Dopamine Receptors - ACS Publications - American Chemical Society

6 Potential Therapeutic Uses of Dopamine Receptor Agonists and Antagonists DONALD Β. C A L N E and T. ANDREO LARSEN

Downloaded by UNIV OF SYDNEY on May 3, 2015 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.ch006

University of British Columbia, Health Sciences Centre Hospital, Division of Neurology, Vancouver, British Columbia, Canada

The various types of dopamine agonists are reviewed, and their applications are discussed in neurological, endocrinological and cardiovascular disease. The major indications for dopamine agonists are Parkinson's Disease, hyperprolactinemia, acromegaly, certain pituitary tumors, and shock. Dopamine antagonists are then considered; these drugs are employed predominately for the treatment of psychiatric disease, notably schizophrenia. More drugs are required with selective actions on the different categories of dopamine receptor; when these are developed i t should be possible to improve the therapeutic index of treatment for the above diseases and extend perhaps the application of these agents to other disorders.

It is less than 25 years since dopamine (DA) became established as a neurotransmitter, rather than simply existing as a precursor for norepinephrine (1). Yet DA has overtaken acetylcholine and norepinephrine as the most extensively investigated neurotransmitter in the nervous system, and i t has now been found to have hormonal functions (in the portal circulation of the pituitary), in addition to its activity as a humerol agent for communication between nerve cells. Analyses of the receptor mechanisms for dopamine have proved more d i f f i c u l t than comparable studies for acetylcholine and norepinephrine, partly because of the limited range of a r t i f i c i a l agonists and antagonists. Nevertheless, at least two types of DA receptor have been characterized,(2) one associated with an adenylate cyclase (D-1 receptors) and another independent of this enzyme (D-2 receptors). Other categories of DA receptor may exist, but the evidence for defining these is less complete (3). The c l i n i c a l impact of the surge in new knowledge on DA has been substantial, but i t is salutory to recognize that the largest 0097-6156/83/0224-0147$06.00/0 © 1983 American Chemical Society

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

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s i n g l e a p p l i c a t i o n of drugs that modify DA f u n c t i o n - the use of DA antagonists i n schizophrenia - d e r i v e s from pragmatic observations which preceded even the f i r s t s p e c u l a t i o n that DA i s a neurotransmitter. In s p i t e of t h i s humbling example of lack of s c i e n t i f i c r a t i o n a l e f o r a major therapeutic advance, i t i s reasonable to claim that the l o g i c a l a p p l i c a t i o n of pharmacological p r i n c i p l e s has l e d to important developments i n the treatment of a wide range of human d i s e a s e s .


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The main agents to have been employed to increase dopaminergic e f f e c t s are:1. DA i t s e l f . 2. The precursor of DA, L-DOPA, whose a c t i o n s d i f f e r from dopamine by v i r t u e of pharmacokinetic f a c t o r s - u n l i k e DA, L-DOPA can cross the blood b r a i n b a r r i e r with reasonable ease. 3· Amphetamine, a drug that acts by r e l e a s i n g DA from nerve terminals. 4· Apomorphine and i t s d e r i v a t i v e s . These drugs are of i n t e r e s t as the f i r s t a r t i c i a l , d i r e c t a c t i n g a g o n i s t s . T h e i r use i s l i m i t e d by rather prominent unwanted a c t i o n s . 5· Ergot d e r i v a t i v e s . The f i r s t and most widely prescribed ergot d e r i v a t i v e with dopaminomimetic p r o p e r t i e s i s bromocriptine. Congeners of bromocriptine that are c u r r e n t l y undergoing c l i n i c a l e v a l u a t i o n include l y s u r i d e , p e r g o l i d e , and CU 32-085. Before reviewing the c l i n i c a l conditions i n which DA agonists have a therapeutic r o l e , i t i s appropriate to mention o c c a s i o n a l paradoxes that occur, where DA agonists appear to be e l i c i t i n g responses that are g e n e r a l l y regarded as the opposite of those expected. For example, very high doses of L-DOPA have been reported, on rare occasions, to induce an exacerbation of Parkinson's disease; t h i s i s thought to be analogous to the way i n which high concentrations o f c h o l i n e r g i c agents can lead to a d e p o l a r i z a t i o n block at c h o l i n e r g i c synapses. S i m i l a r l y , some a r t i f i c a l agonists of DA may act as DA antagonists at high t i s s u e l e v e l s , e i t h e r by the above mechanism, or by behaving as " p a r t i a l a g o n i s t s " (which stimulate receptors at low concentrations but i n h i b i t them at high t i s s u e l e v e l s ) . F i n a l l y , very low concentrations of c e r t a i n dopaminomimetics may s e l e c t i v e l y a c t i v a t e presynaptic receptors, to e l i c i t a homeostatic, "negative feedback" e f f e c t of decreasing the release o f DA from nerve endings; t h i s mechanism has been postulated to account f o r the o c c a s i o n a l improvement i n c h o r e a t i c and dystonic movement d i s o r d e r s , reported, f o r example, with low doses of apomorphine and bromocriptine (4_,5_,6_). A l l the DA agonists employed c l i n i c a l l y a c t i v a t e D-2 receptors, but none are e n t i r e l y s e l e c t i v e . Some a l s o stimulate


