s e of parathyroid hormone from t h i s bovine t i s s u e . However, the r o l e of this enzyme i n e i t h e r the neostriatum or the s u b s t a n t i a n i g r a i s unknown. In the s u b s t a n t i a n i g r a , dopamine was reported to s t i m u l a t e the r e l e a s e of [3H]-GABA, and this e f f e c t was mimicked by d i b u t y r y l c y c l i c AMP (55) . However, as noted e a r l i e r i n t h i s chapter, these observations could not be reproduced by another group (56) . Thus, i n both the neostriatum and the sub s t a n t i a n i g r a , the dopamine-sensitive adenylate c y c l a s e i s a receptor i n search of a f u n c t i o n . At l e a s t a major p a r t of the n e o s t r i a t a l dopamine-sensitive adenylate c y c l a s e a c t i v i t y i s not a s s o c i a t e d with the terminals of the dopamine-containing n i g r o - s t r i a t a l neurons. I n t r a n i g r a l i n j e c t i o n s of 6-OH-dopamine which destroy these dopamine-



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c o n t a i n i n g neurons do not cause a loss of s t r i a t a l dopamines e n s i t i v e adenylate c y c l a s e a c t i v i t y (82). However, i n t r a s t r i a t a l i n j e c t i o n s of k a i n i c a c i d which destroy neuronal soma t a cause a s u b s t a n t i a l loss of t h i s dopamine-sensitive enzyme a c t i v i t y (83, 84). In s t u d i e s of the s u b c e l l u l a r d i s t r i b u t i o n of t h i s enzyme a c t i v i t y , the h i g h e s t s p e c i f i c enzyme a c t i v i t y i s found i n submitochondrial f r a c t i o n s enriched with nerve endings (85). These observations are compatable w i t h a post synaptic l o c a t i o n of the enzyme a c t i v i t y upon interneurons or r e c u r r e n t c o l l a t e r a l s of n e o s t r i a t a l e f f e r e n t s . A dopamines e n s t i v e adenylate c y c l a s e a c t i v i t y a l s o occurs i n the sub s t a n t i a n i g r a (86, 87, 88). This n i g r a l enzyme i s not a s s o c i a t e d w i t h the dopamine-containing neurons . The pharmacological p r o p e r t i e s of the dopamine-sensitive adenylate c y c l a s e a c t i v i t y i n e i t h e r the bovine p a r a t h y r o i d gland or the neostriatum are summarized by Brown and DawsonHughes e a r l i e r i n t h i s volume and by other authors elsewhere (89, 90). Dopamine, i n a d d i t i o n to s t i m u l a t i n g the formation of c y c l i c AMP, i s a l s o able to i n h i b i t the formation of t h i s c y c l i c n u c l e o t i d e . This i n h i b i t o r y e f f e c t of dopamine can be c l e a r l y demonstrated i n e i t h e r the mammotrophs of the a n t e r i o r p i t u i t a r y gland (91-94) or the melanotrophs of the intermediate lobe of the p i t u i t a r y gland (see Kebabian e t a l . , this volume). Both the stimulatory and the i n h i b i t o r y e f f e c t of dopamine under c y c l i c AMP formation can be demonstrated i n the neostriatum u s i n g i n v i t r o s u p e r f u s i o n . E i t h e r dopamine or SKF 38 393 stimulates the e f f l u x of c y c l i c AMP from s l i c e s o f r a t n e o s t r i a tum(Figures 5 and 6,95^, 96) ; this i s i n accord with the a b i l i t y of e i t h e r of these drugs to s t i m u l a t e adenylate c y c l a s e a c t i v i t y i n c e l l - f r e e homogenates o f the neostriatum (37). LY 141865, the s e l e c t i v e agonist upon the D-2 dopamine r e c e p t o r (28), reduced the magnitude of the SKF 38 393-induced e f f l u x of c y c l i c AMP but d i d not change the c o n c e n t r a t i o n of a g o n i s t g i v i n g half-maximal e f f l u x . The i n h i b i t o r y e f f e c t of LY 141865 occurs even i n the absence of c a l c i u m ions from the s u p e r f u s i o n medium. Since i t i s commonly accepted that calcium ions are e s s e n t i a l f o r the r e l e a s e of neurotransmitter (21) this l a t t e r o b s e r v a t i o n suggests that neurotransmitter r e l e a s e i s not required f o r the dopaminergic i n h i b i t i o n of c y c l i c AMP r e l e a s e (96). In a d d i t i o n , ( - ) - s u l p i r i d e , an antagonist of the D-2 dopamine receptor, markedly p o t e n t i a t e s the dopamine-stimulated e f f l u x of c y c l i c AMP but does not appreciably change the molar potency of dopamine (Figure 6). I t must be s t r e s s e d here that i n the experiment depicted i n Figure 6 an unusually high c o n c e n t r a t i o n of ( - ) - s u l p i r i d e has been used (50 μ Μ ) . However, one has to r e a l i z e that approximately 100 μ M dopamine i s r e q u i r e d to maximally a c t i v a t e the D-l dopamine r e c e p t o r . To b l o c k the e f f e c t s of 100 μ M dopamine on the D-2 dopamine receptor high concentrations of ( - ) - s u l p i r i d e are needed. F i g u r e 7 presents a



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10"

7

10"

6

10~

10- 5

S K F 38393 (M) Figure 5. Inhibition by LY 141865 of the SKF 38393-stimulated efflux of cAMP from blocks of rat neostriatum. The efflux of cAMP from neostriatal tissue, stimu lated with the indicated concentrations of SKF 38393, was estimated in the absence (O) or presence (M) of 5 μΜ LY 141865. (Reproduced with permission from Ref. 96. Copyright, Elsevier Biomedical Press.)



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Dopamine Receptors in the Neostriatum: Biochemical and

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