Stimulatory control of prolactin by dopamine

ProB. Neuro-Psychopharrnocol & Biol. Psychiat. 1982, Vol. 6, pp. 355-358

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STIMI]LATORY CONTROL OF PROLACTIN BY DOPAMINE

GREGORYM. BROWNand JO A. SEGGIE Departments of Neurosciences and Psychiatry McMaster University, Hamilton, Ontario, Canada (Final form, June 1982) Abstract Brown, Gregory M. and Jo A. Seggie: Stimulatory control of prolactin by dopamine. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6(4-6) : 355-358. I. 2. 3. 4.

In addition to evidence that dopamine (DA) inhibits prolactin (PRL) via the tuberinfundibular system, there is also evidence for excitatory effects of DA via that system as well as evidence for regulation by DA sites lying behind the blood brain barrier. Apomorphine (APO) was given to rats pretreated with either a peripheral (domperidone, DOM) or a central (haloperidol, HAL) DA blocker and prolactin responses examined. Both DOM and HAL caused prolactin elevation. Further elevation of prolactin was produced by APO in HAL treated animals, indicating an excitatory dopamine effect on prolactin.

Keywords: prolactin, haloperidol, domperidone, apomorphine, dopamine. Abbreviations: dopamine (DA).

prolactin (PRL), haloperidol (HAL), domperidone (DOM), apomorphine (APO),

Introduction There is considerable evidence that dopamine regulation of prolactin is mediated via the tuberoinfundibular dopamine system. In a variety of studies dopamine agonists and antagonists which are incapable of crossing the blood brain barrier have profound effects on prolactin release. Thus, administration of carbidopa, a peripheral L-aminoacid decarboxylase inhibitor which w i l l prevent peripheral synthesis of dopamine causes an elevation in prolactin (Brown et a l . , 1976a). In contrast administration of dopamine i t s e l f causes a lowering of prolactin levels (LeBlanc et a l . , 1976) and administration of domperidone an agent which blocks dopamine receptors, produces a rise in prolactin (Brown et a l . , ). There is also evidence that these effects may be mediated by a direct action on the p i t uitary. Dopaminew i l l cause inhibition of prolactin release in v i t r o (Quijada et a l . , 1973/74). Dopamine infusion into the portal vessels w i l l produce a lowering in prolactin (Takahara et a l . , 1974). Dopaminecan be measured in the portal vessels in concentrations sufficient to have effects on the p i t u i t a r y (Ben-Jonathan et a l . , 1977) and stereospecific dopamine/neuroleptic receptors have been found in the pituitary (Brown et a l . , 1976b). On the basis of this evidence i t is reasonable to conclude that the tuberioinfundibular dopamine may act as a physiologic prolactin inhibiting factor and that this effect is mediated, at least in part, by an action on the pituitary dopamine receptors. In addition to the foregoing there are studies indicating that DA systems lying behind the blood brain barrier may participate in prolactin regulation (Quijada et a l . , 1973/74; Szabo et a l . , 1977). Furthermore, excitatory effects on PRL release have been reported (Denet et a l . , 1980; Besser et a l . , 1981). In the present study we examined effects of APO on PRL release in the presence of blockade by a peripheral (DOM) and a central (HAL) dopamine antagonist. 355

356

G.M. Brown and

J.A. Seggie

Methods Animals: Male wistar rats weighing 200-250 grams were individually housed in a temperature controlled room with free access to food and water, under a 12 hour light/12 hour dark lighting cycle. All subjects were allowed a minimum of lO days to adapt to the imposed conditions prior to experimentation. Experiment #1:

Dose Response Study

Groups of six animals were injected i.p. with one of the following: Vehicle, .l mg/kg, .3 mg/kg, .9 mg/kg, 2.7 mg/kg, or 8.1 mg/kg of HAL or DOM. Vehicle consisted of a solution of I% t a r t a r i c acid in d i s t i l l e d water. HAL and DOMwere dissolved in the vehicle and injected i . p . with constant volume for each dosage level. Two hours after injection animals were quietly removed to another room for immediate decapitation and collection of trunk blood. Plasmawas assayed for PRL levels using kits and procedures from the NIAMDD Pituitary Hormone Distribution Program. HAL and DOMwere supplied by Janssen Pharmaceutica Experiment #2:

