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Results for “Apomorphine”

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PubMed2004

Inhibitory effects of apomorphine and atropine and their combination on myopia in chicks.

PURPOSE: The inhibitory effect of apomorphine on form-deprivation myopia implies a role for dopaminergic pathways in eye growth; however, the effect of apomorphine on lens-induced changes has not been studied. Our study filled this deficiency. After establishing that apomorphine inhibited lens-induced myopia, we investigated whether apomorphine and atropine acted sequentially via the same control pathway or via different parallel pathways. METHODS: This study, conducted in 8-day-old chicks, was comprised of two parts: (1) a comparative study of apomorphine's effect on lens-induced myopia (-15 D), form-deprivation myopia (diffusers), and lens-induced hyperopia (+15 D) and (2) a study of the interacting effects of apomorphine and atropine on lens-induced myopia and form-deprivation myopia. In the first part, dH2O and six apomorphine doses (8 pmole to 800 nmole in log10 steps) were given as 10-microL intravitreal injections in combination with the above visual treatments. Apomorphine was used alone or given with atropine in the second part, which included four drug treatment groups: (1) control (dH2O); (2) 80 pmole of apomorphine; (3) 18 nmole of atropine; and (4) apomorphine + atropine. Additional dH2O injections were used to equalize the number of injections across groups. After 4.5 days of treatment, refractive errors and axial ocular dimensions were measured. RESULTS: The myopic shifts and axial elongation typical of lens-induced myopia (-15 D lens wear) were inhibited to maxima of 43% (4.5 D) and 52% (0.17 mm) by apomorphine, which, in contrast, enhanced lens-induced hyperopia (refractive error: 114%, 1.55 D; axial length: 134%, 0.16 mm). Inhibitory effects of apomorphine on lens-induced myopia were observed at doses > or = 80 pmole, whereas the doses required to enhance lens-induced hyperopia were 2 log10 units higher. Only a weak inhibitory effect of apomorphine on form-deprivation myopia was observed. Although both apomorphine and atropine inhibited lens-induced myopia, atropine was slightly more effective for the doses compared (refractive error, 53% cf. 32%), and the effect of the combination was not significantly greater than that of atropine alone (refractive error, 59% cf. 53%). CONCLUSIONS: Apomorphine inhibits both types of experimental myopia, which implies the involvement of dopaminergic mechanisms in both phenomena; likewise, cholinergic mechanisms are indicated by the inhibitory effects of atropine on both lens-induced myopia and form-deprivation myopia. We speculate that apomorphine and atropine act at different sites on a common control pathway because the combined effect of apomorphine and atropine was no more than atropine alone.

Animals↗
PubMed2006

Expression of cocaine-induced conditioned place preference in apomorphine susceptible and unsusceptible rats.

Differences in cocaine self-administration can be attributed to differences in the rewarding value that cocaine has for the individual. An ongoing debate, however, exists whether a high rewarding or a low rewarding value leads to an increase in self-administration. To investigate which of these two alternatives is correct, we investigated the occurrence of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats. We have recently shown that under specific environmental conditions (challenged-not habituated to the environment-as measured by distance travelled) apomorphine susceptible rats consistently self-administer more cocaine than apomorphine unsusceptible rats do. As conditioned place preference allows the assessment of the rewarding value of cocaine, we investigated the expression of cocaine-induced conditioned place preference in apomorphine susceptible and apomorphine unsusceptible rats under the same conditions as the self-administration experiments in order to establish whether the rewarding value of cocaine is greater or smaller in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats. The data clearly showed that challenged apomorphine susceptible rats had a preference for the cocaine-paired compartment with lower doses of cocaine (10 mg/kg) than challenged apomorphine unsusceptible rats. Apomorphine unsusceptible rats expressed conditioned place preference only with the highest dose tested (20 mg/kg). On the basis of these data, we concluded that the rewarding value that cocaine has in challenged apomorphine susceptible rats is greater than that in challenged apomorphine unsusceptible rats. It is suggested that challenged apomorphine susceptible rats self-administer more of a lower dose of cocaine than challenged apomorphine unsusceptible rats do, because the rewarding value of cocaine is greater in challenged apomorphine susceptible rats than in challenged apomorphine unsusceptible rats.

