ACTA ENDOCRINOLOGICA

84

(1977)

36-44

Cattedra di Patología Medica dell' Universitá degli Studi di Milano, Ospedale San Raffaele, 20090 Milano-Segrate, Ospedale Luigi Sacco, Milano and Ricerca Medica Farmitalia, Milano, Italy

STIMULATORY EFFECT OF THE DOPA-DECARBOXYLASE INHIBITOR Ro 4-4602 ON PROLACTIN RELEASE; INHIBITION BY L-DOPA, METERGOLINE, METHYSERGIDE AND 2-Br-\g=a\-ERGOCRYPTINE

By A. E. Pontiroli, E. Castegnaro, M. P. Vettaro, G. C. Viberti and G. Pozza ABSTRACT In order to evaluate the role of serotonin (5-HT) in the effect of L-dopa prolactin (PRL) release, normal subjects received L-dopa alone or L-dopa plus a dopa-decarboxylase inhibitor (Ro 4-4602) in basal conditions and following the repeated administration of metergoline, a specific anti-5-HT agent. The inhibiting effect of L-dopa on PRL levels was enhanced by metergoline. On the contrary, L-dopa plus Ro 4-4602 induced a sharp increase in serum PRL levels. This effect was completely abolished by metergoline, which also significantly reduced fasting PRL levels in all the subjects studied. Ro 4-4602 alone induced a significant increase in serum PRL levels, similar to that commonly observed with chlorpromazine and TRH. The effect was similar in males and in females and was reproducible in experiments performed on different days. The effect of Ro 4-4602 was completely abolished by 2-Br-\g=a\-ergocryptineand metergoline, and, to a lesser degree, was reduced by methysergide. These results suggest that Ro 4-4602 is a reliable stimulus to PRL release and show that any stimulus to PRL secretion may be blocked by both dopaminergic and anti-serotonin agents. on

0 Present address: Sinai Hospital of Detroit, Outer Drive, Detroit, MI 48235, USA.

Department

of Research, 6767 West

In recent years evidence has arisen concerning the existence of a dopaminergic and serotoninergic control of prolactin (PRL) secretion in the experimental animal and in man. In particular, dopamine and its precursor L-dopa inhibit PRL release (Kamberi et al. 1971a; Malarkey et al. 1971), while serotonin (5-HT) and its precursors tryptophan and 5-hydroxytryptophan stimulate PRL release (Kamberi et al. 19716; Maclndoe 8c Turkington 1973; Chen 8c Meites 1975). It is also known that the administration of L-dopa modifies the cerebral content and distribution of 5-HT and catecholamines (Everett 8c Borcherding 1970). In order to evaluate the role of 5-HT in the effect of L-dopa on PRL secretion, in the present study 12 normal subjects have received either L-dopa intravenously alone or orally in combination with an extracerebral dopadecarboxylase inhibitor, in basal conditions and following a 3 days' treatment with a specific anti-5-HT agent, metergoline (Beretta et al. 1965; Mawson 8c Whittington 1970; Fregnan 1972). L-dopa plus the dopa-decarboxylase in¬ hibitor induced a significant increase in serum PRL levels, this effect being

completely inhibited by metergoline. This finding led us to evaluate the effect on serum ment with the dopa-decarboxylase inhibitor alone.

PRL levels of the treat¬

MATERIAL AND METHODS

Eight

18-45 years, free from endocrine and metabolic dis¬ normal glucose tolerance and without a family history of diabetes, received on the first morning, at 09.00 a. m., 200 mg L-dopa plus 50 mg Ro 4-4602 (Madopar®, Roche) as a single oral dose. This drug is commonly employed in the treatment of Parkinsonism (Tissot et al. 1963; Calne et al. 1971), because it allows a reduction of L-dopa-induced side-effects and better therapeutic results than L-dopa. alone. In previous experiments this formulation was found to be equally active as 500 mg L-dopa in stimulating HGH release (Cavagnini et al. 1972). Starting at noon the subjects received orally metergoline (Liserdol®, Farmitalia), 2 mg at 4 h intervals for 3 days, the last dose being administered at 08.00 a. m. of the 4th day, 1 h before a second L-dopa administration. Four additional subjects received iv L-dopa (75 mg in 10 min) (Ro 5-4759-604, Roche) in basal conditions and following a repeated metergoline administration as previously described. Five normal subjects (1 male and 4 female) received orally Ro 4-4602 50 mg, or an inert placebo on different days, the order of administration being at random allocation. One normal male subject received three consecutive doses of Ro 4-4602 at 2 and Vs h intervals. Seven normal subjects (6 male and 1 female) received 50 mg Ro 4-4602 in basal conditions and following a 3 days' placebo administration. A third Ro 4-4602 ad¬ ministration was performed in these subjects following a 3 days' treatment with 12 mg metergoline/day (3 subjects), 8 mg methysergide/day (Deserril®, Sandoz) 2 subjects), or 7.5 mg 2-Br-ct-ergocryptine/day (CB-154, Sandoz) (2 subjects). All but one subject were treated with only one of these drugs, the sole exception being 1 male

normal

orders, with

volunteers, aged

a

subject who cryptine.

was

treated with

methysergide and,

1 month

later, with 2-Br-a-ergo-

All the tests were performed at 09.00 a. m. after an overnight fast and at least 1 h of bed rest. Time of blood sampling is indicated in the figures. Blood samples

were

obtained

patent by

through

an

indwelling needle inserted in drip. Sera were separated

slow 0.9 °/o saline

a

an antecubital vein kept within 1 h and frozen at

-20°C until assayed. Serum PRL levels were determined by radioimmunoassay, as indicated by Sinha et al. (1973), using a Serono Immuno Chemicals Kit. The sensitivity of the method is around 1.5 ng/ml. No cross-reactivity with HGH was found in our experience. Serum HGH, FSH and LH levels were determined by radioimmunoassay (Hales Se Rändle 1963; Midgley 1966, 1967). All the paired tests were run in triplicate in the same experiment. Statistical analysis were performed by Student's i-test. No side-effect attributable to L-dopa alone, plus Ro 4-4602, Ro 4-4602 alone, metergoline and methysergide were detected by the investigators or spontaneously stated by the volunteers. Following 2-Br-a-ergocryptine, abdominal discomfort in the

epigastric

area was

complained.

PRL

Peak PRL Vaiue ng/ml

ng/ml 20

B

j

15

-i-+—f—K^N—

Nadir PRL

Value

-30

Ó

30

6b

90

120

150

léO min

-30

0 15 30 45 60

90

ng/ml

-120 min

Fig. L in response to L-dopa administration in basal conditions 3 days' treatment with metergoline, 12 mg/day (o-o). A: PRL response to 200 mg L-dopa plus 50 mg Ro 4-4602. B: PRL response to iv L-dopa, 75 mg. On the right side of each graph the mean of the highest (peak) and of the lowest (nadir) serum PRL levels attained by the subjects is indicated, irrespective of the time of occurrence. :'P

Stimulatory effect of the dopa-decarboxylase inhibitor Ro 4-4602 on prolactin release; inhibition by l-dopa, metergoline, methysergide and 2-Br-alpha-ergocryptine.

ACTA ENDOCRINOLOGICA 84 (1977) 36-44 Cattedra di Patología Medica dell' Universitá degli Studi di Milano, Ospedale San Raffaele, 20090 Milano-Segr...
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