Dopamine Agonist Bromocriptine Research Articles

Inhibitory effects of the dopamine agonists quinagolide (CV 205-502) and bromocriptine on prolactin secretion and growth of SMtTW pituitary tumors in the rat

The SMtTW tumor, a spontaneous PRL-secreting transplantable tumor, is the only available animal model sensitive to dopamine agonists. This model has been used to compare the long term in vivo effects of CV 205-502 (CV) and bromocriptine (BR) on PRL secretion and tumor growth. These two drugs were given for 2 months to female Wistar-Furth rats bearing either small or large tumors 4 and 6 months after the graft. Untreated grafted rats served as control. In all rats treated with 5 or 10 mg/kg.day BR or 0.3 mg/kg.day CV, a normalization of plasma PRL levels was observed whatever the pretreatment levels (plasma PRL or CV or BR-treated rats, < 15 ng/ml vs. 28253 ng/ml in control rats 8 months after graft). An inhibition of tumor growth was found for both small and large tumors, but the tumors never disappeared completely (mean tumor weights at autopsy, 440 and 660 mg in BR and CV groups vs. 5270 mg in control group 8 months after graft). Experiments performed with increasing doses of BR (0.15-5 mg/kg.day) or CV (0.03-0.6 mg/kg.day) indicated that CV is effective at doses 5-10 times lower than those of BR. A shrinkage under treatment and a regrowth after drug withdrawal were demonstrated for large tumors by in vivo ultrasonographic measurements of tumor size. Histological and ultrastructural effects were similar for the two drugs: decrease in hemorrhage, reduction of the cell size and secretory activity, increase in immunoreactive PRL cellular content, and inhibition of exocytosis. There was no difference in the PRL mRNA content of treated and untreated tumors, as assessed by in situ hybridization. In conclusion, CV and BR exhibit similar inhibitory effects on tumor growth and PRL secretion. These effects are rapidly and fully reversible after drug withdrawal. The present results give a complete account of the actions of the two dopamine agonists under conditions comparable to those used in the treatment of human prolactinomas.

Mechanism of the prolactin rebound after dopamine withdrawal in rat pituitary cells.

To study the mechanism underlying the effect of dopamine withdrawal on prolactin release, continuous perfusion experiments were performed on rat lactotroph-enriched primary cultures. Removal of dopamine (10(-7) M) after a short-term application (15 min) produced a rebound of prolactin secretion, which was enhanced by pretreatment of the cell culture with 17 beta-estradiol (10(-8) M for 48 h). Ca2+ channel blockade by Co2+ (1 mM) abolished the rebound in prolactin release. An increase in intracellular adenosine 3',5'-cyclic monophosphate by either forskolin (5 microM) or 3-isobutyl-1-methylxanthine (100 microM) enhanced the prolactin rebound after dopamine withdrawal. Application of thyrotropin-releasing hormone (10(-7) M) increased the prolactin rebound after dopamine withdrawal with a maximum effect obtained by commencing treatment immediately after removal of dopamine. Pretreatment of cell cultures with pertussis toxin (100 ng/ml, for 10 h) totally abolished the effects of dopamine on prolactin secretion. The dopamine agonist bromocriptine (10(-9) M) significantly decreased prolactin secretion, but no rebound effect was observed after its removal. We conclude that the rebound of prolactin release after dopamine treatment involves the influx of Ca2+.

Reduction of dopamine synthesis inhibition by dopamine autoreceptor activation in striatal synaptosomes with in vivo reserpine administration.

In an attempt to clarify the mechanisms by which dopamine (DA) autoreceptor activation inhibits DA synthesis, the efficacy and potency of the D2 DA agonists bromocriptine, lisuride, and pergolide, and the D1-D2 DA agonist apomorphine were studied in rat striatal synaptosomes, in which the rate of DA synthesis (formation of 14CO2 from L-[1-14C]tyrosine) was increased 103% by treating the animals from which the synaptosomes were obtained with reserpine (5 mg/kg i.p. twice, 24 and 2 h before they were killed), using the striatal total homogenate as the standard synaptosomal preparation. The increase in DA synthesis evoked by reserpine was additive with that produced by treatment of the synaptosomes with dibutyryl cyclic AMP, suggesting that, not a cyclic AMP-dependent, but possibly a Ca(2+)-dependent mechanism was involved. The DA agonists showed a concentration-dependent inhibition of DA synthesis in the control synaptosomes, which was antagonized by the selective D2 DA antagonist (-)-sulpiride. In the synaptosomes with increased rate of DA synthesis obtained from the rats treated with reserpine, the concentration-response curves of DA synthesis inhibition for the other DA agonists were shifted to the right, and the effect of bromocriptine was completely eliminated, whereas bromocriptine antagonized the effect of apomorphine. The increased rate of DA synthesis was not preserved in the striatal P1 + P2 fraction obtained from the reserpine-treated rats, but the effects of the DA agonists were still reduced to the same degree as those in the total homogenate. (-)-Sulpiride did not enhance DA synthesis in synaptosomes from the reserpine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of vasopressin gene expression: Changes in the level, but not the size, of vasopressin mRNA following endocrine manipulations

