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PubMed1999

Apomorphine protects against MPTP-induced neurotoxicity in mice.

R-apomorphine is a potent radical scavenger and iron chelator. The neuroprotective property of R-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Pretreatment with 5-10 mg/kg R-apomorphine administered subcutaneously in C57BL mice protects against MPTP (24 mg/kg administered intraperitoneally) induced loss of nigrostriatal dopamine neurons as indicated by striatal dopamine content, tyrosine hydroxylase content, and tyrosine hydroxylase activity. In vitro, R-apomorphine inhibited mice striatal MAO-A and MAO-B activities with IC50 values of 93 microM and 241 microM. It is suggested that the neuroprotective effect of R-apomorphine against MPTP neurotoxicity derives from its radical scavenging and MAO inhibitory actions and not from its agonistic activity because the mechanism of MPTP dopaminergic neurotoxicity involves the generation of oxygen radical species-induced oxidative stress.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Effects of apomorphine on globus pallidus neurons in parkinsonian patients.

Current hypotheses of basal ganglia dysfunction in Parkinson's disease (PD) propose that neuronal hypoactivity in the globus pallidus externus (GPe), and hyperactivity in the output nuclei and the external and internal portions of the globus pallidus internus (GPi,e and GPi,i, respectively), result in the cardinal symptoms of PD. To test this theory, the nonselective D1- and D2-dopamine receptor agonist apomorphine (30-100 microg/kg SC) was administered to 14 levodopa-responsive PD patients who were off medication ("off" state) while recording neurons in GP. For 15 neurons that were continuously monitored, apomorphine was found to increase the firing rate of 3 neurons in GPe, and decrease the rate of 12 in GPi. The mean firing rates of many different neurons were determined before (n = 285) and at various intervals after (n = 184) the injection of the drug. The mean rates before apomorphine were as follows: GPe, 45 Hz (SD 15, n = 85); GPi,e, 67 Hz (SD 14, n = 125); and GPi,i, 85 Hz (SD 19, n = 75). At 25 to 35 minutes after APO, the rate of GPe neurons had increased to 72 Hz (SD 18, n = 7), the rate of GPi,e neurons had decreased to 39 Hz (SD 15, n = 15), and in GPi,i the rate decreased to 34 Hz (SD 22, n = 18). Eighty minutes after apomorphine administration, the mean firing rates returned to preadministration values. This study supports current models of basal ganglia dysfunction in PD and suggests that the therapeutic effect of apomorphine results from a normalization of the imbalance of neuronal activity in the direct and indirect pathways.

Action Potentials↗
PubMedDate not supplied

An apomorphine-induced vomiting model for antiemetic studies in man.

Apomorphine-induced vomiting is often used for preclinical efficacy testing of putative antiemetics in normal volunteers. The usual technique of individual intravenous titration for finding the threshold emitic dose of apomorphine in each subject is slow and tedious. We used a uniform dose of 0.05 mg/kg apomorphine given subcutaneously to test the antiemetic action of metoclopramide and votracon in ten healthy, young male volunteers. All ten subjects vomited in response to this dose of apomorphine when pretreated with placebo. Pretreatment with metoclopramide prevented vomiting in all subjects, and votracon prevented vomiting in two. Apomorphine, 0.05 mg/kg, subcutaneously appears to be an appropriate challenge dose for testing compounds for antiemetic activity in normal human volunteers.

Adult↗
PubMed1995

Apomorphine infusional therapy in Parkinson's disease: clinical utility and lack of tolerance.

We assessed the clinical utility of apomorphine infusional therapy in patients with parkinsonism and motor fluctuations and sought evidence for alterations in drug response resulting from chronic treatment. Six patients with Parkinson's disease were treated for 3 months with s.c. infusions of apomorphine administered during waking hours. At the beginning and the end of the study, test doses of apomorphine (12.5-100 micrograms/kg) were administered to establish a dose-response curve. Over the study, the patients reported a significant improvement in the number of "on" hours experienced per day and substantially reduced the dose and frequency of levodopa and other antiparkinsonian medications. No average change in apomorphine dose-response relationships or pharmacokinetics was observed during the study. However, two patients lowered the infusion rate during the 3-month observation and exhibited higher drug levels and longer responses following test doses of apomorphine given at the end of the study. Although pragmatic concerns with the use of infusion pumps solutions and adverse effects limited the overall benefit afforded by the treatment, this kind of drug treatment may be useful in selected patients with severe parkinsonism and fluctuations.

