Action Of Bromocriptine Research Articles

Prolactin Secretion in Myotonic Dystrophy

In order to evaluate prolactin secretion in females with myotonic dystrophy (MD) prolactin responses to TRH, metoclopramide and bromocriptine were studied in 13 women with myotonic dystrophy (10 normoprolactinaemic and 3 hyperprolactinaemic) and 8 healthy women. Following TRH administration mean maximal net increase was significantly higher in a group of normoprolactinaemic patients with MD in comparison to controls (p less than 0.05). In three patients with increased basal prolactin levels an exaggerated prolactin response to TRH has been observed. Normal prolactin response in a group of normoprolactinaemic as well as in hyperprolactinaemic patients have been observed following metoclopramide bolus injection. Following bromocriptine administration, maximal net decrease in prolactin levels has been found to be greater in normoprolactinaemic patients compared to healthy subjects, although the difference was statistically insignificant. The suppressive action of bromocriptine was more pronounced in patients with hyperprolactinaemia. Those results showed that there is some derangement in prolactin secretion in myotonic dystrophy leading to increased prolactin levels in some patients. Although the mechanism of this derangement has not been clarified yet it seems that it is not mediated via dopaminergic receptors.

Hypoprolactinemia decreases tyrosine hydroxylase activity in the tuberoinfundibular dopaminergic neurons acutely by protein dephosphorylation and chronically by changes in gene expression

This study evaluated the roles of protein dephosphorylation or suppressed gene expression in reducing tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons after acute or chronic bromocriptine (BROMO) administration. Diestrous or ovariectomized rats were injected with BROMO (3 mg/kg, s.c.) at 1000 h and were sacrificed 4 h later or were injected with BROMO at 12 h intervals for 3 days.In vitro tyrosine hydroxylase activity was assessed by incubating hypothalamic explants with brocresine, an L-aromatic amino acid decarboxylase inhibitor, and measuring 3,4-dihydroxyphenylalanine (DOPA) accumulation in the stalk-median eminence (SME). The incubation medium also contained either 2 μM okadaic acid, a protein phosphatase 1 and 2A inhibitor, or its vehicle (0.25% dimethylsulfoxide). Acute (4 h) and chronic (3 days) BROMO treatment suppressed circulating PRL levels from 10-12 ng/ml to<1 ng/ml and reduced tyrosine hydroxylase activity in the SME by 60% or 40% in diestrous or ovariectomized rats, respectively. Okadaic acid increased tyrosine hydroxylase activity in the SME 2-fold in control diestrous or ovariectomized rats. The reduced tyrosine hydroxylase activity in the SME after acute BROMO treatment was increased by okadaic acid 5-or 3-fold in diestrous or ovariectomized rats respectively, to a value similar to the controls. In sharp contrast, after chronic BROMO treatment, the response to okadaic acid was blunted. As assessed byin situ hybridization, tyrosine hydroxylase mRNA signal levels in the arcuate nucleus of diestrous rats were not altered after acute BROMO treatment, but were reduced by 70% after chronic BROMO treatment. The acute BROMO-induced decrease in tyrosine hydroxylase activity was reversed by co-administration of oPRL or rPRL, indicating that the action of BROMO is via a reduction in PRL. The data suggest that protein dephosphorylation may be a primary mechanism for the rapid BROMO-dependent suppression of tyrosine hydroxylase activity, whereas suppression of tyrosine hydroxylase gene expression may contribute to the lower tyrosine hydroxylase activity after chronic BROMO treatment.

Action of intravenously administered talipexole on the rat striatal neurons receiving excitatory input from nigral dopamine neurons.