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D-1 receptors; these include DA, L-DOPA, amphetamines, apomorphines and c e r t a i n ergot d e r i v a t i v e s such as p e r g o l i d e . Other D-2 agonists ergot d e r i v a t i v e s i n h i b i t the D-1 receptor; these include bromocriptine, l y s u r i d e , and CU32-085- The commoner adverse r e a c t i o n s induced by DA agonists comprise nausea, hypotension, d y s k i n e s i a , h a l l u c i n a t i o n s and d e l u s i o n s . Neurological Disorders. The major a p p l i c a t i o n f o r DA agonists i n neurology i s the treatment of Parkinson's disease ( 7 ) · The r a t i o n a l e f o r t h i s i s a l o g i c a l example of therapeutic science. DA i s a neurotransmitter that normally e x i s t s i n very high concentrations i n the s t r i a t u m of the b r a i n , but i n Parkinson's disease the nerve c e l l s that produce and r e l e a s e DA undergo degeneration. T h i s s i t u a t i o n can be markedly a l l e v i a t e d by o r a l a d m i n i s t r a t i o n of DA agonists. By comparing the r e l a t i v e a c t i o n of d i f f e r e n t DA a g o n i s t s , i t seems that a c t i v a t i o n of the D-2 receptor i s p a r t i c u l a r l y important f o r the achievement of a therapeutic response i n Parkinson's disease. While Parkinson's disease represents by f a r the commonest n e u r o l o g i c a l d i s o r d e r amenable to treatment by DA agonists, the p a r a d o x i c a l a c t i o n of these drugs has o c c a s i o n a l l y been reported to e l i c i t favorable responses i n Huntington's disease (4^6^), dystonia musculorum deformans (5} and c e r t a i n segmental and f o c a l dystonias. Endocrinological Disorders. The discovery that DA i s a potent p r o l a c t i n i n h i b i t o r y f a c t o r i n the p o r t a l c i r c u l a t i o n of the p i t u i t a r y i s the basis f o r the use of DA agonists to suppress unwanted normal puerperal l a c t a t i o n , and i n t r e a t i n g p a t h o l o g i c a l hyperprolactinaemia together with i t s associated anovular infertility. A f u r t h e r e n d o c r i n o l o g i c a l a p p l i c a t i o n f o r dopamine agonists i s the treatment of acromegaly. Normally, dopaminomimetics stimulate the release of growth hormone from the p i t u i t a r y , but i n acromegaly there i s an unexplained r e v e r s a l of the response such that DA agonists suppress the abnormal e l e v a t i o n of growth hormone. These agents represent the f i r s t medical form of treatment f o r acromegaly. F i n a l l y , another s e r e n d i p i t o u s discovery i s having a major impact on endocrinology. I t has been found that the same long a c t i n g , a r t i f i c i a l DA agonists (ergot d e r i v a t i v e s ) that have been employed to t r e a t hyperprolactinaemia and acromegaly induce atrophy of c e r t a i n p i t u i t a r y tumors, i n p a r t i c u l a r those that secrete p r o l a c t i n . The mechanism of t h i s antitumor e f f e c t i s unknown, but here again a new medical treament has become a v a i l a b l e f o r what was p r e v i o u s l y regarded as a disease that required e i t h e r s u r g i c a l or X-ray therapy. One curious aspect of the a c t i o n of DA agonists on p i t u i t a r y tumors i s the remarkable speed of t h e i r e f f e c t . Dramatic changes i n tumor s i z e , with c l i n i c a l concomitants such as s h r i n k i n g of


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v i s u a l f i e l d d e f e c t s , can occur w i t h i n 10 days of s t a r t i n g treatment (8).


