Effects of different dopaminergic antagonists on bromocriptine-induced inhibition of norepinephrine release.

In this study we evaluated the effects of placebo or acute bromocriptine (BC) administration (2.5 mg orally) on plasma catecholamines, systolic and diastolic blood pressure (BP), heart rate, and plasma PRL in six normal subjects [group I, mean age 33.2 +/- 5.4 (SD) yr] in the supine as well as upright position. BC induced a significant decrease in plasma norepinephrine in the supine [167.7 +/- 16.8 (SEM) vs. 101.9 +/- 33.7 pg/ml, P less than 0.005] and upright positions [397.3 +/- 27.7 vs. 211.3 +/- 26.7 pg/ml, P less than 0.005], a decrease in systolic and diastolic BP and a decrease in plasma PRL (P less than 0.01). After standing, epinephrine levels increased significantly (53.6 +/- 11.8 vs. 226.4 +/- 71.0 pg/ml, P less than 0.05). The study was repeated in a second group of seven normal subjects (mean age, 32.3 +/- 12.9 yr) after placebo or metoclopramide (20 mg orally) plus BC. In this group metoclopramide, a central and peripheral antidopaminergic agent, counteracted the BC-induced effects found in group I, both in the basal and stimulated conditions. Plasma PRL increased significantly (P less than 0.025). Finally, to assess the effect of peripheral dopaminergic blockade on BC-induced changes in sympathetic outflow, we repeated the study in seven normal subjects (group III, mean age, 30.1 +/- 5.0 yr) after placebo or domperidone (20 mg orally) plus BC. Domperidone blocked the effects of BC on norepinephrine and BP in the supine position. On standing there was a significant decrease in systolic (P less than 0.05) and diastolic (P less than 0.05) BP and an increase in epinephrine levels (58.9 +/- 12.2 vs. 109.8 +/- 24.6 pg/ml, P less than 0.05) was still observed. Plasma PRL increased significantly (P less than 0.025). The results of this study suggest that the inhibition of sympathetic outflow induced by BC is peripherally mediated. As peripheral dopamine receptor blockade did not counteract all the effects after BC during standing, dopaminergic modulation of central reflex sympathetic activation is suggested.

Effect of bromocriptine on DNA synthesis, growth and hormone secretion of spontaneous pituitary tumours in the rat.

The 'spontaneous' development of pituitary tumours has been studied in the Wistar-Furth strain of rat. In females aged 64--135 weeks the incidence was as high as 69% whereas in males aged 72--116 weeks only 6% developed tumours. Hyperprolactinaemia was invariably associated with these spontaneous pituitary tumours but excessive secretion of growth hormone (GH) was found in one animal only. Bromocriptine inhibited secretion of prolactin and DNA synthesis of the tumours. In a mixed GH- and prolactin-secreting tumour transplanted to a peripheral site, bromocriptine reduced the size of the tumour as well as the secretion of both hormones. Oestradiol reversed the inhibitory action of bromocriptine on prolactin secretion and tumour growth but failed to influence the reduction in GH secretion caused by the drug.

The mode of action of bromocriptine following pretreatment with reserpine and alpha-methyl-p-tyrosine in rats.