Electrophysiological studies using rats anesthetized with chloral hydrate were performed to elucidate whether or not intravenously injected talipexole acted as a D2 receptor agonist on the striatal neurons in comparison with the action of bromocriptine. The activities of the striatal neurons were extracellularly recorded using a glass microelectrode attached along a seven-barreled micropipette, each barrel of which was filled with talipexole, bromocriptine, SCH23390 (D1 antagonist), domperidone (D2 antagonist), glutamate or 2 M NaCl. These drugs were iontophoretically applied to the immediate vicinity of the target neuron being recorded. The effects of talipexole and bromocriptine were examined on the neurons, whose spikes (induced by the stimulation of the substantia nigra pars compacta) were inhibited by the iontophoretic application of domperidone. Iontophoretic application of talipexole or bromocriptine increased spontaneous firing of these neurons and this increase in firing was also inhibited by iontophoretically applied domperidone. In the same neurons, intravenously administered talipexole (0.01, 0.02 and 0.04 mg/kg) dose-dependently increased firing, and this increase was inhibited by microiontophoretically applied domperidone, but not by SCH23390. On the other hand, the intravenous injection of bromocriptine (0.1, 0.2 and 0.4 mg/kg) also increased the firing rate. However, the increase was not dose-dependent and fluctuated; the firing transiently decreased during the increase in firing with intravenously administered bromocriptine. However, the bromocriptine-induced increase in firing was also suppressed by domperidone, and decrease in firing was inhibited by SCH23390. These findings suggest that talipexole acts as a D2 agonist on the striatal neurons receiving input from substantia nigra pars compacta and increases firing when intravenously applied.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind cross-over placebo-controlled trial of the effects of bromocriptine on psychomotor function, cognition, and mood in de novo patients with Parkinson??s disease

The effects of bromocriptine on potentially dissociable functions were investigated in this double-blind placebo-controlled trial in previously untreated Parkinsonian patients. Bromocriptine-induced reductions in response time were independent of variations in the complexity of the cognitive or motor programming components of reaction time tasks. These results suggest that bromocriptime speeds up response initiation, and it may also improve some "early" visual processes. No clear-cut verbal memory, visuospatial or general intellectual changes were produced by bromocriptine; however, further evaluation of the effects of bromocriptine on "executive" cognitive functions is clearly required. Psychiatric distress was significantly reduced when the active drug was administered. While mood improvements could not be statistically dissociated from motor improvements, review of the literature suggested that decreased emotional distress may have arisen through bromocriptine's action on neural circuits modulating mood. Some clinical implications of bromocriptine's effect on mood are mentioned.

Protein kinase C regulation of prolactin gene expression in lactotroph cells: involvement in dopamine inhibition.

The role of protein kinase C (PKC) on dopamine inhibition of PRL messenger RNA (mRNA) levels was studied in anterior pituitary cells kept in primary culture. PKC was desensitized by long-term exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA). Effectiveness of PKC desensitization was confirmed by the fact that after TPA pretreatment, short-term (1-h) exposure to TPA was no longer able to trigger PRL release. In contrast, the capacity of nonreceptor-mediated secretagogues as depolarization with 48 mM K+ to release the hormone was preserved. Pretreatment with TPA did not affect basal PRL mRNA levels. In contrast, it significantly reduced the dose-dependent inhibition of PRL mRNA induced by 1 nM bromocriptine after a 4-day incubation period. Since dopamine inhibition of PRL release is mediated by several second messager pathways, including cAMP, inositol phosphates, and Ca2+, we investigated whether PKC depletion was able to interact with direct stimulation of these pathways. Pretreatment with PKC suppressed stimulation of PRL mRNA levels induced by either Forskolin (FK) or 8Br-cAMP. In parallel, it reduced basal as well as FK stimulated intracellular cAMP levels. In addition, chronic exposure to TPA completely suppressed PRL mRNA inhibition induced by nifedipine, a dihydropyridine antagonist which blocks voltage-dependent Ca2+ channels. TPA desensitization also affected the action of bromocriptine, FK or nifedipine on PRL release measured under the same conditions. The data indicate that endogenous PKC can interfere with the regulation of PRL gene expression induced by both cAMP and Ca2+ pathways, two second messengers associated with the action of dopamine in lactotroph cells.

Contribution of Spinal Dopamine Receptors to the Hypotensive Action of Bromocriptine in Rats

Bromocriptine, a dopamine (DA) receptor agonist, has been reported to have hypotensive effects in anesthetized and conscious normotensive rats but its mechanism of action is still not fully understood. Therefore, we studied the changes in mean arterial blood pressure (MAP) and heart rate (HR) elicited by an intravenous (i.v.) administration of bromocriptine (150 micrograms/kg), in either pentobarbital-anesthetized or conscious normotensive rats, pretreated with either i.v. (0.3 mg/kg) or intrathecal (i.t.) (93 nmol) domperidone, a DA receptor antagonist that does not cross the blood-brain barrier. In these preparations, i.v. administration of bromocriptine elicited dose-dependent decreases in MAP and rises in HR. The hypotensive effect was antagonized partially by i.t. and fully by i.v. domperidone. However, the latter compound did not modify the tachycardia, which could be blocked by propranolol (0.5 mg/kg i.v.). In rats pretreated with the latter beta-adrenoceptor antagonist, bromocriptine produced only a decrease in blood pressure that was inhibited by i.v. and i.t. domperidone. These results suggest that, in anesthetized and conscious normotensive rats, the hypotension induced by systemic administration of bromocriptine is fully mediated by DA2 dopamine receptors, which are located partly within the spinal cord and partly in the peripheral circulation.