Animals↗
PubMed2003

Quercetin inhibits the sulfation of r(-)-apomorphine in human brain.

The first aim of this investigation was to study the sulfation of R(-)-apomorphine in human brain. The second aim was to investigate the inhibition of R(-)-apomorphine sulfation by quercetin in human brain. R(-)-apomorphine is hereafter referred to as apomorphine. Apomorphine sulfation was measured in 5 brain specimens; 3 derived from the frontal cortex and 2 derived from the temporal cortex. The rate of apomorphine sulfation was 5.6 +/- 4.3 pmol/min/mg. The activities of SULT1A1 and SULT1A3, which were also measured in these samples, were 11 +/- 9.1 and 2.6 +/- 1.7 pmol/min/mg, respectively. The rate of apomorphine sulfation correlated with the activity of SULT1A1 (r = 0.989; p = 0.002) and SULT1A3 (r = 0.973; p = 0.005). Apomorphine sulfotransferase followed Michaelis-Menten kinetics, the Km (mean +/- SD) and Vmax values (mean +/- SD) of which, measured in 5 brain samples, were 32 +/- 7.3 microM and 8.9 +/- 7.9 pmol/min/mg, respectively. Quercetin was a potent inhibitor of apomorphine sulfation with an IC50 value, measured in 5 brain samples, of 16 +/- 2.3 nM. The inhibition mechanism of quercetin using apomorphine sulfation in 5 brain samples was mixed, non-competitive with a Ki and Kies (mean +/- SD) of 16 +/- 4.1 and 87 +/- 37 nM, respectively (p = 0.008). The intrinsic clearance value of apomorphine (mean +/- SD) was 247 +/- 170 ml/min/mg(-1) and was decreased to 100 +/- 85 ml/min/mg(-1) (p < 0.01) in the presence of 25 nM quercetin. In conclusion, apomorphine is sulfated in human brain. Sulfation might reduce the level of apomorphine in human brain and be a factor limiting the effect of this drug. Quercetin is a potent inhibitor of apomorphine sulfation and may inhibit the sulfation of apomorphine in human brain in vivo.

Adult↗
PubMedDate not supplied

Pharmacokinetics, enantiomer interconversion, and metabolism of R-apomorphine in patients with idiopathic Parkinson's disease.

The pharmacokinetics and metabolism of R-apomorphine were determined in 10 patients with idiopathic Parkinson's disease after intravenous infusion of 30 micrograms.kg-1 in 15 min. Specifically, emphasis was on enantiomeric interconversion into S-apomorphine and on the formation of apocodeine and isoapocodeine, since these metabolites may interfere with the pharmacodynamics of R-apomorphine. The pharmacokinetics of R-apomorphine in plasma were determined using an enantioselective high-performance liquid chromatography assay. In most patients, the plasma concentration versus time profile was characterized by a biexponential function. The values of relevant pharmacokinetic parameters were as follows: clearance 40 +/- 15 ml.min-1.kg-1, volume of distribution at steady state 1.6 +/- 0.5 l.kg-1, and terminal half-life 41 +/- 13 min. No measurable concentrations of S-apomorphine were detected in plasma, indicating that enantiomeric interconversion does not occur in vivo. Furthermore, no measurable concentrations of the methylated metabolites apocodeine and isoapocodeine could be detected in plasma. The metabolism of apomorphine was characterized on basis of the excretion of unchanged R-apomorphine, S-apomorphine, apocodeine, isoapocodeine, and their respective sulfate and glucuronide conjugates in urine. The total excretion of unconjugated S-apomorphine, apocodeine, and isoapocodeine was less than 0.1% of the administered dose. The total excretion of unchanged apomorphine, apomorphine sulfate, and apomorphine glucuronide amounted to 0.3 +/- 0.4%, 3.8 +/- 1% and 6.0 +/- 2.2% of the administered dose, respectively. The findings of this study show that on intravenous administration, S-apomorphine and the metabolites apocodeine and isoapocodeine are unlikely to interfere with the pharmacologic actions of R-apomorphine in patients with idiopathic Parkinson's disease. Furthermore, no pharmacokinetic interaction between R-apomorphine and catechol-O-methyl transferase inhibitors is expected.