1. Regulatory interactions between the hypothalamoneurohypophyseal vasopressin (VP) axis and the endocrine systems of the anterior pituitary have been investigated in the rat by observing changes in VP mRNA expression following endocrine manipulations. 2. An increase in the level, but not size, of VP mRNA was found in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus and in the neurointermediate lobe (NIL) of the pituitary following hypothyroidism (induced by drinking 6-n-propyl-2-thiouracil; PTU) and adrenalectomy. Hypothyroidism induced by alternative procedures (surgical thyroidectomy or PTU injections) did not exert similar effects. 3. Treatment with the dopamine agonist bromocriptine to reduce prolactin secretion raised levels of VP mRNA in the NIL only. Castration did not up-regulate VP mRNA levels. 4. Since the observed effects on VP mRNA levels occur in the absence of changes in plasma osmolality, these results provide evidence of nonosmotic regulation of VP gene expression, an effect which is observed most clearly in the NIL pool of VP mRNA. Furthermore, the effects are distinct from changes in VP mRNA levels associated with raised plasma osmolality since the VP mRNA size was not increased.

Free Radicals and Their Scavengers in Parkinson’s Disease

In recent years, it has been shown that active oxygen species or free radicals are closely involved in various diseases. Accumulating information supports the hypothesis that oxidative stress involving lipid peroxidation may contribute to the pathogenesis of Parkinson's disease. The objectives of this review are, first, to discuss some of the roles of active oxygen species in the pathogenesis of Parkinson's disease; second, to examine the possible effects of antioxidants as the protective therapy for Parkinson's disease, and, third, to summarize results from in vitro experiments that the dopamine agonist bromocriptine, used for treatment of Parkinson's disease, has a strong antioxidative effect.

Catecholamines in Autistic Disorder: Effects of Amisulpride and Bromocriptine in a Controlled Crossover Study

ABSTRACT The biochemical effects on catecholaminergic systems of the dopamine antagonist amisulpride and the dopamine agonist bromocriptine were evaluated in a double-blind, randomized, crossover study in children with autistic disorder. Plasma levels of dopamine, norepinephrine, and epinephrine; urinary concentrations of homovanillic acid (HVA), vanillyImandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG); and plasma prolactin were measured. At doses of amisulpride and bromocriptine that had the expected opposing effects on plasma prolactin, the drugs' effects on the catecholaminergic systems were similar. Both agents unexpectedly lowered urinary HVA (total, free, and sulfated) although only amisulpride decreased the HVA levels significantly. This paradoxical decrease in HVA levels suggests that both dopamine agonists and antagonists could act on autoreceptors or presynaptic dopaminergic receptors in the central nervous system. There was no significant action of either drug on plasma epinephrine, urinary VMA, or urinary MHPG, suggesting that neither drug altered norepinephrine or epinephrine systems; however, a weak increase of plasma norepinephrine occurred after amisulpride treatment, consistent with effects observed with other neuroleptics. Neither agent altered plasma dopamine, suggesting that peripheral dopamine metabolism was unchanged. The clinical effects of amisulpride and bromocriptine have been reported to be unexpectedly complementary. The complementary clinical effects of a dopamine agonist and dopamine antagonist might speculatively be related to their similar action on dopamine autoreceptors, leading to a correction of the dopaminergic hyperactivity that has been postulated in autistic children.

Women with prolactin-producing pituitary adenoma show decreased serum placental lactogen during pregnancy.