Administration, Cutaneous↗
PubMed1995

Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson's disease: a study of five different suppositories.

The pharmacokinetics and clinical effects of apomorphine after rectal administration were determined in five patients with idiopathic Parkinson's disease (PD). Three different pharmaceutical formulations were tested: a rectal solution of apomorphine (10 or 15 mg), a gelatin suppository (25 and 50 mg), and a Witepsol-H15 suppository (50 and 100 mg). The pharmacokinetics of apomorphine were determined by measuring plasma concentrations using a sensitive and specific high-performance liquid chromatography method. The mean bioavailability varied between 14.7% and 40.2%, which was the bioavailability until the end of clinical benefit. Also, despite the differences in dose, the values of the Cmax were similar, with average values of 12.7-25.6 ng/ml. Wide differences in Tmax were observed, with values varying between 16 min for the enema and 127.5 min for the Witepsol-H15 100-mg suppository. The time course of the clinical effect was determined by assessing the time needed for walking a 25-m course and by calculating a tremor and dyskinesia score. Onset of effect was similar for each of the preparations, with an average onset time of 14-28 min. Significant differences with respect to the duration of the effect were observed. The duration of effect after administration of the Witepsol-H15 100-mg suppository was 156 +/- 43 min versus 50 +/- 13 min after rectal administration of the apomorphine solution. These results show that rectal administration of apomorphine may present an alternative to subcutaneous administration. The sustained-release properties of the Witepsol-H15 suppositories are especially of interest in the treatment of on-off fluctuations in PD.

Aged↗
PubMed1998

Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine.

A significant body of evidence has been provided to support the hypothesis that oxidant stress may be responsible for the degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Apomorphine, a dopamine D1/D2-receptor agonist in the clinical therapy of Parkinson's disease, has been found to be a potent antioxidant and to prevent free radical reaction in rat brain mitochondrial fraction. In this article we show that 1-10 microM of apomorphine protects rat pheochromocytoma (PC12) cells from the toxic effects of H2O2 (0.6 mM) and the neurotoxin 6-hydroxydopamine (150 microM). These effects were not exhibited by ascorbic acid, desferal, lisuride, or bromocriptine. Although pergolide exhibited some protection of PC12 cells against H2O2 toxicity, it was not as potent as apomorphine. In light of the present findings and the clinical reports that parkinsonian patients on long-term apomorphine stabilize clinically and can be weaned off L-dopa, one may assume that apomorphine can exert a neuroprotective activity via its potent antioxidant properties.

Animals↗
PubMed1998

Apomorphine-induced penile erections in Parkinson's disease.

Penile erections were regularly induced by intermittent subcutaneous injections of apomorphine in five patients with Parkinson's disease (PD) complicated by motor fluctuations. Four of the patients reported erectile dysfunction before beginning apomorphine and two of these report a significant improvement in their sexual function resulting from apomorphine use. Animal studies suggest central D2-type dopamine receptor stimulation and oxytocin release from the paraventricular nucleus of the hypothalamus mediate the effect. Erections reported with other dopamine agonists and levodopa are probably mediated by the same mechanism. Apomorphine-induced erections in PD are probably more common than previously thought. The benefit of apomorphine on sexual function in some patients suggests a possible role in the treatment of impotence in PD.

Adult↗
PubMed1998

Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine.

A significant body of evidence has been provided to support the hypothesis that oxidant stress may be responsible for the degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Apomorphine, a dopamine D1/D2-receptor agonist in the clinical therapy of Parkinson's disease, has been found to be a potent antioxidant and to prevent free radical reaction in rat brain mitochondrial fraction. In this article we show that 1-10 microM of apomorphine protects rat pheochromocytoma (PC12) cells from the toxic effects of H2O2 (0.6 mM) and the neurotoxin 6-hydroxydopamine (150 microM). Neither of these effects were exhibited by ascorbic acid, desferal, lisuride, or bromocriptine. Although pergolide exhibited some protection of PC12 cells against H2O2 toxicity, it was not as potent as apomorphine. In light of the present findings and the clinical reports that parkinsonian patients on long-term apomorphine therapy stabilize clinically and can be weaned off L-dopa, one may assume that apomorphine can exert a neuroprotective activity by way of its potent antioxidant properties.

Animals↗
PubMed1995

In vivo characterization of two cell types in the rat globus pallidus which have opposite responses to dopamine receptor stimulation: comparison of electrophysiological properties and responses to apomorphine, dizocilpine, and ketamine anesthesia.