PET studies with l-[1-11C]tyrosine, l-[methyl-11C]methionine and 18F-fluorodeoxyglucose in prolactinomas in relation to bromocryptine treatment

Aspects of metabolism in prolactinomas were investigated by positron emission tomography using L-[1-11C]tyrosine, L-[methyl-11C]methionine and 18F-fluorodeoxyglucose (18FDG). Using L-[1-11C]tyrosine, four patients were monitored prior to and 18 h after an injection of 50 mg bromocriptine. At 18 h after bromocriptine intervention, L-[1-11C]tyrosine uptake into tumour was reduced with 28% (P less than 0.07). A correlation analysis of the bromocriptine-induced decrease in L-[1-11C]tyrosine uptake and the reduction of serum prolactin levels indicated that the action of bromocriptine on prolactin synthesis and prolactin release is not coupled. In the untreated situation, the four patients were investigated with 18FDG as well, but the prolactinomas could not be visualized. Three untreated patients were studied with L-[methyl-11C]methionine. The tumour-imaging potential of L-[methyl-11C]methionine and L-[1-11C]tyrosine appeared to be nearly equivalent for prolactinomas. Unlike prolactinoma tissue, the salivary glands showed a pronounced preference for L-[1-11C]tyrosine as compared to L-[methyl-11C]methionine. L-[1-11C]tyrosine is a valuable tool to obtain information on the metabolism and treatment of prolactinomas.

Adenohypophysis hormone gene products in 14 pituitary adenomas : Analysis by immunohistochemistry and Northern blotting

We investigated 14 pituitary adenomas (10 silent adenomas; 3 prolactinomas and one GH-secreting tumor) for the presence of hormone gene transcripts (Northern blot) as well as for translation products (immunohistochemistry). The GH-secreting tumor was shown to express the genes coding for GH and PRL and to synthesize the corresponding hormones. In the cases of prolactinomas, immunohistochemical data demonstrated the synthesis of prolactin only. In addition to the PRL gene, Northern blot analysis revealed the transcription of the alpha-subunit gene in one case. Hormone genes were found to be expressed in 7 out of the 10 silent tumors, whereas no hormone synthesis was detected in any of these tissues. LH-beta mRNA was found in 3 cases, FSH-beta mRNA in 5 cases and alpha-subunit gene was shown to be expressed in one case. Surprisingly, the level of expression of the FSH-beta gene was higher than in normal tissue. This study confirms that some so called "silent" adenomas are expressing alpha- and/or beta-subunit glycoprotein hormone genes, even if no hormone is synthesized. The therapeutic action of bromocriptine described in some "silent" adenomas cases could be related to that hormone gene expression potentiality.

Dopamine D1- and D2-receptor interaction in turning behaviour induced by dopamine agonists in 6-hydroxydopamine-lesioned rats.

The selective dopamine D2-antagonist sulpiride potentiated contralateral circling behaviour induced by the D1-agonist CY 208-243 in rats with unilateral lesions of substantia nigra, but reduced the effects of the selective D2-agonist bromocriptine. Similarly, the D1-antagonist SCH 23390 tended to increase the effects of bromocriptine but markedly inhibited CY 208-243 induced turning. The mixed D1/D2-antagonist fluphenazine was effective in reducing circling behaviour induced by either agonist, whereas pimozide (D1/D2) inhibited only the actions of bromocriptine. These results indicate that the actions of CY 208-243 and bromocriptine are mediated via distinct but interacting receptor subtypes.

