Bromocriptine

Bromocriptine is a potent dopamine D2/D3 receptor agonist, which binds D2 dopamine receptor with pKi of 8.05±0.2.

Signaling Pathways >> GPCR/G Protein >> Dopamine Receptor

Signaling Pathways >> Neuronal Signaling >> Dopamine Receptor

Research Areas >> Neurological Disease

pKi: 8.05±0.2 (dopamine D2 receptor)[1]

Bromocriptine stimulates [35S]-GTPγS binding at D2 dopamine receptor expressed in CHO cells with pEC50 of 8.15±0.05[1]. Bromocriptine also is a strong inhibitor of brain nitric oxide synthase. The ergot alkaloid Bromocriptine (BKT) is found to act as a strong inhibitor of purified neuronal nitric oxide synthase (NOS) (IC50=10±2 μM) whereas it is poorly active towards inducible macrophage NOS (IC50>100 μM) [2]. Bromocriptine is found to inhibit the activity of at least one human cytochrome P450 enzyme. Bromocriptine is a potent inhibitor of CYP3A4 with a calculated IC50 value for the interaction of 1.69 μM[3].

Bromocriptine (a dopamine agonist) treatment (2 mg/kg, i.p.) group shows significant anti-immobility action as compared to control. When Bromocriptine administered 30 min after the last dose of 7 days MPE treatment and subjected to FST, this dopaminergic agonist produces significant and dose dependent potentiation of anti-immobility action of MPE (200 mg/kg, p.o.) as compared to MPE treatment alone. Bromocriptine (a dopamine agonist) treatment (2 mg/kg, i.p.) group shows a significant reduction of immobility time as compared to control. Bromocriptine administration after 7 days pretreatment with MPE (100 and 200 mg/kg, p.o.) shows significant and dose dependent potentiation of anti-immobility action of MPE as compared to MPE treatment alone[4]. Intraperitoneal administration of Bromocriptine induces a significant, dose dependent (0.1 mg and 1 mg/Kg) decrease in pain scores in CCI-IoN group when compared to sham and its effect lasted for 6 h. The highest dose induces the highest score decrease, (P<0.01). As a positive control SKF8129 (DR1 agonist) is used. Its intraperitoneal administration induces a non-significant increase in the SMA score when compared to sham (saline-injected). Intracisternal administration of Bromocriptine decreases significantly the SMA score when compared to sham (saline-injected). Bromocriptine effect lasted for 20 min. Intraperitoneal administration of Bromocriptine induces a significant dose dependent decrease in SMA score in CCI-IoN?+?6-OHDA lesioned group compared to that of sham. Its effect lasted for 6 h. SKF81297 administration increases the allodynic score. Intracisternal administration of Bromocriptine decreases significantly the SMA score compared to that of sham (saline-injected rats) and its effect lasted for 30 min[5].

The [35S]-GTPγS binding assay is carried out. Cell membranes (25 ±75 ug) are incubated in Buffer B containing 0.1 mM dithiothreitol (DTT) and 1 uM GDP and drugs in a volumeof 0.9 mL for 30 min at 30°C. This preincubation ensures that the agonists tested are at equilibrium when the [35S]-GTPγS (50±150 pM, final concentration) is added (in 100 uL ofBuffer B) to initiate the reaction. The assay mixture is incubated for a further 20 min unless otherwise stated. The assays are terminated by rapid filtration and bound radio-activity determined as described for the radio-ligand binding assays above. The total binding of [35S]-GTPγS is less than 20% of that added[1].

Mice[4] Swiss mice (20-25 g) of either sex (total 150) are used. Bromocriptine mesylate is used as dopamine receptor (D2) agonist. Haloperidol is diluted in distilled water which is used for a vehicle of injection. Bromocriptine mesylate is dissolved in one drop of glacial acetic acid and made up to volume in distilled water. Imipramine is dissolved in 0.9% normal saline. Haloperidol (0.1 mg/kg, i.p.) and Bromocriptine mesylate (2 mg/kg, i.p.) are administered for 7 days in groups of mice in Forced Swimming Test (FST) and Tail Suspension Test (TST). Imipramine (10 mg/kg, p.o.) as a standard is administered in positive control groups for 7 days. Rats[5] Adult male Sprague-Dawley rats (N=112, 275-325 g) are used. Two weeks after the 6-OHDA injection, the animals are briefly (<3 min) anesthetized with 2 % halothane using a mask and received for intracisternal administration Bromocriptine (7 μg/kg dissolved in 5 μL vehicle) or the vehicle alone (5 μL of 0.9 % saline). For i.p. injection we used Bromocriptine (1 mg/kg) and SKF81297 (3 mg/kg dissolved in 0.9 % saline) concentrations. Following a recovery period (<2 min), the rats are placed in the observation field for 40 min period-test by a blind-experimenter.