The ability of bromocriptine (BRC), a selective dopamine D-2 receptor agonist, to induce yawning responses was studied in rats pretreated with reserpine and alpha-methyl-p-tyrosine (alpha-MPT). BRC (1 20 mg/kg IP) evoked yawning responses, which were pronounced at 2.5 mg/kg and characterized by the head moving downward. Higher doses of BRC (5 20 mg/kg) dose-dependently delayed the onset and peak time of yawning. A low dose of the selective D-1 dopamine receptor agonist SK&F38393 did not induce yawning but enhanced the BRC-induced response. Pretreatment with reserpine (1 and 5 mg/kg SC), alpha-MPT (100 and 300 mg/kg IP) and reserpine (1 mg/kg) plus alpha-MPT (100 mg/kg) was able to significantly reduce BRC-induced yawning. The inhibitory effects were prevented by a low dose of SK&F38393 (0.5 mg/kg IP). In particular, combined treatment with reserpine (5 mg/kg) and BRC (10 and 20 mg/kg) elicited upright fighting and jumping behaviors which were inhibited by haloperidol (1 mg/kg IP), a non-selective D-1 and D-2 receptor antagonist, SCH23390 (0.05 mg/kg SC). a selective D-1 receptor antagonist, or sulpiride (20 mg/kg IP), a potent D-2 receptor antagonist, and were potentiated by SK&F38393 (0.5 mg/kg). SCH23390 (0.05 mg/kg) decreased BRC-induced yawning and the apomorphine (low doses)-induced potentiation of BRC yawning, and prevented the apomorphine (high doses)-induced reduction of BRC yawning. SCH23390 also inhibited apomorphine-induced stereotypy and BRC-induced potentiation of apomorphine stereotypy.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromocriptine and apomorphine stimulation of cortisol secretion in conscious dogs; evidence for a stimulatory site located outside the blood brain barrier.

IV injections of the dopamine receptor agonists bromocriptine (0.1 mg/kg) and apomorphine (0.05 mg/kg) induced rapid and long-lasting increases of cortisol levels as measured by RIA in peripheral venous plasma of conscious dogs. Pretreatment with dopamine receptor antagonists which do not readily penetrate the blood brain barrier (domperidone, halopemide, sulpiride) abolished the release responses induced by the dopamine agonists. These results suggest that the dopamine receptor agonists stimulate cortisol release at a site located outside the blood brain barrier. In addition, some dopamine receptor antagonists (haloperidol, chlorpromazine, milenperone) were shown to cause a rapid and long-lasting increase of cortisol levels.

Effects of SR 48692, a selective non-peptide neurotensin receptor antagonist, on two dopamine-dependent behavioural responses in mice and rats.

One major mechanism underlying the central action of neurotensin is an interaction with the function of dopamine (DA)-containing neurons. In addition, direct or indirect DA agonists have been reported to promote neurotensin release. We have found that SR 48692, a non-peptide neurotensin receptor antagonist (0.04-0.64 mg/kg orally), antagonizes (50-65%) yawning induced by apomorphine (0.07 mg/kg SC) or bromocriptine (2 mg/kg IP) in rats, and turning behaviour induced by intrastriatal injection of apomorphine (0.25 micrograms), (+) SKF 38393 (0.1 micrograms), bromocriptine (0.01 ng) or (+) amphetamine (10 micrograms) in mice. Other apomorphine-induced effects in mice and rats such as climbing, hypothermia, hypo- and hyper-locomotion, penile erections and stereotypies were not significantly modified by SR 48692. Taken together, these data suggest that neurotensin may play a permissive role in the expression of some but not all behavioural responses to DA receptor stimulation.

Metabolite involvement in the behavioral effects of bromocriptine in cats.

There is a lag phase of 30-60 min before the onset of bromocriptine (BC) action. This delay may be necessary for the formation of active metabolites. The objective was to determine whether the abnormal behavioral effects induced by BC involve active hepatic metabolites. Thus, we studied the effect of an inhibitor of hepatic hydroxylation metabolism (SKF 525A) on the behavior of BC-treated cats. Experiments began after six weeks of habituation and involved i.p. injections of: (1) propylene glycol (drug vehicle); (2) SKF 525A (70 mg/kg); (3) BC (10 mg/kg); and (4) SKF 525A followed 30 min later by BC. Each cat received the four treatments with two weeks elapsing between consecutive experiments. The frequency of 12 behaviors was scored for 60 min after 1 h posttreatment. BC alone induced emergent behavioral changes (hallucinatory-like, limb flicks, abortive grooms) that were not observed following control injections (vehicle and SKF 525A). There was a complete elimination of BC-induced hallucinatory-like behavior/escape by SKF 525A pretreatment. Other emergent behaviors were similarly reduced but persisted in all cats. The large frequency of grooming induced by BC was significantly reduced. SKF 525A pretreatment was correlated with a significant increase in staring and quiet sitting and a failure of BC to increase activities such as rubbing, treading and kneading. But many other BC-induced behaviors showed no changes. The data demonstrated that particular BC-induced changes in cats are antagonized by SKF 525A. The behavioral suppression caused by SKF 525A is compatible with the involvement of active hepatic metabolites from BC.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromocriptine and lisuride stimulate the accumulation of cyclic AMP in intact slices but not in homogenates of rat neostriatum.