The mode of action of bromocriptine following pretreatment with reserpine and ?-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)

The antiparkinson action of bromocriptine in combination with levodopa

The antiparkinson action of bromocriptine in combination with levodopa

The effects of bromocriptine on the pulsatile pattern and the circadian profile of gonadotropins and testosterone secretion in normal adult men

To investigate the effects of bromocriptine on the secretion mechanism of pituitary gonadotropins and testosterone, 5 mg of bromocriptine was administered to five young adult men who were normal in their endocrinological states. Blood samplings were taken from two hours before until six hours after the administration every 15 min., and after that, blood samplings were continued until 21 hours every one hour by an intravenous indwelling catheter. Serum FSH, LH, prolactin and testosterone levels were determined by RIA, and the changes of the pulsatile patterns of FSH and LH, and the circadian profile of these hormones by the administration of bromocriptine were analysed. Serum prolactin levels decreased significantly (p less than 0.005) from two hours after the administration of bromocriptine and remained in a very low range until the end of the experiment. The basal levels of FSH showed a significant decrease from two to six hours after the administration (p less than 0.005). Also the basal levels of LH showed a significant decrease from two to six hours after the administration (p less than 0.005). However, the basal levels of serum FSH and LH did not show significant decreases after that until the end of the experiment. No significant change was observed in the amplitude or the frequency of the pulsatile patterns of FSH and LH until six hours after the administration of bromocriptine. The serum levels of testosterone were also significantly decreased from two to six hours after the administration (p less than 0.005), but they did not show a significant decrease after that until the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between thioridazine and bromocriptine in a patient with a prolactin-secreting pituitary adenoma

Reported herein is the possible interaction between two drugs used to treat a man with a large prolactin-secreting pituitary adenoma. The patient had a long history of schizophrenia that was treated with many different medications, including phenothlazines. Evaluation of progressive lethargy led to the discovery of a large parasellar tumor and a prolactin level of 7,981 ng/ml. His serum prolactln level fell to the 400 ng/ml range during bromocriptine therapy but rose whenever the antipsychotic thioridazine was added to his regimen. A marked deterioration of his visual fields was noted after 3 months' therapy with both drugs, and this abnormality resolved five days after the thioridazine was stopped. The use of dopamlne antagonists such as thioridazine in patients with prolactinoma may interfere with bromocriptine's action, resulting in potentially serious complications.

Plasma growth hormone suppressive effect of bromocriptine in acromegaly. Evaluation by plasma GH day profiles and plasma GH concentrations during oral glucose tolerance tests.

In most studies reporting favourable results of chronic bromocriptine treatment in acromegaly, plasma GH levels are measured at fixed intervals during the day. Negative results are reported in one major study measuring plasma GH levels during oral glucose tolerance tests (Lindholm et al., 1981). This study does not mention the time interval between the last dose of bromocriptine and the performance of an OGTT, but due to the short duration of action of bromocriptine this may be critical. Therefore, in the present report the plasma GH suppressive effect of bromocriptine in acromegaly is studied using plasma GH day-profiles as well as OGTT's during continued bromocriptine administration and OGTT's at two different time intervals after the last dose of bromocriptine. Twelve patients with clinically active acromegaly were treated with 10-20 mg bromocriptine for 6-9 months. After 6-9 months during continued bromocriptine administration the plasma GH suppressive effect of bromocriptine was evaluated by the mean of four plasma GH determinations during the day and by the mean of seven plasma determinations during oral glucose tolerance tests (OGTT's) performed 1 h, 10 h and 34 h after the last dose. The percentage decrease of the mean plasma GH level during the day induced by chronic bromocriptine treatment showed a good correlation (r = 0.86, P less than 0.001) with the percentage decrease of the mean plasma GH level during OGTT, if the post-treatment test was carried out one hour after the last dose of bromocriptine.(ABSTRACT TRUNCATED AT 250 WORDS)

One minute of bromocriptine irreversibly inhibits prolactin release for hours

The ability of the dopamine receptor antagonist spiperone to block dopamine- or bromocriptine-inhibited prolactin release from dispersed rat anterior pituitary cells was tested in vitro. In a continuously perfused cell column apparatus, spiperone rapidly counteracted the inhibitory effect of dopamine but was unable to reverse the inhibitory effect of the potent dopamine agonist bromocriptine when added 30 min after bromocriptine. However, spiperone completely blocked the bromocriptine action if added simultaneously with bromocriptine. These basic data were confirmed, and the time relationships more accurately defined, in static incubations of monolayer cultures. Spiperone blocked the typical inhibition of prolactin release by bromocriptine only if the cells were pre- or coincubated with the antagonist. If spiperone was added as soon as 1 min after bromocriptine, the antagonist was unable to block the complete expression of the bromocriptine inhibition. These results suggest that bromocriptine is a functionally irreversible dopamine agonist for at least the 4 h of these studies.