Extracellular single-unit recording techniques were used to examine the rat globus pallidus (GP). In both locally anesthetized, paralyzed rats and ketamine-anesthetized rats, we observed two distinct biphasic extracellular waveforms, which we have labeled Type I (negative/positive waveform) and Type II (positive/negative waveform). No significant differences were observed in the firing pattern or number of cells per track between these cell types, although the Type II neurons had a faster mean firing rate in the locally anesthetized animals. A portion of both cell types could be antidromically activated from the subthalamic nucleus, although Type II neurons had significantly slower conduction velocities. The most striking pharmacological difference between the two cell types was that Type I GP neurons were inhibited by systemic administration of the dopamine agonist apomorphine; previous studies have repeatedly shown that Type II GP cells are excited by this treatment. Pretreatment with a subthreshold dose of apomorphine reduced the responsiveness of Type I cells to a subsequent high dose of apomorphine, as has been shown for Type II cells. However, pretreatment with the NMDA antagonist dizocilpine (MK801) produced a significant change in the pattern of response to apomorphine for Type II GP neurons only. Relative to observations in locally anesthetized, paralyzed rats, ketamine anesthesia reduced the firing rate of both cell types, but did not significantly alter their direction of response to apomorphine. Thus, this study has confirmed the existence of two GP cell types with distinct extracellular waveforms and different responses to dopamine receptor stimulation. These data may necessitate a reevaluation of general theoretical models of basal ganglia function in order to account for these opposite effects of dopamine receptor stimulation on pallidal output.

Anesthesia↗
PubMed2001

Acute trazodone and quipazine treatment attenuates apomorphine-induced aggressive behaviour in male rats without major impact on emotional behaviour or monoamine content post mortem.

We have studied the effect of acute trazodone (3--20 mg kg(-1)) and quipazine (1--3 mg kg(-1)) treatment on the apomorphine-induced (1 mg kg(-1), once daily over 2 weeks) aggressive behaviour in male Wistar rats. All doses of trazodone and quipazine tested attenuated the aggressiveness as evidenced by the abolished intensity of aggressive behaviour and increased time of latency before the first attack. The acute trazodone (3--10 mg kg(-1)) or quipazine (1--3 mg kg(-1)) treatment had no or only a minor effect on rat behaviour in the elevated plus-maze, open field, and forced swimming test. Concomitant apomorphine (1 mg kg(-1)) plus trazodone (3 mg kg(-1)), but not apomorphine (1 mg kg(-1)) plus quipazine (1 mg kg(-1)), treatment slowed the development of aggressive behaviour. Repeated apomorphine treatment moderately reduced the dopamine post mortem and increased the DOPAC and HVA contents in striatum. Other monoamines or their metabolites were unchanged. Neither trazodone and quipazine treatment nor forced swimming stress induced any changes in the monoamine contents. In conclusion, our results indicate that acute trazodone and quipazine treatment attenuates the apomorphine-induced aggressive behaviour in male rats, but this phenomenon cannot be implicated in the changes in emotional and motivational behaviour, or in changes of monoamine content post mortem.

Aggression↗
PubMed2001

Electrophysiologic and hemodynamic effects of apomorphine in dogs.

Apomorphine is a dopamine receptor agonist used as an emetic, for Parkinson's disease, and for treating erectile dysfunction. This study was conducted to monitor cardiovascular function in dogs given the standard emetic dose (0.05 mg/kg) or 10 times that. Measurements were made during baseline and at 1, 5, 15, 30, 45, and 60 min after iv administration. There were no changes produced by the 0.05 mg/kg dose of apomorphine except for a decrease in mean systemic arterial pressure (AoPm) at the 1 through 15 min recordings. For the 0.5 mg/kg dose, there were reductions in systemic vascular resistance at the 1 and 5 min recordings and in AoPm at the 1 through 60 min recordings. Although not significant, when AoPm fell, heart rate, stroke volume, and cardiac output tended to increase. Action potentials were recorded from superfused Purkinje and endocardial ventricular fibers while exposed to 10(-9) to 10(-5) M apomorphine (10(-10) M is considered therapeutic and 10(-7) M is considered lethal). There were no changes in action potential characteristics of Purkinje fibers, but action potential duration at 90% repolarization prolonged approximately 10-12% in endocardium at concentrations of 10(-6) M and greater. At the usual emetic dose (0.05 mg/kg) apomorphine resulted in no signs of cardiovascular toxicity and, at 0.5 mg/kg, cardiovascular changes were minimal. The emetic dose is higher than that for Parkinson's disease or erectile dysfunction; thus apomorphine appears to be a safe compound for clinical use in dogs and by extrapolation to man.