Prolactin (PRL), growth hormone (GH), placental lactogen (PL), chorionic gonadotropin (CG), estradiol (OE), progesterone (P4) and sex hormone-binding globulin (SHBG) were measured in serum throughout gestation in 9 women with PRL-producing pituitary adenomas. They had been treated at least 1 year with the dopamine agonist bromocriptine before pregnancy occurred. All women bore healthy babies of normal birthweight. Their PRL levels did not show the successive increase seen in normal pregnancies; serum PRL was unphysiologically increased in all patients up to the 20th week of gestation, whereafter PRL levelled off and fell within the normal range. Serum PL levels were lower in the women with prolactinoma compared to healthy pregnant women, despite normal placental weight. The serum GH levels in the patients determined with an immunoassay based on a monoclonal antibody, were low or nondetectable, similar to healthy pregnant controls. In contrast, high molecular weight GH in serum as determined with a monoclonal antibody which also recognizes PL appeared to be increased in comparison with healthy pregnant women. The serum levels of CG, OE, P4 and SHBG were all within the normal range. These results show that the unphysiological secretion of PRL in pregnant women with PRL-producing pituitary adenomas is associated with decreased serum levels of PL.

Sensitization, response fluctuation and long-term effect of SKF-82958 and bromocriptine in the hemi-parkinsonian rat

Rats with a unilateral 6-hydroxydopamine lesion of substantia nigra were treated with the dopamine agonist SKF-82958 (D 1 receptor selective) or bromocriptine (D 2 receptor-selective) and their circling response recorded. Both of the compounds induced an acute episode of rotation directed away from the lesioned side. Consecutive daily treatments with either compound usually resulted in a significantly increased average response (sensitization) over a 3- to 6-day treatment period. But nearly all animals treated with low doses of either SKF-82958 or bromocriptine exhibited one or more days when they were totally unresponsive to drug treatment. Response fluctuations thus were not exclusively associated with D 1 or D 2 receptor agonist treatment. When subsequently tested, undrugged, in the drug-associated environment, 2,4 and 10 weeks after their last drug treatment, rats that had previously been treated with SKF-82958 exhibited rapid contralateral rotation while rats that had previuosly been treated with bromocriptine showed no such undrugged rotation. This result is consistent with previous findings that the D 1 receptor agonist, SKF-38393, but not the D 2 receptor agonist, quinpirole, had long-term behavioral effect in nigral rats, and suggests that persistent motor consequences of limited treatment with dopamine receptor agonists are D 1 receptor-related.

Influences of dopamine receptors on chewing behaviour in rats

1. 1. Intraperitoneal (i.p.) injection of different doses of pilocarpine induced purposeless chewing in rats. Physostigmine (i.p.), but not neostigmine (i.p.) also induced chewing behaviour. 2. 2. Subcutaneous (s.c.) pretreatment of animals with the D-1 receptor blocker SCH 23390 decreased the number of chews induced by pilocarpine. 3. 3. The D-2 dopamine antagonist sulpiride (i.p.) and anticholinergic atropine (i.p.) pretreatment also decreased the frequency of chews induced by the drug. 4. 4. The response induced by pilocarpine (1 mg/kg i.p.) also was dose-dependently decreased in animals pretreated with apomorphine (0.25-1 mg/kg s.c.). 5. 5. Administration of low doses of apomorphine (s.c.) also induced chewing, which was decreased with increasing the doses of the drug. 6. 6. Chewing-induced by apomorphine was decreased by sulpiride or atropine and increased by SCH 23390 pretreatment. 7. 7. Single administration of D-2 dopamine agonist bromocriptine also showed a slight but significant purposeless chewing, which was decreased by sulpiride pretreatment. 8. 8. Single administration of D-2 agonist quinpirole, D-1 agonist SKF 38393 or D-1 antagonist SCH 23390, but not sulpiride caused a slight chewing. 9. 9. It may be concluded that D-1 or D-2 activation exert opposite influences on chewing behaviour in rats, although to prove this effect more elucidation is needed.

Protein kinase C activity and expression in normal and adenomatous human pituitaries.