The effects of bromocriptine and lisuride on cyclic AMP concentrations in homogenates and in intact slices of rat neostriatum were investigated. Significant increases in cyclic AMP concentration were found after a 10-min exposure to bromocriptine and lisuride in striatal intact slices. On the contrary, as previously found, the two dopaminergic ergot derivatives did not stimulate dopamine-senstiive adenylate cyclase present in striatal homogenates. The stimulatory effects observed only in intact tissues were blocked by the specific dopamine receptor blocking agent fluphenazine. It is tempting to conclude that dopaminergic ergot derivatives have a site of action different from that stimulated by classic dopamine agonists in tissue homogenates.

A new nonvascular interpretation of syncopal migraine.

Migraine suffers who experience spontaneous syncopes (syncopal migraine) during attacks exhibit a dramatic intolerance to bromocriptine, a dopamine agonist. An oral dose of this drug renders these patients unable to stand, even for some hours, because of precipitously falling of arterial blood pressure. Treatment with domperidone, a specific dopamine receptor antagonist, abolishes the syncopal effect of bromocriptine. This evidence is compatible with a supersensitivity of those dopamine receptors, which exert an inhibiting activity and are located on blood pressure regulating centers as well as on cardiovascular sympathergic neurons.

Behavioral effects of dilazep on cholinergic, dopaminergic, and purinergic systems in the rat.

This study examined the effects of 1,4-bis[3-(3,4,5-trimethoxy benzoyloxy)-propyl] perhydro-1,4-diazepine (dilazep; Comelian) on central dopaminergic, cholinergic, and purinergic neuronal systems in rats. Intraperitoneal injections of dilazep (1-5 mg/kg) produced yawning responses, the most effective dose being 2 mg/kg. Dilazep potentiated physostigmine-induced yawning but not pilocarpine- and bromocriptine-induced yawning. Dilazep-induced yawning was not affected by low doses of haloperidol or sulpiride, but was completely inhibited by atropine, a muscarinic M1 receptor antagonist. Dilazep-induced yawning, as well as physostigmine-induced yawning, were markedly inhibited by pretreatment with SK & F 38393, a dopamine D1 receptor agonist, and were potentiated by SCH23390, a dopamine D1 receptor antagonist that alone does not elicit yawning. Caffeine, an adenosine receptor antagonist, inhibited dilazep- and physostigmine-induced yawning responses but N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl, adenosine (L-PIA), adenosine A1 receptor agonists, were inactive. These results suggest that because the effects of dilazep on central cholinergic neurons are similar to those of physostigmine dilazep may potentiate indirectly the action of endogenous acetylcholine. Cholinergic neurons activated by dilazep may be modulated by postsynaptic dopamine D1 receptor activity but may not be affected by dopamine D2 receptor activity. Furthermore, the stimulatory effects of dilazep on cholinergic neuron may not be due to an inhibition of dopamine D1 receptors via purinergic (adenosine A1 receptor) stimulation by dilazep.

Metoclopramide blocks bromocriptine induced antihypertensive effect in hypertensive patients.

Two groups of patients with essential hypertension were studied at the Vargas Hospital of Caracas. The first group of 9 patients under placebo treatment for 1 week received a single 2.5 mg oral dose of bromocriptine. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone levels were evaluated during the 6-hour period before and after the administration of drugs. The second experimental design was as follows: 9 patients received 30 mg metoclopramide daily (divided in 3 doses) for 1 week. At the end of the period a single oral dose of 2.5 mg of bromocriptine was given to each patient. The cardiovascular and biochemical parameters were also determined. Bromocriptine reduced both systolic and diastolic arterial pressure. The peak antihypertensive effect was shown 3 hours after administration of the drug, but the reduction of arterial pressure lasted approximately 6 hours. At the same time bromocriptine reduced plasma aldosterone levels and plasma renin activity. This reduction persisted 6 hours after its administration. Metoclopramide reversed the antihypertensive effect of bromocriptine and its effect on aldosterone secretion and plasma renin activity. We conclude from these findings that bromocriptine acts as an antihypertensive agent by stimulating DA2 dopaminergic receptor, the dopaminergic receptor involved in aldosterone and renin secretion is possibly DA2.