Inhibitory action of bromocriptine and tamoxifen on the growth of human pituitary tumors in soft agar.

Human pituitary tumors were studied in vitro using the clonogenic stem cell assay. Mechanical dispersion was used to prepare single cell suspensions for plating. Colony formation occurred in 21 of 24 tumors plated. Bromocriptine (Brc; 10 nM) added to the medium resulted in a significant decrease in the number of colonies formed in 5 of 10 prolactinomas and in 1 tumor secreting both PRL and GH. However, PRL secretion was decreased in 8 of 9 tumors tested. Brc had no effect on either colony formation or hormone secretion in other tumors secreting GH (n = 2), ACTH (n = 2), or FSH (n = 1) or in nonsecreting tumors (n = 4). Tamoxifen (Tam; 10(-7) M) inhibited colony formation in 6 of 10 prolactinomas and in 1 tumor secreting GH and PRL. PRL secretion into the medium correlated with the changes in the number of colonies. Tam was not effective in any other tumor tested. In only 1 instance was there a synergistic action between Brc and Tam on inhibition of colony formation. Brc, but not Tam, caused a significant decrease in the size of the colonies formed from cells of PRL-secreting tumors. The least numbers of colonies per plate were found in 3 prolactinomas from patients treated preoperatively with Brc. We conclude that the soft agar clonogenic assay technique is a feasible method to study human pituitary tumors in vitro. Both Brc and Tam inhibited colony formation in this system in a significant proportion of tumors. The potential antiproliferative action of Tam in vivo needs to be studied in view of these results.

Atresia of preovulatory follicles in rats treated with sodium pentobarbital: effects of bromocriptine.

Preovulatory rat follicles matured during normal cycles go gradually into atresia if ovulation is inhibited by injections of sodium pentobarbital from proestrus for 2 or more days. The gradual process of atresia is characterized by a rapid decrease of follicular estrogen secretion within 1 day after the start of pentobarbital injections. Furthermore, structural signs of atresia appear in predictable order during the ensuing 3 days. In the present study experiments are described demonstrating clear and reproducible effects of daily treatment with bromocriptine on the above processes. Bromocriptine delayed the decrease of follicular estrogen production by about 1 day and also delayed the occurrence of structural signs of atresia. Further study revealed that the effect on estrogen secretion was likely through the action of bromocriptine to suppress prolactin secretion. It thus seems that prolactin is involved in the mechanisms whereby preovulatory follicles lose their capacity to secrete estrogen. This effect of prolactin may occur at the ovarian level and, thus, be involved in reduced secretion of estrogen by the ovaries during physiological or pathological hyperprolactinemic states.

Dopaminergic modulation of evoked vasopressin release from the isolated neurohypophysis of the rat

