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PubMed1987

Microwave facilitation of domperidone antagonism of apomorphine-induced stereotypic climbing in mice.

The dopaminergic agonist apomorphine produced dose-dependent stereotypic climbing behavior in mice housed in cages with vertical bars. This drug effect was competitively inhibited by systemic pretreatment with the centrally acting dopaminergic antagonist haloperidol but not by microwave irradiation (2.45 GHz, 20 mW/cm2, CW, 10 min) nor by systemic pretreatment with domperidone, a dopaminergic antagonist that only poorly penetrates the blood-brain barrier (BBB). Yet when mice were systemically pretreated with domperidone and then subjected to microwave irradiation (as above), the apomorphine effect was significantly reduced. Microwave irradiation also facilitated antagonism of the apomorphine effect by low and otherwise ineffective systemic pretreatment doses of haloperidol. Apomorphine-induced stereotypic climbing behavior was also reduced by domperidone administered intracerebrally, which bypassed the BBB. Exposure of intracerebral domperidone-pretreated animals to microwave irradiation failed to increase the degree of antagonism. These findings indicate that microwave irradiation can facilitate central effects of domperidone, a drug which acts mainly in the periphery. One possible explanation for these findings is that microwave irradiation alters the permeability of the BBB and increases the entry of domperidone to central sites of action.

Animals↗

PubMed1980

Determination of apomorphine in plasma by selected ion monitoring.

A selected ion monitoring assay for apomorphine using N-n-propylnorapomorphine as an internal standard is described. The molecular ions of the TMS derivatives of apomorphine (m/z 411) and N-n-propylnorapomorphine (m/z 439) were assayed simultaneously by selected ion monitoring. Sensitivity was 30 ng per ml plasma. The results obtained by plasma apomorphine concentration time course study in rats suggested that this method was applicable to pharmacokinetic studies for apomorphine.

Animals↗

PubMed2006

Determination of apomorphine in canine plasma by liquid chromatography-electrospray ionization mass spectrometry and its application to a pharmacokinetic study.

An LC-ESI-MS method was developed and validated for the assay of apomorphine in canine plasma using one-step liquid-liquid extraction. The analytes were separated on a Phenomenex Gemini C18 (150 mm x 2.0 mm id 3 microm) column and determined by MS in the positive ion mode. The linear range was 0.4-40 ng/mL with an LOD of 0.2 ng/mL for apomorphine in plasma. The intraday and interday precision and accuracy of quality control samples were < 5.9% RSD and < 7.5% bias for apomorphine. Extraction recoveries were > 80%. The validated method was successfully applied to analyze canine plasma samples in a pharmacokinetic study of apomorphine in dogs and detailed pharmacokinetic parameters were calculated.

Administration, Intranasal↗

PubMed1993

Correlation of clinical response in apomorphine test with D2-receptor status as demonstrated by 123I IBZM-SPECT.

The knowledge of functional capacities of postsynaptic dopaminergic receptors in parkinsonian syndromes is important for differential diagnosis and for planning therapeutic approaches. Subcutaneous apomorphine challenges serve as a pharmacological tool in testing dopaminergic responsiveness, but discrepancies between results of the apomorphine test and long-term levodopa treatment remain. 123I IBZM (I-123 labeled iodobenzamide) as a dopaminergic receptor ligand allows depiction of D2-receptors by means of SPECT methods. The correlation between dopaminergic responsiveness and D2-receptor status as demonstrated by 123I IBZM-SPECT imaging was assessed by applying an apomorphine test to 41 patients with parkinsonian syndromes. All subsequently underwent an 123I IBZM-SPECT. Apomorphine responders showed a significantly higher binding of 123I IBZM than nonresponders, and patients with idiopathic Parkinson's disease (IPD) had higher D2-receptor density as visualized by SPECT than patients with other parkinsonian syndromes. The marked overlap between the groups allowed a reliable prediction only in patients with an abnormally low basal ganglia/frontal cortex ratio of 123I IBZM binding.