[1]. Gardner B, et al. Agonist action at D2(long) dopamine receptors: ligand binding and functional assays. Br J Pharmacol. 1998 Jul;124(5):978-84.

[2]. Renodon A, et al. Bromocriptine is a strong inhibitor of brain nitric oxide synthase: possible consequences for the origin of its therapeutic effects.FEBS Lett. 1997 Apr 7;406(1-2):33-6.

[3]. Wynalda MA, et al. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos. 1997 Oct;25(10):1211-4.

[4]. Rana DG, et al. Dopamine mediated antidepressant effect of Mucuna pruriens seeds in various experimental models of depression. Ayu. 2014 Jan;35(1):90-7.

[5]. Dieb W, et al. Nigrostriatal dopaminergic depletion increases static orofacial allodynia. J Headache Pain. 2016;17:11.

MOLECULAR FORMULA :

C32-H40-Br-N5-O5

MOLECULAR WEIGHT :

654.68

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

6 mg/kg/60D-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Olfaction) - effect, not otherwise specified

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

72 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>800 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

200 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

>1 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

12 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

7 gm/kg/2Y-C

TOXIC EFFECTS :

Tumorigenic - Carcinogenic by RTECS criteria Reproductive - Tumorigenic effects - uterine tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

2423 ug/kg

SEX/DURATION :

lactating female 3 week(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1500 ug/kg

SEX/DURATION :

lactating female 9 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1500 ug/kg

SEX/DURATION :

lactating female 15 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

1750 ug/kg

SEX/DURATION :

lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

21700 ug/kg

SEX/DURATION :

female 28 week(s) pre-mating female 1-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - respiratory system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

3500 ug/kg

SEX/DURATION :

female 14 day(s) pre-mating female 1-21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

11900 ug/kg

SEX/DURATION :

female 77 day(s) pre-mating female 1-42 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - urogenital system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

11200 ug/kg

SEX/DURATION :

female 44 day(s) pre-mating female 1-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

2800 ug/kg

SEX/DURATION :

female 24-52 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - body wall

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

70 mg/kg

SEX/DURATION :

female 13-19 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - behavioral

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

1950 ug/kg

SEX/DURATION :

female 5-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - other measures of fertility

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

5100 ug/kg

SEX/DURATION :

lactating female 3 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

17500 ug/kg

SEX/DURATION :

male 35 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count) Reproductive - Paternal Effects - testes, epididymis, sperm duct

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

88 mg/kg

SEX/DURATION :

female 1-22 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Fertility - other measures of fertility

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

8125 ug/kg

SEX/DURATION :

female 6-18 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - extra-embryonic structures (e.g., placenta, umbilical cord) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

84 mg/kg

SEX/DURATION :

lactating female 21 day(s) post-birth

TOXIC EFFECTS :

Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

200 mg/kg

SEX/DURATION :

female 50 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

212 mg/kg

SEX/DURATION :

female 32 day(s) pre-mating female 21 day(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - parturition

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

4 mg/kg

SEX/DURATION :

male 10 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

DOSE :

750 ug/kg

SEX/DURATION :

female 43-48 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - abortion

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

600 ug/kg

SEX/DURATION :

female 42-47 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - abortion

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

8 mg/kg

SEX/DURATION :

female 27-30 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - other effects to embryo

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

400 ug/kg

SEX/DURATION :

male 50 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - testes, epididymis, sperm duct

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

3 mg/kg

SEX/DURATION :

male 84 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands Reproductive - Paternal Effects - other effects on male

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

75200 ug/kg

SEX/DURATION :

female 42-49 week(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - parturition Reproductive - Maternal Effects - postpartum

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

22400 ug/kg

SEX/DURATION :

female 42-44 week(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - other effects Endocrine - estrogenic

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intramuscular

DOSE :

1 mg/kg

SEX/DURATION :

female 23 day(s) after conception

TOXIC EFFECTS :

Reproductive - Maternal Effects - parturition Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

MUTATION DATA

TEST SYSTEM :

Rodent - rat

DOSE/DURATION :

4 mg/kg

REFERENCE :

CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 36,2223,1976 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X6252 No. of Facilities: 9 (estimated) No. of Industries: 1 No. of Occupations: 1 No. of Employees: 339 (estimated) No. of Female Employees: 170 (estimated)