C a r d i o v a s c u l a r D i s o r d e r s . DA i t s e l f i s a u s e f u l agonist where intravenous therapy i s required f o r immediate e f f e c t s l i m i t e d to the periphery ( i . e . outside the blood b r a i n b a r r i e r ) . I t has therefore been employed as a pharmacolgical agent i n shock - a c o n d i t i o n i n which there i s no disease i n v o l v i n g dopaminergic mechanisms, but where the i n o t r o p i c a c t i o n s on the heart and v a s o d i l a t o r e f f e c t s on the kidney can reverse the p o t e n t i a l l y l e t h a l consequences of profound a r t e r i a l hypotension, whatever i t s cause. This subject i s discussed i n d e t a i l elsewhere i n t h i s symposium. Other a p p l i c a t i o n s f o r dopamine a g o n i s t s . The t r a d i t i o n a l use of apomorphine as an emetic stems from i t s dopaminomimetic a c t i o n s i n the brainstem. T h i s mechanism of a c t i o n has been i d e n t i f i e d r e t r o s p e c t i v e l y , since apomorphine was employed to induce vomiting long before i t was known to be a DA agonist. Other areas of i n t e r e s t as p o t e n t i a l a p p l i c a t i o n s f o r DA a g o n i s t s include a l l e v i a t i o n of premenstural tension, c o r r e c t i o n of normoprolactinaemic i n f e r t i l i t y , the treatment of mastalgia, impotence, Cushing's syndrome, and hypertension ( 8 ) . The use of DA agonists i n p e p t i c u l c e r i s a very recent a p p l i c a t i o n discussed f u r t h e r i n another s e c t i o n of t h i s book (Chapter 8 ) . The v a l i d i t y of the claims f o r therapeutic e f f i c a c y i n these conditions remains unproven, and the mechanisms by which DA agonists might e l i c i t these b e n e f i c a l e f f e c t s are i l l defined. More c l i n i c a l information i s needed before any conclusions can be drawn on the p o s s i b l e value of dopaminomimetics i n these s e t t i n g s . Dopamine Antagonists A v a r i e t y of drugs that block DA receptors are a v a i l a b l e f o r c l i n i c a l use, and even more f o r experimental purposes. These drugs, a l s o r e f e r r e d to as n e u r o l e p t i c s , include phenothiazines (e.g., chlorpromazine), thioxanthenes (e.g., c h l o r p r o t h i x e n e ) , butyrophenones (e.g., h a l o p e r i d o l ) , d i p h e n y l b u t y l p i p e r i d i n e s (e.g., pimozide), and dibenzodiazepines (e.g., c l o z a p i n e ) . The major medical a p p l i c a t i o n s f o r these drugs are i n the treatment of severe p s y c h i a t r i c i l l n e s s e s , c e r t a i n movement d i s o r d e r s , emesis and i n t r a c t a b l e hiccough. The d i f f e r e n t i a l c l i n i c a l a c t i o n s of DA blockers on the DA receptor subtypes have not been defined with p r e c i s i o n . Most n e u r o l e p t i c s appear to act at both D-1 and D-2 r e c e p t o r s . Some d i f f e r e n c e s e x i s t , however. The thioxanthenes bind to s i t e s r e l a t e d to both DA receptor subtypes, but the butyrophenones seem to p r e f e r s i t e s a s s o c a i t e d with D-2 r e c e p t o r s , binding only weakly to those i d e n t i f i e d with D-1 r e c e p t o r s . S u l p i r i d e , molindone and metoclopramide are r e l a t i v e l y s e l e c t i v e D-2 antagonists.