Adult↗

PubMed1996

Effects of central dopaminergic stimulation by apomorphine on swallowing disorders in Parkinson's disease.

Swallowing disorders are common in Parkinson's disease but are of obscure and complex nature and pathophysiology. The effect of central dopaminergic stimulation on disordered swallowing is not well known. We studied the effects of apomorphine (in combination with domperidone) on buccolinguofacial motoricity and on various swallowing stages by using videofluoroscopy in eight patients with dysphagia. Swallowing abnormalities more frequently encountered were vallecular stasis (n = 7), fragmentation of the bolus (n = 7), and buccal stagnation of the bolus. Apomorphine improved vallecular stasis and fragmentation in about half the cases and improved buccal stagnation in all cases. Direct laryngeal penetration was found in three cases and improved in two of them. The total swallowing duration was improved by apomorphine in a subset of patients (n = 5). This improvement correlated with an improvement of the buccolinguofacial motoricity and was combined with an improvement of pharyngeal transit time. Thus central dopaminergic stimulation by apomorphine improved swallowing in a subgroup of patients, mainly in its early stages.

Aged↗

PubMed1998

The role of EDTA in provoking allergic reactions to subcutaneous infusion of apomorphine in patients with Parkinson's disease: a histologic study.

One of the formulations of apomorphine, used in clinical practice, contains sodium edetate (EDTA). EDTA is a chelator which indirectly prevents oxidation of apomorphine. A clinical and histologic study in four patients revealed that apomorphine with EDTA caused severe subcutaneous nodules, histologically characterized by an inflammatory infiltrate with a large amount of eosinophils, indicating a cell-mediated allergic reaction. After withdrawal of EDTA, this allergic component completely disappeared, which was accompanied clinically by less extensive nodule formation with a softer consistency. It is therefore recommended that EDTA be excluded from apomorphine formulations.

Abdominal Muscles↗

PubMed2000

Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes.

Apomorphine, a D1/D2 dopamine agonist, is an anti-parkinsonian drug. We examined the effects of apomorphine on synthesis of neurotrophic factors in cultured mouse astrocytes. After 24 h incubation with apomorphine, NGF and GDNF contents in the culture medium increased to 122-fold and 1.8-fold of the control, respectively; whereas the BDNF content did not change significantly. In Northern blot analysis, expression of NGF mRNA in astrocytes reached the maximum level at 6 h after addition of the drug. By semiquantitative RT-PCR analysis, the GDNF transcript level was found to reach 2.9-fold of the control level at 15 h. These results suggest that apomorphine may exert neuroprotective effects by stimulation of NGF and GDNF synthesis in astrocytes.

Animals↗

PubMed1997

Enhancement of the behavioral response to apomorphine administration following repeated treatment in the 6-hydroxydopamine-lesioned rat is temporally correlated with a rise in striatal preproenkephalin-B, but not preproenkephalin-A, gene expression.

Repeated dopamine receptor stimulation in the 6-hydroxydopamine (6-OHDA)-lesioned rat produces a marked enhancement in the behavioral response to a given dose of dopamine agonist. Such treatment also increases the synthesis of preproenkephalin-B (PPE-B) throughout the striatum and preproenkephalin-A (PPE-A) rostrally. To examine the relationship between these changes, 6-OHDA-lesioned rats were treated with apomorphine (5 mg/kg) twice-daily. Between 0.5 and 7 days treatment, behavior was monitored and the levels of PPE-A and PPE-B mRNA were determined by in situ hybridization. A single injection of apomorphine induced a well-known rotational response contraversive to the lesion (314 +/- 22 rotations h-1). However, with repeated injection, the response to apomorphine was markedly enhanced, being significantly higher on Days 3 (704 +/- 60 rotations h-1), 5 (1354 +/- 104 rotations h-1), and 7 (1680 +/- 117 rotations h-1). In the lesioned caudate-putamen, but not in the nucleus accumbens, PPE-B expression rose in a manner that was temporally correlated with the enhanced locomotor response to apomorphine. PPE-A expression in the lesioned striatum, significantly increased only after 7 days treatment, did not correlate with the behavioral response. In conclusion, PPE-B may contribute to the development of behavioral supersensitivity following repeated dopamine-replacement therapy in animal models of Parkinson's disease.