Adult↗
PubMed1999

Sensitization of apomorphine-induced stereotyped behavior in mice is context dependent.

RATIONALE: The role of the environment in the sensitization of the stereotyped behavioral effects of apomorphine is unclear, since sensitization of this drug effect has either been difficult to demonstrate or has been shown to occur with a low but not a higher dose of apomorphine. OBJECTIVES: The present study was designed to determine whether sensitization of the stereotyped behavioral effects induced by a single dose of apomorphine is dependent on environmental context. METHODS: CF-1 mice were pretreated with apomorphine or vehicle under different environmental conditions and tested for stereotyped behavior after apomorphine challenge. Animals were scored positively for stereotyped behavior if they remained stationary and exhibited repetitive head and/or fore-limb movements, and data are reported as the percentage of mice rated as positive for stereotyped behavior. RESULTS: When mice were pretreated with 40 mg/kg apomorphine and later tested in the same environment, the dose-response curve for stereotyped behavior elicited by apomorphine was shifted threefold to the left 48 h after pretreatment, and this sensitization persisted for at least 28 days after pretreatment. Mice pretreated with apomorphine did not have higher brain levels of apomorphine after administration of the test dose of apomorphine. When the pretreatment environment was different from the test environment, mice did not exhibit sensitization to apomorphine. CONCLUSIONS: These results show that pre-exposure to a single high dose of apomorphine induces a long-lasting sensitization of apomorphine-induced stereotyped behavior that is context dependent. Since apomorphine directly activates dopamine receptors, these observations suggest that a mechanism located postsynaptic to dopamine neurons may be responsible for sensitization of stereotyped behavior.

Animals↗
PubMed1986

Disposition of apomorphine in rat brain areas: relationship to stereotypy.

Apomorphine-induced stereotyped behavior and apomorphine levels in plasma, striatum and nucleus accumbens were determined in rats at various intervals after a single i.p. injection of serial doses of apomorphine hydrochloride (0.625, 1.25, 2.5 and 5 mg/kg). Apomorphine disappeared from plasma in a mono-exponential mode with a half-life of about 10 min. In striatum and nucleus accumbens apomorphine concentrations peaked 10 min after administration, declining thereafter with a half-life comparable to that in plasma. Apomorphine was concentrated and distributed similarly in the two brain regions; the brain areas/plasma ratio was approximately seven for all doses tested. The rise of apomorphine levels in brain areas slightly preceded the behavioral response, whereas after the peak effect (20-30 min) the intensity of stereotypy declined almost parallel with the log drug concentrations. Plotting apomorphine levels in the tissues assayed against the drug response at the same interval for individual rats, regardless of dose, indicated a highly significant relation between the degree of behavioral effects and brain apomorphine levels. The threshold apomorphine concentrations for inducing stereotyped behaviour were 108 and 95 ng/g respectively in striatum and nucleus accumbens. These findings show that the time course and magnitude of the behavioral effects of apomorphine corresponded with its brain levels in 'dopaminergic' areas, suggesting that apomorphine-induced stereotyped behavior in rats can be described by a direct mechanism. Reserpine (5 mg/kg s.c.) enhanced the apomorphine stereotypy but did not affect apomorphine's disposition in brain and plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Sulfation of R(-)-apomorphine in the human liver and duodenum, and its inhibition by mefenamic acid, salicylic acid and quercetin.