Action Potentials↗
PubMed1993

Conditioned effects of apomorphine are manifest in regional EEG of rats both in hippocampus and in striatum.

Previously, in own studies, it was shown that stereotyped behaviour produced by apomorphine can be conditioned if the drug is repeatedly paired with defined environmental stimuli (conditioned stimuli, CS). Eventually, the presentation of CS alone produces stereotyped behaviour as conditioned response (CR). Furthermore, in electrocorticographic recordings it could be demonstrated that the characteristic pattern following acute apomorphine treatment, namely a selective increase in the power of the alpha-1 band, could be conditioned as well. In the present study, regional EEG was recorded in the striatum and in the hippocampus of freely moving rats. For conditioning, apomorphine (0.5 mg/kg s.c.) was paired with auditory and olfactory stimuli as CS for seven times, and on the eighth day the drug was substituted by the solvent in the presence of the CS. The effects were compared with those obtained in "pseudoconditioned" controls. Acute apomorphine administration led to an increase in power in the alpha-1 band (7.00-9.50 Hz), which effect was obvious in the hippocampus, above the cortex and in the striatum. After performing the conditioning procedure, these effects in regional EEG were found to be conditioned as well: as CR, activation in power in the alpha-1 band in hippocampus and striatum were manifest in the presence of the CS, but in absence of the drug. These effects occurred sporadically, but with a significantly higher frequency than in the pseudoconditioned controls. The results suggest that both the hippocampus and the striatum play important roles in classical conditioning of apomorphine effects which are primarily mediated by the striatum.

Animals↗
PubMed1987

Conditioning of behavioural effects produced by an intermediate dose of apomorphine: hypokinesia, ptosis and stereotypies.

Apomorphine, in an intermediate dose (0.18 mg/kg s.c.) decreased dopamine turnover and produced signs generally attributed to a decrease in dopaminergic neurotransmission, e.g. ptosis and yawning, as well as signs of an increased stimulation of dopamine receptors in dopaminoceptive target neurones, e.g. stereotyped sniffing. In contrast, the former signs were exclusively observed after smaller doses and the latter after larger doses of apomorphine. Since it had been shown in previous studies that these signs, except yawning, could be conditioned in association with discriminative stimuli in the environment, the present study using conditioning experiments with this intermediate dose aimed at determining, 1. the time course of each conditioned response, 2. the interaction of conditioned and unconditioned responses, and 3. the conditions under which hypokinesia occurred. In each series, conditioned animals were compared with pseudoconditioned controls. Rats were conditioned for 8 days with apomorphine, and on day 9, treated with saline in presence of the conditional stimuli (a test cage in combination with acoustic and olfactory stimuli). In contrast to pseudoconditioned controls, ptosis and stereotyped behaviour were observed in conditioned rats, sometimes occurring alternatingly. These signs closely resembled the direct, unconditioned pharmacological effects. In addition, akinesia occurred after conditioning, although it was never manifest as a pure drug response, nor during the conditioning period. In contrast, yawning was observed in pseudoconditioned as well as in conditioned rats, although slightly more frequently in the former animals. Subsequently, the rats were again conditioned (or pseudoconditioned) on days 10-14 with apomorphine and both groups tested with the same dose (0.18 mg/kg) of apomorphine in the presence of the conditioned stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Effects of dopamine receptor antagonists on gastrin and vomiting responses to apomorphine.

Apomorphine (0.05 mg/kg intravenously) was given to conscious dogs, and gastrin levels were measured in peripheral venous blood with a radioimmunoassay. Apomorphine induced an increase of gastrin levels which peaked at 5 min. The peripheral dopamine D-2/DA2 receptor antagonist domperidone (0.2 mg/kg), but not halopemide (0.1-1 mg/kg) nor the D-1/DA1 receptor antagonist SCH 23,390 (0.1 mg/kg), blocked the gastrin response to apomorphine. Both domperidone and halopemide, but not SCH 23,390, blocked the apomorphine-induced vomiting. These results suggest that apomorphine increases gastrin levels by an action at D-2/DA2 receptors, which are situated outside the blood brain barrier and differ from the receptor inducing the vomiting.

Animals↗
PubMed1987

A long lasting gastrin response to apomorphine revealed by inhibitors of gastric acid secretion.