Antagonism by naloxone of anti-tremorine effect of bromocriptine in mice.

Effects of the opioid antagonist naloxone (10 mg/kg) and its interaction with anticholinergic (scopolamine) and dopaminergic (bromocriptine) agents against tremorine-induced tremors was studied. Naloxone (10 mg/kg) per se gave significant protection and significantly potentiated the protective effect of scopolamine against tremorine-induced tremors at 5 min only. When naloxone and subeffective dose of bromocriptine (2 mg/kg) were administered simultaneously, instead of protection, an enhancement of tremorogenic activity was seen. Although the exact mechanism of this drug interaction is far from clear, a multireceptor involvement (i.e. opioid, dopaminergic and cholinergic type) in the modulation of tremorine-induced tremors in mice has been speculated.

Antagonism of bromocriptine-induced cage climbing behaviour in mice by the selective D-2 dopamine receptor antagonists, metoclopramide and molindone.

Bromocriptine (5-30 mg/kg, ip), 2 hr after administration, induced cage climbing behaviour in mice. Pretreatment with haloperidol, an antagonist of both D-1 and D-2 dopamine receptors, metoclopramide and molindone, the selective D-2 dopamine receptor antagonists, effectively antagonised bromocriptine-induced climbing behaviour. The results indicate that bromocriptine most probably induces climbing behaviour in mice by stimulating the postsynaptic striatal D-2 dopamine receptors.

[Antagonism of l-stepholidine against bromocriptine-inhibition on prolactin level in lactational rats].

AIM: To study the antagonism of l-stepholidine (SPD) against bromocriptine (Bro)-inhibition on prolactin (PRL) level. METHODS: Bro (0.5 mg.kg-1.d-1, s.c.) reduced the PRL and caused a dysplasia of mammary gland in lactational rats. The weight growing of newborn rats was retarded. The PRL of the lactational rats was assessed by immunoradiometric assay (IRMA); the weight of newborn rats and development of mammary glands in lactational rats were also examined. Antagonism of SPD was evaluated. RESULTS: SPD (30 & 100 mg.kg-1.d-1, i.p.) obviously antagonized the Bro that induced lowering the PRL level in lactational rats, the PRL was 11 +/- 4 & 23 +/- 6 micrograms.L-1 (NS 7 +/- 2) respectively on d 15 of postpartum and the development of mammary gland in lactational rats was normal. The newborn rats grew rapidly in 11-15 d. CONCLUSION: SPD possessed an antagonism with Bro inhibition on D2 receptors located in the pituitary gland, and was an antagonist of dopamine D2 receptors.

The extracerebral dopamine antagonist domperidone block the suppressive effect of bromocriptine on prolactin and TSH secretion in man.

The effects of a single oral dose of 2.5 mg bromocriptine on serum level of TSH and prolactin were studied in a group of normal male subjects. Bromocriptine effectively inhibited basal TSH and prolactin concentration as well as the prolactin and TSH response to TRH given 4 hours later. The prior administration of the extracerebral dopamine antagonist domperidone reversed the endocrine effects of bromocriptine. The results suggest that dopamine receptors located at the pituitary may regulate TSH (and prolactin) release in man.

Attenuation of the locomotor-sensitizing effects of the D2 dopamine agonist bromocriptine by either the D1 antagonist SCH 23390 or the D2 antagonist raclopride.