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I t appears, t h e r e f o r e , that D-1 blockade i s not relevant to the a n t i p s y c h o t i c e f f e c t or suppression of h y p e r k i n e t i c movement disorders. Many e a r l i e r reports considered extrapyramidal side e f f e c t s unavoidable when t r e a t i n g p a t i e n t s with n e u r o l e p t i c s . There appeared to be a p a r a l l e l between a n t i p s y c h o t i c a c t i o n and the incidence of unwanted n e u r o l o g i c a l e f f e c t s . However, the development of newer n e u r o l e p t i c s has changed t h i s view. Drugs l i k e clozapine have a high a n t i p s y c h o t i c potency and yet produce few n e u r o l o g i c a l problems. I t has therefore been proposed that the DA receptors involved i n the b e n e f i c i a l a c t i o n s of n e u r o l e p t i c s i n the treatment of p s y c h i a t r i c d i s o r d e r s are s i t u a t e d i n mesolimbic areas, such as the nucleus accumbens, whereas the extrapyramidal e f f e c t s are mediated by s t r i a t a l receptors. By b l o c k i n g the s t r i a t a l DA receptors, the n e u r o l e p t i c drugs may cause s e v e r a l unwanted n e u r o l o g i c a l r e a c t i o n s ; these comprise acute dystonic r e a c t i o n s , t a r d i v e d y s k i n e s i a and a k a t h i s i a (motor r e s t l e s s n e s s ) . The most common and the most d i f f i c u l t management problem i s t a r d i v e d y s k i n e s i a , a l a t e r e a c t i o n appearing a f t e r months or years of treatment. The proposed mechanism i s a pharmacologically induced "denervation h y p e r s e n s i t i v i t y " , although other explanations have been proposed e.g. o v e r a c t i v i t y i n the noradrenergic systems (9)· There i s no s a t i s f a c t o r y treatment a v a i l a b l e f o r t a r d i v e d y s k i n e s i a . The p i p e r a z i n e group of phenothiazine drugs and h a l o p e r i d o l are p a r t i c u l a r l y prominent i n causing t h i s problem; there i s l e s s l i k e l i h o o d with t h i o r i d a z i n e , clozapine and s u l p i r i d e (10). P s y c h i a t r i c Disorders. The main i n d i c a t i o n s f o r DA antagonists are the treatment of adult schizophrenia, and childhood psychosis. H a l o p e r i d o l and chlorpromazine are the most f r e q u e n t l y employed. In a d d i t i o n to acute and chronic schizophrenia, the n e u r o l e p t i c s are sometimes used i n the management of mania, d e l i r i u m , and severe a g i t a t i o n , whatever the cause of these symptom complexes. I t must be noted that u n l i k e parkinsonism, where a d e f i n i t e dysfunction i n the DA system has been e s t a b l i s h e d , f o r schizophrenia and other p s y c h i a t r i c diseases, no unequivocal evidence has y e t been presented to prove that there i s a disturbance of the DA system (e.g., dopaminergic o v e r a c t i v i t y or receptor h y p e r s e n s i t i v i t y ) . In untreated schizophrenics the production of DA metabolites i s normal. C o n f l i c t i n g r e s u l t s have been obtained i n studies of the DA receptors i n schizophrenics (JJ_,J_2 ), but i n the case o f p a t i e n t s who have not received n e u r o l e p t i c s , the receptor density and a f f i n i t y appear to be normal (1?). The "dopamine hypothesis" i n these disorders derives from the b e n e f i c i a l e f f e c t s of drugs that block DA receptors. Neurological

Disorders.

Huntington's chorea i s a h e r e d i t a r y


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disease c h a r a c t e r i z e d by c h o r e a t i c i n v o l u n t a r y movements and mental d e t e r i o r a t i o n . There i s gross atrophy of the corpus striatum, with a d d i t i o n a l neural degeneration i n the f r o n t a l c e r e b r a l cortex. The c h o r e a t i c movement d i s o r d e r responds to phenothiazines and butyrophenones. There i s , however, no treatment for the mental d e c l i n e . Improvement has been reported f o l l o w i n g the use of h a l o p e r i d o l and chlorpromazine i n other c h o r e a t i c movement d i s o r d e r s i n c l u d i n g s e n i l e chorea, Sydenham's chorea and the chorea asociated with hyperthyroidism (14,15). The syndrome of G i l l e s de l a Tourette i s a rare childhood i l l n e s s c h a r a c t e r i z e d by m u l t i p l e , chronic t i c s , grunts and v o c a l i z a t i o n s that are f r e q u e n t l y obscene ( c o p r o l a l i a ) . Neuroleptics a l l e v i a t e t h i s c l i n i c a l p i c t u r e . Although most of the therapeutic experience i n t h i s d i s o r d e r has been gained with h a l o p e r i d o l , phenothiazine n e u r o l e p t i c s have also been shown to be e f f i c a c e o u s (1 6 ) . Ernesis. DA receptor b l o c k i n g agents suppress nausea and vomiting. Phenothiazines, such as chlorpromazine and prochlorperazine, are u s u a l l y employed. T h e i r a c t i o n i s probably mediated v i a blockade of DA receptors i n the chemoreceptor t r i g g e r zone of the medulla oblongata. Hiccough. Chlorpromazine and prochlorperazine have been used i n the treatment of i n t r a c t a b l e hiccough (10). T h e i r mechanism of a c t i o n i s unknown. Conclusions Manipulation of the DA receptors i s employed i n therapeutics f o r n e u r o l o g i c a l , e n d o c r i n o l o g i c a l , p s y c h i a t r i c and c a r d i o v a s c u l a r d i s o r d e r s . When f u r t h e r knowledge of the receptors i s gained, "it i s probable that drugs w i l l be developed with more s e l e c t i v e a c t i o n s on various subtypes i n diverse l o c a t i o n s . These pharmacological refinements should r e s u l t i n an increase i n the therapeutic index of treatment - an improvement i n the balance between wanted and unwanted e f f e c t s . Literature Cited 1. 2. 3. 4.