Time Response Study

On the basis of the PRL data from experiment l two doses each of HAL and DOMwere chosen to study the time characteristics of the prolactin response. Doseswere chosen that gave near maximal and maximal PRL elevation with minimum drug. Separategroups of six animals were taken individually from t h e i r home cage and rated for resistance to capture on a scale of 0 to 4. Theywere then injected with a .3 mg/kg or .9 mg/kg dose of HAL or DOM or vehicle and sacrificed by decapitation 30, 60, 90, 120 or 180 minutes after i n j e c t i o n . , Trunk blood was collected for PRL assay. Immediatelyprior to sacrifice animals were removed to another room and subjected to behaviour rating (Seggie, 1974). Individual subjects were taken from their home cage and rated for resistance to capture on a scale of 0 to 4. Theywere then placed in the center of a 2 feet diameter drum whose f l o o r was marked o f f into quadrants. Locomotionduring a three minute period was quantified by counting the number of quadrant into which three feet were placed by the animal. Following locomotion scoring animals were subjected to an unexpected tap on the back. The vigor of the response to the f i r s t tap was rated on a scale of 0 to 4 and the number of consecutive non zero responses up to a maximumof 4 was observed. Startle response t r i a l s were done at lO second intervals. An additional group of six animals that was not handled and not injected was decapitated as a control group. Experiment #3:

APO Challenge in Presence at Peripheral and Central DA Blockers

On the basis of the data from experiment 2, i t was observed that .3 mg/kg of HAL or DOM did not cause equivalent PRL elevation. Thus for the present experiment .6 mg/kg of HAL was used instead in order to achieve equivalent effects. Separategroups of six animals were subjected to the following drug treatments. Animals were pre-treated with .6 mg/kg or .9 mg/kg of HaL or .3 mg/kg and .9 mg/kg of DOM. Thirty minutes after this pretreatment with DA blockers they were given a challenge dose i . p . of vehicle or APO in the following doses: .006 mg/kg, .043 mg/kg, or .3 mg/kg. Vehicle for APO was 0.1% sodium metabisulfate. One hour after injection of APO animals were sacrificed by decapitation and trunk blood was collected for assay of PRL. Results Experiment #1:

DoseResponse Study

Two hours after injection a l l doses of HAL and DOM resulted in significant elevation in PRL compared to the vehicle injected control group. The two drugs caused equivalent PRL elevation at each dose and .3 mg/kg and .9 mg/kg were chosen as the near maximal effective doses for further study.

Dopamine stlmulation of prolactln

Experiment #2:

357

Time Response Study

PRL responses were examined during the three hour period following injection of .3 mg/kg and .9 mg/kg of HAL or DOM compared to a vehicle or non-injected control. Two way analysis of variance on log transformed data showed a drug effect (F 16.3; df 4, 16; p < .OOl), a time effect (F 4.53; df 4, 16; p < .004) but no interaction, The vehicle injected group had s i g n i f i c a n t l y less PRL levels (p < .05) than a l l other groups at each of the five observation times (Multiple range test). The .3 mg/kg HAL group tended to be associated with less PRL but the effect only reached significance at 90 minutes at which time the vehicle and .3 mg/kg HAL group had equivalent but s i g n i f i c a n t l y lower PRL levels than the other three groups which did not d i f f e r . With respect to behaviour, an analysis of variance was performed on the scores from l ) pre drug resistance to capture 2) post drug resistance to capture at the five observation times. 3) post drug magnitude of startle responses at the five observation times. 4) post drug number of consecutive startle responses at the five observation times and 5) post drug locomotion at the five observation times. Groups did not d i f f e r prior to injection (p<.05). The only behaviour s i g n i f i c a n t l y affected by drug treatment was locomotion. Drug effect was highly significant (F 17.0; df 4, 16; p < .O001) but there was no time effect or interaction. The .9 mg/kg HAL group was unique and evidenced s i g n i f i c a n t l y less locomotion than the other four groups (Multiple range test). The .3 mg/kg HAL and the .3 mg/kg and .9 mg/kg DOM treatment had no effect on locomotion compared to the vehicle injected control group. Experiment #3:

APO Challenge in Presence of Central and Peripheral Dopamine Blockers

PRL data from this experiment are shown in figures l and 2. An analysis of variance in the vehicle and APO injected control groups indicated that no dose of APO alone influenced PRL levels (F= .764, df = 3, 20). DOM and HAL at both doses resulted in significant PRL elevation. The APO challenge at a l l dose levels did not influence PRL levels in the presence of peripheral blockade of DA receptors induced with DOM compared to the effects of DOM alone. In the presence of .9 mg/kg HAL pretreatment however, the .3 mg/kg APO challenge resulted in a further significant elevation in PRL over that seen with HAL alone (F = 4.72, df = 3, 19). Although a similar trend was seen following pretreatment with .6 mg/kg of HAL the effect was not significant (F = .837, df = 3, 19).

EFFECT OF CENTRAL DOPAMINE BLOCKER 30 MIN BEFORE APOMORPHINE CHALLENGE EFFECT OF PERIPHERALOOPAMINE BLOCKER 30 MIN BEFORE APOMORPHINE CHALLENGE

L. 160

140 120 E

100

Z

80

r.

No

Pretreatment

~{

I= Oomperldome ~m,,k° "i Pyetreatment

No

Pyetreatmont

~1

~

J mg/kg HalopMIdol PnJt r M t m e n l

~-I

I<

J mg/kg :_; Hllleplwldol Pretreet mmlt

140

'-+m°~+ "i l- Domperldoml Pretreatment

120

;

10o e0

E

0

E 0 .006.043 .3 Vehicle

0 .006.043 Vehicle

Control

Control

.3

0 .006,1143 3 Vlhlcle Control

A P O M O R P H I N E CHALLENGE DOSE m g / k g

Fig. I. Prolactin response to dopamine agonist in presence of peripheral dopamine blocker.

0

0 .006.043 .3 Vehicle

0 .OOE .043 .3 Vehicle

0 .006.043 .3 Vehicle

Control

Control

Control

A P O M O R P H I N E CHALLENGE DOSE n~l/kg

Fig. 2. Prolactin response to dopamine agonist in presence of central dopamine blocker.

358

G.M.

Brown and J.A. Seggie

Discussion

In confirmation of previous studies (Brouwers et a l . , 1980; Brown et a l . , 1981) domperidone was shown to produce a s i g n i f i c a n t r i s e in p r o l a c t i n . The maximum r i s e produced by domperidone and haloperidol was equivalent suggesting that i n h i b i t o r y effects of DA on p r o l a c t i n are largely i f not e n t i r e l y mediated outside the blood brain b a r r i e r . Dose response curves for domperidone and haloperidol with p r o l a c t i n were equivalent at 2 hours. However, at 90 min. 0.3 mg domperidone had more e f f e c t than the same dose of haloperidol, i n d i c a t i n g that domperidone is somewhat more potent than haloperidol at that time. Haloperidol but not domperidone had an e f f e c t on locomotion. These data confirm that domperidone in doses up to 0.9 mg/kg lacks central dopamine blocking a c t i v i t y . PRL elevation by APO was seen f o l l o w i n g pretreatment with HAL but not f o l l o w i n g DOM. Since DOM does not enter the central nervous system f r e e l y this may indicate a central s i t e of action of APO in elevating PRL. On the other hand stimulatory effects of DA on PRL release have been shown in v i t r o i n d i c a t i n g a d i r e c t e f f e c t on the p i t u i t a r y (Denef et a l . , 1980) as well as an i n h i b i t o r y e f f e c t of high doses of neuroleptics (Besser et a l . , 1981). Further studies with a range of doses of DOM was to be necessary to determine whether stimulatory effects of APO can also be seen following DOM pretreatment, which would be i n d i c a t i v e of a peripheral action of APO. Conclusion