1. Neurointermediate lobes of rat pituitaries were incubated in Locke or Krebs solution, and the vasopressin released into the medium was assayed on the blood pressure of the pithed rat or by a radioimmunological procedure. Release of vasopressin over resting levels was evoked either by incubation with 60 mM KCl (high K) solution or by electrical stimulation of the pituitary stalk. Two different kinds of electrical stimulation were carried out. Procedure A (1 ms, 10 Hz, 5 times for 1 min within 10 min) induced a vasopressin overflow which was greatly calcium-dependent but only insignificantly sensitive to tetrodotoxin (TTX). Procedure B (0.2 ms, 15 Hz, 10 s trains with 10 s intervals for 10 min) evoked a completely calcium-dependent and TTX-sensitive vasopressin overflow. 2. The vasopressin output evoked by high K was unaltered in the presence of dopamine 10 μM or apomorphine 100–300 μM. 3. The vasopressin overflow evoked by stimulation procedure A was decreased by 50–67% in the presence of apomorphine 10 μM. However, the dopamine antagonists sulpiride 1–100 nM and flupenthixol 10 μM also inhibited the vasopressin release by 30–40%. Nevertheless, the combination of apomorphine 10 –M with sulpiride 1 nM or flupenthixol 10 μM resulted in a significant increase of the vasopressin release if compared with apomorphine (or sulpiride) alone. Thus, apomorphine antagonized the inhibition of the vasopressin release by the dopamine antagonists, and these drugs blocked the inhibitory action of apomorphine, indicating complex but specific agonist-antagonist interactions. Naloxone 1 μM which failed to change vasopression overflow, prevented the inhibitory effect of sulpiride 100 nM. This indicates that the inhibition of vasopressin release by sulpiride may be mediated by an increased secretion of endogenous opioids probably from the intermediate lobe. 4. The vasopressin overflow evoked by stimulation procedure B was decreased by 20% in the presence of apomorphine 100 nM or 1 μM. Bromocriptine had a biphasic effect on vasopressin release, stimulating it by 20% at 1 nM and inhibiting it by 35% at 3 μM. Sulpiride 10 nM to 1 μM stimulated the vasopressin release by about 20% and antagonized the inhibitory actions of apomorphine and bromocriptine in a concentration-dependent manner. However, sulpiride 100 nM had no effect on the facilitatory action of bromocriptine 1 nM. 5. These findings suggest a complex dopaminergic modulation, in the neurointermediate lobe, of vasopressin release evoked by intermittent electrical stimulation, and support a physiological role for the intrinsic dopaminergic fibres described by others. We propose the existence of two dopamine receptors, one mediating inhibition of vasopressin release (activated by apomorphine, bromocriptine at high concentrations or endogenous dopamine, and blocked by sulpiride), and the other one mediating facilitation of release (activated by endogenous dopamine, and blocked by flupenthixol). It is further suggested that under the field-stimulation conditions of procedure A an endogenous opioid is secreted which inhibits vasopressin release and which itself is under inhibitory control by endogenous dopamine.

Bromocriptine suppresses ACTH secretion from human pituitary tumour cells in culture by a dopaminergic mechanism.

Bromocriptine (0.13-13 microM) significantly inhibited ACTH secretion in a dose-dependent manner when added to cell cultures of a human corticotrophic adenoma for 24 h. Haloperidol (13 microM), but not serotonin (13 microM), blocked this inhibition but had no significant effect when added alone. In addition, dopamine (10 microM) reduced ACTH secretion during a 4-h incubation, whereas serotonin (0.01-10 microM) was ineffective. An ectopic ACTH secreting lung carcinoid was non-responsive to doses of bromocriptine up to 13 microM. These results demonstrate a direct suppressive action of bromocriptine on a human pituitary corticotrophic adenoma through dopaminergic rather than serotoninergic mechanisms.

Increase in rat striatal acetylcholine content by bromocriptine: Evidence for an indirect dopaminergic action

Bromocriptine, at the optimal dose and time of 4 mg/kg, 90 min, increased the content of acetylcholine in the rat striatum by about 30% without affecting the acetylcholine content in other brain regions. Striatal choline acetyltransferase and acetylcholinesterase activities and sodium-dependent high affinity choline uptake were not affected by the in vivo administration or the in vitro incubation with even high amounts of the drug. The increase in striatal acetylcholine by bromocriptine was mediated through the dopaminergic system since pretreatment with pimozide or penfluridol, powerful dopamine receptor antagonists, completely prevented the effect while parachlorophenylaline and phenoxybenzene pretreatment were ineffective. The action of bromocriptine, differently from that of apomorphine, was also blocked upon inhibition of tyrosine hydroxylase by alphamethylparatyrosine, suggesting that intact catecholamine synthesis is necessary for the drug to act. The requirement of dopamine by bromocriptine was further indicated when no potentiation of the cholinergic response to bromocriptine occurred following induction of dopamine receptor supersensitivity by long-term 6-hydroxydopamine lesion of the nigroneostriatal pathway. On the other hand, evidence is presented to show that bromocriptine acts in synergism with dopamine as the latency period for the onset of bromocriptine's cholinergic action was significantly decreased when it was administered in combination with a subthreshold dose of L-dopa, the dopamine precursor. There also was no summation of bromocriptine's increase with apomorphine's increase in striatal acetylcholine content at supramaximal doses possibly indicating that the same population of intrastriatal cholinergic neurons is the common target of both drugs. It is proposed that bromocriptine exerts an inhibitory effect on the striatal cholinergic neurons through a stimulation of the dopaminergic system but, differently from apomorphine, it requires the presence of endogenous dopamine for its action.