Protein kinase C (PKC) activity and expression were measured in 54 adenomas (prolactin (PRL)-, growth hormone (GH)- and non-secreting), 1 of them obtained from a patient treated with the dopamine agonist bromocriptine and 2 from patients treated with the somatostatin analog octreotide. They were also measured in normal human and rat pituitaries. Total PKC activity was measured by incorporation of 32P into histones, and PKC expression by dot blot immunoquantification using purified PKC as a standard. Both enzyme activity and expression were higher in adenomatous pituitaries than in normal human or rat pituitaries. PKC expression in GH-secreting and non-secreting tumors was significantly higher than that in PRL-secreting tumors. Furthermore, it was significantly higher invasive tumors than in non-invasive tumors. In the 3 adenomas which were obtained from patients treated with bromocriptine or octreotide and which were used for PKC-activity measurement, particulate- and soluble-PKC activities were significantly lower than those measured in non-treated adenomas.

Enhancement of dopaminergic agonist bromocriptine of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

The effects of the dopamine agonist 2-bromo-alpha-ergocryptine methanesulfonate (bromocriptine) on the incidence, number and histology of gastric cancer induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats. Rats were given 1 or 2 mg kg-1 body weight of bromocriptine subcutaneously every other day in depot form after 25 weeks of oral treatment with MNNG. Prolonged administration of bromocriptine at both dosages every other day resulted in a significant increase in the incidence and number of gastric cancers of the glandular stomach by week 52. Bromocriptine treatment did not influence the histological type of gastric cancer, but caused a significant increase in the labelling index of epithelial cells of the antrum. These findings indicate that the dopamine agonist bromocriptine promotes gastric carcinogenesis, and that this effect may be related to its effect in increasing proliferation of epithelial cells in the antral mucosa.

Isolation of cleaved prolactin variants that stimulate DNA synthesis in specific cell types in rat pituitary cell aggregates in culture

Using an affinity column of monoclonal antibodies against rat prolactin (PRL), PRL immunoreactive material secreted by rat pituitary aggregate cell cultures was purified in milligram amounts from the culture medium. Further purification of the PRL immunoreactive molecules was achieved by anion-exchange and reversed-phase h.p.l.c. At least four variants could be distinguished which showed PRL-like bioactivity in the Nb2 lymphoma bioassay. On SDS/PAGE two variants migrated as single bands under both reducing and non-reducing conditions. The two other variants migrated as single bands under non-reducing conditions, but yielded under reducing conditions two fragments, the larger of which had molecular masses of approx. 16 and 17 kDa respectively. These variants were therefore considered to be cleaved PRL (clPRL) variants, and were designated clPRL-1 and clPRL-2 respectively. These variants were not artefactually produced at low pH during the h.p.l.c. purification step. Each of the clPRLs represented about 0.6-1.0% of total PRL. The cleavage site of clPRL-1, determined by N-terminal and C-terminal amino acid sequence analysis, was in the large disulphide loop between Tyr-145 and Leu-146. Purified clPRL-1 added to pituitary aggregate cell cultures from 14-day-old female rats in the presence of the dopamine agonist bromocriptine increased [3H]thymidine incorporation into DNA in gonadotrophs and thyrotrophs, but not in other pituitary cell types. Under the same experimental conditions the main forms of PRL and clPRL-2 were inactive. These data demonstrate that PRL is cleaved within the pituitary gland between specific amino acid residues, and that PRL cleaved between Tyr-145 and Leu-146 may have a specific biological role as a paracrine growth regulator in this tissue.

Differentiation of the melanotrophic cells of rat pituitary primordium in organotypic culture in defined medium

Organotypic cultures, in defined medium, of pituitary primordia obtained from 15-day-old rat fetuses were performed in order to study the in vitro differentiation of melanotrophic cells. The morphological and ultrastructural features of the transplants resembled those of the gland developing in vivo. In situ hybridization on semi-thin sections, using a 35S-labelled oligonucleotide probe, revealed pro-opiomelanocortin-mRNA-containing cells on the first day of culture in the anterior lobe and after 2-3 days in the intermediate lobe. Immunoperoxidase labelling of adjacent sections showed that the same cells reacted with antibodies against alpha-melanocyte-stimulating hormone (alpha MSH), gamma 3MSH and adrenocorticotropic hormone in both lobes. The pro-opiomelanocortin-mRNA-containing cells formed progressively conspicuous areas in the intermediate lobe, which was almost uniformly labelled after 6 days. In the anterior lobe, these cells remained scattered in small cell groups, and colloidal gold immunolabelling showed the progressive disappearance of alpha MSH labelling from the secretory vesicles in cells exhibiting morphological features of adult corticotrophic cells. Both the alpha MSH content of the explants and alpha MSH release into the culture medium increased with time. Treatment with the dopamine agonist bromocriptine induced a strong dose-dependent decrease in alpha MSH secretion, which was significant after 3 days in culture, indicating that dopamine D2 receptors are able to regulate hormonal release of melanotrophic cells at early stages. This system constitutes a suitable model for further studies of factors controlling cell differentiation and cellular interactions involved in histogenesis.