Gastrin levels, in the peripheral venous blood of conscious dogs treated with apomorphine (0.05 mg/kg IV), were analysed with a radioimmunoassay. Pretreatment (30 min) with the gastric acid inhibitors cimetidine, ranitidine (H2 receptor antagonists, 4 mg/kg and 1 mg/kg respectively) or omeprazole (H+-K+ ATPase inhibitor, 1.6 mg/kg) prolonged the elevation of gastrin levels occurring in response to an administration of apomorphine. Haloperidol (0.1 mg/kg), but not the peripheral dopamine receptor antagonist domperidone (0.2 mg/kg), abolished the enhanced gastrin response to apomorphine occurring after pretreatment with cimetidine. Cimetidine did not increase the gastrin response to apomorphine in vagotomized dogs. The results are interpreted in terms of an additive gastrin response to apomorphine (different from the short lasting initial peak previously described) which is vagally mediated and inhibited by the gastric acid.

Animals↗
PubMed1987

Apomorphine-induced pecking in pigeons classically conditioned to environmental cues.

The dopamine agonist apomorphine elicits protracted pecking when injected systemically (1 mg/kg) into pigeons. In two experiments it was investigated whether apomorphine would function as an unconditioned stimulus in the classical conditioning of pecking in these animals. An experimental design based on a differentiation procedure was used so that possible pseudoconditioning effects were controlled. Two differently coloured test chambers served as negative (CS-) and positive conditioned (CS+) stimuli. During the training phase the subjects experienced the former while injected with saline, and the latter while injected with apomorphine. In later tests not involving any injections the pigeons made significantly more pecks (conditioned response) in the CS+ chamber than in the CS- chamber. In the first and second experiments the conditioned stimuli were, respectively, discrete and diffuse visual cues, but both had similar effects. The conditioning obtained may explain sensitization effects that are observed with repeated apomorphine injections. Apomorphine probably also functions as a positive reinforcer for instrumental conditioning in pigeons.

Animals↗
PubMed1991

Conditioning of apomorphine effects: simultaneous analysis of the alterations in cortical electroencephalogram and behaviour.

The possible conditioning of pharmacological effects of apomorphine on the electroencephalogram was studied using telemetric recordings in rats. Previous studies have shown that apomorphine-induced stereotyped behaviour can be conditioned: after repeated pairings of defined stimuli with the drug effect, the presentation of the external stimuli alone elicited stereotype sniffing, licking, and gnawing. Since apomorphine, an agonist at dopamine receptors, also produces a characteristic EEG pattern with an increase of power in the alpha-1 band, the possibility that this effect could also be conditioned was studied. In fact, conditioning with a dose of 0.5 mg/kg apomorphine (s.c.) led to a significant increase in the number of short-lasting episodes with enhancement of the power in the alpha-1 range in the presence of the conditioned stimuli, according to a comparison of the results obtained in the conditioned group and those of the controls ("pseudoconditioned"). Moreover, behavioural studies were performed simultaneously in order to find possible correlations between conditioned effects on EEG and conditioned alterations in behaviour. In general, a fair correlation between the increase of power in the alpha-1 band and stereotyped behaviour was found. This was also the case during extinction, when the conditioned stimuli were repeatedly uncoupled from apomorphine administration: both behavioural parameters and EEG alterations showed similar time-courses and had almost disappeared during the fourth extinction session.

Animals↗
PubMed1980

Responses to apomorphine, amphetamine, and neuroleptics in schizophrenic subjects.

Twenty-one schizophrenic subjects, who had been neuroleptic-free, were tested for responsiveness to dopaminergic agonists: Apomorphine emesis threshold was determined and change in psychopathology after 0.5 mg/kg d-amphetamine orally was rated. The subjects' subsequent response to neuroleptic treatment were also determined. Sensitivity to apomorphine emesis was also determined in a nonschizophrenic control group. Apomorphine emesis threshold was not significantly different in the schizophrenic and control groups. Correlations were done between baseline psychopathology, apomorphine sensitivity, and changes in psychopathology after amphetamine and after neuroleptic treatment. On the Brief Psychiatric Rating Scale (BPRS), baseline psychopathology correlated with improvement after neuroleptics and, on the clinical global impressions (CGI), increase of psychopathology after amphetamine also correlated with improvement after neuroleptic treatment. An inverse correlation was found between several indices of sensitivity to amphetamine (psychopathology change) and emetic sensitivity to apomorphine. An examination of individual subjects' responses to amphetamine and, subsequently, neuroleptics, suggested that in the absence of significant clinical change after amphetamine a brisk therapeutic response to neuroleptics was rare.

Adult↗