1. The aims were to study the sulfation of R-(-)-apomorphine (hereafter apomorphine) in the human liver and duodenum, and to study the rate of inhibition of apomorphine sulphation by mefenamic acid, salicylic acid and quercetin also in the human liver and duodenum. 2. A rapid and sensitive method was developed to measure the sulfation rate of apomorphine in the human liver and duodenum. The method was based on the use of 0.4 micro M 3'-phosphoadenosine-5'-phosphosulfate-[(35)S] (PAPS) and 50 micro M apomorphine. The unreacted PAPS was precipitated with barium hydroxide, barium acetate and zinc sulfate. 3. The rate of apomorphine sulfation (mean +/- SD and median) was 261 +/- 82 and 242 pmol min(-1) mg(-1), respectively (liver), and 433 +/- 157 and 443 pmol min(-1) mg(-1), respectively (duodenum). The apomorphine sulfation rate was higher in the duodenum than in the liver (p = 0.0005). 4. Apomorphine sulfation was correlated with SULT1A1 activity in the liver (r(2) = 0.363, p = 0.005) and duodenum (r(2) = 0.494, p = 0.0005), but it did not correlate with SULT1A3 activity both in the liver and duodenum. 5. The K(m) estimate of apomorphine sulfation rate was 20 +/- 3.6 (liver) and 6.5 +/- 0.2 microM (duodenum, p = 0.024), and the V(max) estimate was 248 +/- 99 (liver) and 636 +/- 104 pmol min(-1) mg(-1) (duodenum, p = 0.018). 6. Mefenamic acid, salicylic acid and quercetin were potent inhibitors of apomorphine sulfation rate in the liver, and the IC(50) estimates were 16 +/- 0.2 nM, 54 +/- 8.6 microM and 18 +/- 2.8 nM, respectively. These compounds were poor inhibitors of apomorphine sulfation in the duodenum. 7. Apomorphine is sulfated by the human liver and duodenum, the highest activity being associated with the duodenum. The K(m) of apomorphine sulfotransferase is in the order of micro M both in the liver and duodenum. The non-steroidal anti-inflammatory drug mefenamic acid and the natural flavonoid quercetin inhibit the hepatic sulfation of apomorphine with an IC(50) in the order of nM.

Adult↗
PubMed1984

Genotoxicity of apomorphine and various catecholamines in the Salmonella mutagenicity test (Ames test) and in tests for primary DNA damage using DNA repair-deficient B. subtilis strains (rec assay).

Apomorphine, N-nor-N-propyl-apomorphine, dopamine, L-DOPA, 6-hydroxydopamine and adrenaline were evaluated for genotoxicity using the Ames test and DNA repair-deficient and DNA repair-proficient Bacillus subtilis strains (rec assay, H17/M45; HLL3g/HJ-15). In the absence of an S9 liver homogenate, apomorphine induced frame-shift mutations in Salmonella typhimurium, mainly in strain TA1537; no indication of DNA-damaging effects in B. subtilis was observed. N-Nor-N-propyl-apomorphine was tested using strain TA1537 only and found to be mutagenic. Dopamine, L-DOPA, 6-hydroxydopamine and adrenaline were non-mutagenic when tested without S9, whereas they were all more toxic for DNA repair-deficient than for DNA repair-proficient B. subtilis strains, indicating a DNA-damaging potential. In a second set of experiments the mode of action of apomorphine and the relevance of the positive Ames test data were investigated. Glutathione in physiological concentrations reduced the mutagenic effect of apomorphine in a dose-dependent way, both in the presence and the absence of S9. S9 also reduced the mutagenicity of apomorphine. By comparing the effects of a complete S9 mix with those of a preparation without glucose-6-phosphate and NADP, it became clear that S9 also had an activating effect, overshadowed under standard conditions by its deactivating activity. Apomorphine was not mutagenic under anaerobic conditions. Superoxide dismutase and catalase reduced the mutagenic effect of apomorphine. All test conditions which reduced the mutagenic effect also inhibited the dark discoloration of the tester plates, indicating a retardation of apomorphine oxidation. It can, therefore, be concluded that oxidation of apomorphine leads to mutagenic products which induce frame-shift mutations in Salmonella typhimurium. This oxidation was prevented both by glutathione in concentrations well below physiological levels and/or by catalase and superoxide dismutase. Under these conditions, apomorphine was non-mutagenic in therapeutic concentrations as well as at higher dose levels. The possibility of genotoxic side effects occurring in patients treated with apomorphine as an emetic drug is therefore considered to be very unlikely.

Animals↗
PubMed1999

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors.

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED50 values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D2 antagonist), 0.023 mg/kg for SCH 23390 (dopamine D1 antagonist), 6.42 mg/kg for clozapine (dopamine D4 antagonist). This supports the involvement of D1 and D1 receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D1 and D2, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.

Amphetamine↗