Effect of dopamine agonist medication on prolactin producing pituitary adenomas

Conventional light microscopy, immunocytochemistry, electron microscopy and in situ hybridization were used to evaluate the effect of dopamine agonists (bromocriptine-LAR and bromocriptine) on the morphology of surgically removed prolactin (PRL)-producing pituitary adenomas. Dopamine agonist therapy resulted in decrease of serum PRL, clinical improvement and tumour shrinkage. Using light and electron microscopy cellular atrophy, interstitial and perivascular fibrosis were noted; in several tumours connective tissue accumulation was pronounced. The cellular response was not uniform. In some adenomas populations of large cells and small cells were distinguished. The large cells contained immunoreactive PRL and expressed the PRL gene indicating resistance to dopamine agonists. It appears that these cells retained the potential to secrete PRL and proliferate despite exposure to dopamine agonists. In the small cells, PRL immunoreactivity and PRL gene expression decreased providing evidence that both PRL release and synthesis were blocked. Small cells can persist in tumours after discontinuation of dopamine agonist medication suggesting these small cells are irreversibly suppressed and are not capable of regaining their endocrine function and proliferative capability. The formation of irreversibly suppressed PRL cells may explain why some PRL-producing adenomas do not recur after withdrawal of dopamine agonists.

Pharmacological characterization of dopamine receptors in parasympathetic innervation of rat heart

The action of dopamine agonists (apomorphine, bromocriptine, pergolide and quinpirole) on the bradycardia induced in vivo by electrical stimulation of the vagus nerves was studied in pithed rats pretreated with atenolol. The dopamine agonists decreased significantly the vagal-induced but not the acetylcholine-induced bradycardia. The first effect was blocked by (S)-sulpiride or domperidone but not by yohimbine, prazosin or SCH 23390. Both effects were antagonized by methylatropine. The data suggest the presence of presynaptic and/or ganglionic dopamine DA 2 receptors in the parasympathetic innervation of the rat heart, stimulation of which inhibits the release of acetylcholine.

Dopamine modulation of prolactin and vasopressin but not behavior on satiation of sheep

We have investigated the rapid changes in plasma prolactin and arginine vasopressin (AVP) associated with water satiation in ruminants. Sheep deprived of water for 72 h were allowed voluntary access to ad libitum water. Each sheep drank approximately 5 liters in a single draft. This was performed in a head-down position, which was maintained for approximately 2-3 min and ceased rapidly with an abrupt movement to the upright position. During dehydration, plasma sodium, osmolality, and AVP all increased significantly, but prolactin was unaffected. On rehydration, AVP fell to basal levels within 5 min, but prolactin increased as a short pulse, after which it rapidly fell again. Plasma sodium and osmolality returned to predehydration levels within 6 h of satiation. A possible role of dopaminergic mechanisms in these responses was investigated by the administration of the dopamine agonist bromocriptine or the antagonist metoclopramide. Neither of these agents had any observable effects on the drinking behavior of the sheep during water satiation. During metoclopramide treatment, dehydration was associated with a marked fall in prolactin, and on rehydration there was a prompt and very marked increase in prolactin level. There was also an exaggerated increase of AVP during dehydration and a decrease on rehydration. Bromocriptine had relatively little effect on prolactin responses but prevented the drinking-associated inhibition of AVP, demonstrating an unexpected dissociation between AVP secretion and the stereotyped drinking response.

Neuroleptic Malignant Syndrome: Occurrence in a Child after Reconstructive Surgery

The occurrence of the rare but potentially fatal neuroleptic malignant syndrome must be considered by the surgeon treating a patient who develops hyperthermia, mental abnormalities, autonomic instability, and muscle rigidity after exposure to phenothiazines or other neuroleptic drugs. The dopamine agonist bromocriptine appears to be the treatment of choice in adults and seemed to be effective and well tolerated in our patient. Although the syndrome cannot be prevented, recognition is crucial, since effective general and specific therapy is available. Differentiating neuroleptic malignant syndrome from malignant hyperthermia allows early appropriate treatment with bromocriptine.