In conclusion, stimulatory effects of APO on PRL can be demonstrated in vivo i n d i c a t i n g that effects previously demonstrated in v i t r o are at work in the whole organism. These findings support the concept of a stimulatory dopamine regulation of p r o l a c t i n . References

BEN-JONATHAN, N., OLIVER, C., WEINGER, H.J., MICAL, R.S., and PORTER, J.C. (1977). Dopamine in hypophyseal portal plasma of the rat during the estrous cycle and throughout pregnancy. Endocrinology, I00: 52-458. BESSER, G.M., DELITALA, G., GROSSMAN,A., STABBS, W.A., and YEO, T. (1981) Chlorpromozine, haloperidol, meoclopramide and domperidone release p r o l a c t i n through dopamine antagonism at low concentrations but paradoxically i n h i b i t p r o l a c t i n release at high concentrations. Br. J. Pharmacy, 71: 569-573. BROUWERS, J.R.B.J., A-~SSIES, J . , WIERSlNGA, W.M., HUIZING, G., and TYTGAT, G.N. (1980). Plasma p r o l a c t i n levels a f t e r acute and subchrone oral administration of domperidone and of metoclopramide: a crossover study in healthy volunteers. C l i n . Endocrinol. 12: 435-440. BROW~N, G.M., GARFINKEL, P.E., WARSH, J.J. and STANCER, H.C. (1976a). Effect of carbidopa on p r o l a c t i n , growth hormone and c o r t i s o l secretion in man. J. C l i n . Endocrinol. Metab., 43: 236-239. BROW~N, G.M., SEEMAN, P., and LEE, T. (1976b). Dopamine/neuroleptic receptors in basal hypothalamus and p i t u i t a r y . Endocrinology, 99: 1407-1410. BROWN, G.M., VERHAEGEN, H., VanWIMERSMAGREIDONU--S, T.B., and BRUGMANS, J. (1981). Endocrine effects of domperidone: a peripheral dopamine blocking agent. C l i n . Endocrinol. 15: 275-282. DENEF, C., MANET, D., and DEWALS, R. (1980) Dopaminergic Stimulation of Prolactin Release. Nature, 285: 243-246. LANGER, G., AHN, H.S., PEREL, J.M., MAKMAN,M.H., and SACHAR, E.J. (1977). No effects of quaternary neuroleptics on human p r o l a c t i n and Adenylcyclase. Lancet, I : 493. LEBLANC, H., LACHELIN, G.C.L., ABU-FADIL, S., and YEN, S.S.C. (1976). Effects of dopamine infusion on p i t u i t a r y hormone secretion in humans. J. C l i n . Endocrinol., Metabol., 43: 668-674. QUIJ-~ADA, M., ILLNER, P., KRULICH, L., and McCANN, S.M. (1973/74). The e f f e c t of catecholamines on hormone release from a n t e r i o r p i t u i t a r i e s and ventral hypothalami incubated in v i t r o . Neuroendocrinology, 13: 151-163. SEGGIE, J. (1971) Effect of adrena-~lectomy or gonadectomy on a f f e c t i v e behaviour changes following septal lesions in the rat. J. of Comparative and Physiological Psychology, 74: 11-19. SZAB-~O, M., NAYJ~WATOSE,C., KOP~ATHANA,N., and FROHFtAN, L.A. (1977). The Dopa decarboxylase i n h i b i t o r MK-436 on L-Dopa - induced i n h i b i t i o n of p r o l a c t i n secretion: Evidence f o r C.N.S. p a r t i c i p a t i o n in the L-Dopa effects. Neuroendocrinology, 24: 24-34. TAKAHARA, J . , ARIMURA, A., and SCHALLY, A.V. (1974). Effect of catec~holamines on the TRH stimulated release of p r o l a c t i n and growth hormone from sheep p i t u i t a r i e s in v i t r o . Endocrinology, 95: 1490-1494.