Injections of the selective D2 dopamine agonist bromocriptine (5.0 mg/kg, IP) produced progressively stronger locomotion over 10 days of repeated testing. Concurrent treatment with either the D1 antagonist SCH 23390 (0.01 or 0.1 mg/kg, IP) or the D2 antagonist raclopride (0.1 or 1.0 mg/kg, IP) suppressed bromocriptine-induced locomotion on treatment days and attenuated or blocked the progressive increases in locomotion that accompanied repeated injections of bromocriptine alone. The fact that D1 and D2 antagonists each block the acute actions of bromocriptine and attenuate the development of bromocriptine sensitization is suggested to imply a striatal rather than a ventral tegmental mechanism for the sensitization produced by repeated treatments with direct dopamine agonists.

MK-801 disrupts the expression but not the development of bromocriptine sensitization: a state-dependency interpretation.

Repeated administration of the D2-type agonist bromocriptine (5.0 mg/kg, IP) caused progressive increases in the locomotor-stimulating effects of the drug in rats. Similar progressive increases in locomotor activity were observed in rats that received repeated coadministration of the NMDA receptor antagonist MK-801 (0.25 mg/kg, IP) plus bromocriptine. However, when rats previously treated with the combination of drugs received either bromocriptine or MK-801 alone, their levels of activity were comparable to those of rats having no prior experience with either drug. A second group of rats was sensitized to the effects of bromocriptine alone; no evidence of bromocriptine sensitization was seen when MK-801 was subsequently coadministered with bromocriptine. Thus, either the presence or the absence of MK-801 could--depending upon the conditions of previous drug treatment--block the expression of bromocriptine sensitization. When a third group of rats was sensitized to the combination of MK-801 plus bromocriptine and subsequently tested following 2 or 6 drug-free weeks, evidence of sensitized responses was still present. Thus, at the very least, blockade of NMDA receptors with MK-801 fails to compromise the cellular changes associated with sensitization to the repeated combination of MK-801 plus bromocriptine. Bromocriptine sensitization may prove to be unique in this regard, but the present findings suggest a control condition that should be carefully explored in studies of the effects of MK-801 on sensitization involving other stimulant drugs.

Bromocriptine inhibits growth hormone release from rat pituitary cells in primary culture.

The action of the potent dopamine receptor agonist bromocriptine was studied in primary cultures of rat anterior pituitary cells. Bromocriptine inhibited both prolactin and growth hormone release in a concentration-dependent manner. This effect was blocked by the dopamine receptor antagonist spiperone when the agonist and antagonist were added coincidently. In contrast, spiperone was unable to affect the actions of bromocriptine if added 1 min after bromocriptine application or later. These results suggest that dopamine receptors exist not only on mammotrophs, but also on somatotrophs in vitro.

Metabolic and clinical studies on patients with acromegaly treated with bromocriptine over 22 months.

In twenty-two patients with active acromegaly who were untreated or unsuccessfully operated or irradiated (mean growth hormone (GH) values greater than 4 ng/ml) the following investigations were performed: routine laboratory tests, tomography of pituitary fossa, oral glucose tolerance tests, TRH and other pituitary function tests and GH profiles over 5-10 h before and during bromocriptine treatment with daily doses between 7.5 and 50 mg. In seventeen patients GH was suppressed to less than 50% by bromocriptine, in thirteen of them it was normalized on at least one occasion. A TRH induced GH release was observed in all but two responders to bromocriptine before therapy. This effect of TRH was not blunted during treatment with bromocriptine and also in the two patients with negative tests before therapy a significant GH increase was observed. In no non-responder to bromocriptine was a significant increase of GH after TRH observed. One patient showed a secondary resistance to bromocriptine during a period of treatment with griseofulvin. In the remaining sixteen patients the GH suppression has been consistent for between 3 and 22 months. A single dose of pimozide abolished the bromocriptine effect on GH totally in one patient; in others a slight or no significant effect was observed. Tissue swelling and sweating decreased in all bromocriptine responders and glucose tolerance improved in five patients. In four diabetic patients a partial or full remission of diabetes occurred. Apart from postural hypotension after the first administration in two patients no other severe side effects have been observed. Sella size and the other pituitary functions did not change during the time of the study. It seems that a high percentage of acromegalics may be successfully treated with bromocriptine.