Prolactin Stimulates the Release of Oxytocin in Lactating Rats: Evidence for a Physiological Role via an Action at the Neural Lobe

The present studies were designed to investigate whether prolactin (PRL) influences the secretion of oxytocin (OT) in lactating rats, and to test whether the previously reported inhibitory and stimulatory effects of dopamine-2 (D-2) agonists and antagonists, respectively, on OT release might be secondary to their respective inhibitory and stimulatory effects on the release of PRL. Intravenous administration of either rat (r) or ovine (o) PRL to lactating, nonsuckled rats increased basal plasma concentrations of OT. rGH was ineffective, but administration of oGH did produce some stimulation of OT release. Both oPRL and rPRL significantly enhanced the electrical stimulation-induced release of OT from isolated stalk-neurointermediate lobes, in vitro, without affecting the basal release of the peptide. oGH was ineffective on basal or stimulated in vitro OT release, and neither hormone altered basal or stimulation-induced release of vasopressin from these tissues. Both rPRL and oPRL reversed the inhibitory effect of the D-2 dopamine agonist bromocriptine. Immunoneutralization of circulating PRL with a highly specific antiserum abolished the increases in OT in response to either suckling or to administration of the D-2 dopamine antagonist domperidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of dopamine receptor involvement in rat feeding behaviour

1. The anorectic effect of dopamine agonists and antagonists were studied in rats. 2. Dopamine agonists bromocriptine, quinpirole or SKF 38393 treatment induced, a dose-dependent anorexia in rats. 3. Anorectic effect of bromocriptine was decreased in animals pretreated with pimozide (D-2 antagonist), but not by sulpiride (D-2 antagonist) or SCH 23390 (D-1 antagonist) pretreatment. 4. Anorexia induced by quinpirole was decreased by sulpiride or pimozide, but not by SCH 23390 administration. 5. While sulpiride and SCH 23390 failed to antagonize the anorectic response of SKF 38393, methergoline (5-HT antagonist) decreased anorexia induced by the drug. 6. A combination of quinpirole with SKF 38393 did not elicit potentiated anorectic response. 7. Decrease in food intake induced by bromocriptine, quinpirole or SKF 38393 was potentiated in reserpinized animals, although single administration of reserpine also induced a marked decrease in feeding. 8. Single administration of sulpiride, pimozide or methergoline did not change the feeding behaviour of rats, but SCH 23390 induced anorexia. 9. It is concluded that D-2 activation may induced inhibition of feeding and anorexia induced by SKF 38393 may be mediated through serotonergic mechanism(s).

Effects of Bromocriptine Treatment on Immune Responses and 3–Methylcholanthrene-Induced Tumorigenesis in Rats

Seven-week-old male Sprague-Dawley rats were given a single injection of 1.5 mg of 3-methylcholanthrene (3MC) to induce in situ fibrosarcomas. The rats were also treated with the dopamine agonist bromocriptine (BCR) from two days prior to 14 days after 3MC treatment and again for 14 consecutive days beginning at week 5. Tumor incidence was markedly increased and latency decreased in BCR-3MC rats compared to 3MC controls. Natural killer (NK) cell cytotoxicity responses and production of interleukin 2 (IL2) was enhanced at two weeks in rats treated with only BCR. Natural killer cell activity was suppressed at two weeks in rats treated with only 3MC. This effect was reversed by BCR treatment. Rats treated with 3MC and BCR had suppressed NK cell responses and production of IL2 and interferon-gamma (IFN) at 12 weeks. In another study, rats injected with 1, 3 or 5 mg/kg BCR for 14 consecutive days had increased NK cell activity and IL2 production at all doses and increased IFN production at the two high doses. Antibody (IgG) responses to an injected antigen and delayed-type hypersensitivity reactions were not affected by BCR treatment. Animals treated with the two high doses of BCR had decreased serum prolactin (PRL) levels. Serum growth hormone (GH) concentrations were markedly increased in the group treated with 3 mg/kg BCR. These data suggest that BCR enhances 3MC-induced tumorigenesis. The mechanism of this effect is apparently not mediated by suppression of the immune system since BCR-treated rats had selectively enhanced immune function. Enhancement of immune responses by BCR has not been previously reported.