5.

Carlsson, A. Pharmacol. Rev. 1959,11,490. Kebabian, J.W.; Calne, D.B. Nature 1979,277,93-6. Seeman, P. Pharmacol. Rev. 1980,32.229-313 F r a t t o l a , L.; A l b i z z a t i , M.G.; B a s s i , S.; Trabucchi, M. Dyskinesia, dystonia and dopaminergic system: e f f e c t of apomorphine and ergot a l k a l o i a s . In "Apomorphine and Other Dopaminomimetics".Vol.2, ed. C o r s i n i , G.U. and Gessa, G.L. Raven Press: New York, 1981, 145-51. S t a h l , S.M.; Berger, P.A. Lancet 1981,2,745.


6. 6. 7· 8.


9. 10.

11. 12. 13. 14. 15.

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Tolosa, E.S.; Sparber, S.Β. L i f e S c i . 1975, 15, (7) 1371-80. Calne, D.B. "Therapeutics i n Neurology", B l a c k w e l l Scientific P u b l i c a t i o n s : Oxford, 1980. Thorner, M.O.; F l u c k i g e r , E.; Calne, D.B. "Bromocriptine: A Clinical and Pharmacological Review". Raven Press: New York, 1980 J e s t e , D.V.; Wyatt, R.J. J . C l i n . P s y c h i a t . 1981,42,455-7. B a l d e s s a r i n i , R.J. Drugs and the treatment of p s y c h i a t r i c disorders. In Goodman Gilman A, Goodman L.S. and Gilman A (eds.) "The Pharmacological Basis of Therapeutics". VIth ed. Macmillan, New York, 1980, 391-47. Lee, T.; Seeman, P. Am. J . P s y c h i a t . 1980,137,191-7. Seeman, P. Lancet 1981,1,1103. Mackay, A.V.P.; B i r d , O.; B i r d , E.D.; Spokes, E.G.; Rosser,M; Iversen,L.L.; Creese,I; Snyder,S.H. Lancet 1980,2,915-6 Shenker, D.M.; Grossman, H.; Klawans, H.L. Dev. Med. C h i l d . Neurol. 1973, 15, 19-24. Klawans, H.L.; Shenker, D.M.;Weiner, W.J. Observations on the dopaminergic nature of chorea. In "Advances i n Neurology." Barbeau,A.;Chase T.N.; Paulson G.W.(eds.) Raven Press, New York, 1973, 547-9. Levy, B.S.; Ascher, E. J . Neurol. Ment. D i s . 1968, 146,36-40.

R E C E I V E D February 16,

1983


Commentary: Potential Therapeutic Uses of Dopamine Receptor Agonists and Antagonists M I C H A E L O. T H O R N E R


University of Virginia Medical Center, Charlottesville, VA 22908

This chapter reviews the clinical applications of the dopamine system i n man. It gives a balanced view of the subject. There are only a few areas where I feel qualified to review the material presented. 1. The c l a s s i f i c a t i o n of dopamine receptors. Although Kebabian and Calne (1) performed an excellent service to the s c i e n t i f i c community in proposing the D-1 and D-2 receptor hypothesis, this remains to be proven by isolating and characterizing these receptors. These have been excellently reviewed by Cronin (2). Indeed the statement that the "D" receptors of the anterior pituitary are independent of adenylate cyclase is incorrect. We (3) and others (4,5) have shown a consistant and specific inhibitory relationship of the anterior pituitary dopamine receptor and adenylate cyclase. 2. I believe it is dangerous to claim that dopamine agonist drugs lead to atrophy of some prolactin-secreting pituitary tumors. Atrophy implies that the tumors may ultimately disappear. In our own experience we have shown that as soon as treatment is withdrawn, prolactin levels rise again, and the tumors increase i n size again, and visual f i e l d defects may recur. In a study performed with Drs. Tindall (Emory University) and Kovacs and Horvath (Toronto University) we have been able to show marked changes i n the morphology of prolactinoma c e l l s during bromocriptine therapy (6). The c e l l s lose the characteristics of active secretion and there i s a marked reduction i n the size of the individual c e l l s . When the treatment is withdrawn the changes are reversed, thus the dopamine agonists suppress the synthesis and secretion of prolactin for as long as they are given; this is associated with morphological changes i n the c e l l s which ultimately lead to a reduction i n tumor size. However, this is not a permanent effect and when therapy i s withdrawn as long as one year after i n i t i a t i o n of therapy the c l i n i c a l picture reverses, often within days to that seen prior to treatment with an increase i n 0097-6156/83/0224-0154$06.00/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


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p r o l a c t i n l e v e l s , i n c r e a s e i n tumor s i z e , and r e c u r r e n c e o f c o m p r e s s i v e symptoms i f t h e y were i n i t i a l l y p r e s e n t . Thus t h i s therapy i s u s e f u l p r o v i d i n g i t i s continued probably l i f e long. 3. The d i s c u s s i o n o f t h e r o l e o f b r o m o c r i p t i n e i n a c r o m e g a l y c o n f i r m s my own p e r s o n a l b e l i e f t h a t i t i s u s e f u l a d j u n c t i v e t r e a t m e n t but i n c o n t r a s t t o p r o l a c t i n o m a s , a c r o m e g a l y s h o u l d p r o b a b l y be t r e a t e d p r i m a r i l y w i t h p i t u i t a r y s u r g e r y and i f t h a t f a i l s , w i t h i r r a d i a t i o n and/or m e d i c a l therapy w i t h dopamine a g o n i s t d r u g s . I t s h o u l d be s t r e s s e d t h a t t h e r e i s some d i s p u t e i n l i t e r a t u r e as t o t h e e f f i c a c y o f dopamine a g o n i s t s i n t h e t r e a t m e n t o f a c r o m e g a l y (7_,§)· In general i t i s agreed t h a t b r o m o c r i p t i n e therapy g i v e s e x c e l l e n t c l i n i c a l r e s u l t s b u t t h e mechanism o f t h i s improvement i s u n c l e a r . G r o w t h hormone l e v e l s a r e r a r e l y s u p p r e s s e d t o n o r m a l and somatomedin C l e v e l s a r e o n l y v a r i a b l y a f f e c t e d ( 9 ) . The c l i n i c a l r e s p o n s e i s much g r e a t e r t h a n what one w o u l d e x p e c t j u d g i n g f r o m t h e b i o c h e m i c a l d a t a ; however, t h i s i s not a new observation related to bromocriptine. S i m i l a r o b s e r v a t i o n s have b e e n made a f t e r p i t u i t a r y s u r g e r y and r a d i a t i o n t h e r a p y . 4. One o f t h e d r u g s u s e d t o s u p p r e s s n a u s e a , m e t o c l o p r a m i d e , a l s o a dopamine r e c e p t o r b l o c k i n g d r u g , i s now becoming i n c r e a s i n g l y used p a r t i c u l a r l y i n nausea a s s o c i a t e d w i t h the a d m i n i s t r a t i o n of chemotherapeutic agents.

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9.

Kebabian, J . W.; Calne, D. B. Nature (London) 1979, 277 93. Cronin, M. J . "Neuroendocrine Perspectives"; Elsevier Biomedical Press: New York, 1982; p 169. Cronin, M. J.; Thorner, M. O. J . Cyclic Nucleotide Res., in press. Swennen, L.; Denef, C. Endocrinology 1982, 111, 398. Giannattasio, G.; DeFerrari, M. E.; Spada, A. Life Sci. 1981, 28, 1605. T i n d a l l , G.; Kovacs, K . ; Horvath, E . ; Thorner, M. O. J . C l i n . Endocrinol. Metab. 1982, 55, 1178. Lindholm, J.; Riishede, J.; Vestergaard, S.; Hummer, L.; Faber, O.; Hagen, C. N. Engl. J . Med. 1981, 304, 1450. Thorner, M. O.; Besser, G. M.; Wass, J . A. H . ; L i u z z i , Α.; Hall R.; Muller, Ε. E . ; Chiodini, P. G. N. Engl. J . Med. 1981, 305, 1092. Wass, J . A. H . ; Clemmons, D. R.; Underwood, L. E . ; Barrow, I . ; Besser, G. M . ; Van Wyk, J . J . C l i n . Endocr. 1982, 17, 369.

RECEIVED

January 27,

1983


Dopamine Receptors - ACS Publications - American Chemical Society

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