Adrenergic Agents↗

PubMed2004

Worsened motor test performance following acute apomorphine injection in previously untreated patients with Parkinson's disease.

Instrumental tests and clinical rating assess motor disability in Parkinson's disease (PD) patients. Previous long-term dopaminergic substitution influences the behaviour following acute dopaminergic stimulation. Objective of this study was to investigate the motor response following an apomorphine application in previously untreated-, treated- and before treated PD patients, who received placebo. Outcomes of instrumental tests worsened in previously untreated-, but not in before treated PD patients after apomorphine injection and in the PD subjects under the placebo condition. Generally, rating scores of motor symptoms significantly improved after apomorphine administration, whereas placebo application showed no effects. Tolerance to sedative effects of apomorphine in treated PD patients or sensitivity of employed motor tests to presynaptic dopaminergic autoreceptor mediated inhibition of endogenous dopamine release or postsynaptic dopaminergic overstimulation with resulting decreased cognitive function in previously untreated PD patients hypothetically caused this discrepancy between outcomes of subjective clinical rating and objective motor test performance.

Adult↗

PubMed2000

Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine.

There have been many attempts to discover neuroprotective drugs for the treatment of Parkinson's disease (PD). Many of these compounds either do not cross the blood brain barrier or are not very effective in the 6-hydroxydopamine or MPTP (N-methyl-4-phenyl-1,2,3,6-terahydropyridine) models of PD. We have examined several compounds including dopamine receptor agonist bromocritine, lisuride, pergolide and R-apomorphine for their neuroprotective action against the above neurotoxins in PC12 and dopamine neuroblastoma cell lines in culture and in vivo. R-apomorphine exhibited relatively potent neuroprotective action in vitro, cell culture and in vivo as a radical scavenger and iron chelator, because of its catechol structure. The recent clinical trials with apomorphine, where parkinsonian subjects can be weaned off L-dopa would suggest that this drug either exerts a neuroprotective action or that continuous sustained stimulation of dopamine receptor may be responsible for its unusual pharmacological activity. Apomorphine has a far more broad neuroprotective activity in the various models as compared with 1-selegiline and may therefore be an ideal drug to study neuroprotection in parkinsonian subjects with the use of PET or SPECT.

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

PubMed1986

Individual and morphological differences in the behavioural response to apomorphine in rats.

The topography of stereotyped behaviour produced by apomorphine in rats was studied by using either a scoring system, based on observation in a wire cage, or by quantification of horizontal and vertical activities, and of the total distances run in an open field, using an automatic recording system. The latter design was combined with a classification of the type of stereotyped behaviour observed during recording. In addition, the reproducibility of the nature of the stereotyped behaviour and its dose-dependence in individual animals was evaluated. In rats observed in a wire cage, apomorphine at lower doses (0.25 or 0.50 mg/kg SC) produced stereotyped sniffing. Increasing the doses led to stereotyped licking and the largest dose (5.00 mg/kg SC) produced predominantly stereotyped gnawing, as was demonstrated graphically. The type of behaviour produced by 2 mg/kg apomorphine in the open field was reproduced well in individuals after a second administration 4 days later. The shift from sniffing to gnawing was observed in most, but not all of the individually classified animals after administration of the largest dose (5 mg/kg). The locomotor part of motility was highest in "sniffing animals" and lower when gnawing occurred. The non-locomotor part of motility was low in "sniffing rats" and increased when licking and gnawing occurred. In some of the animals a characteristic "climbing" behaviour was observed in addition after the larger doses, which did not interfere with sniffing, licking or gnawing. A combination of classification by observation and automatic recording seems the most appropriate way to study the topography of stereotyped behaviour produced by apomorphine.

Animals↗

PubMed1986

Antagonism of apomorphine-induced yawning by SCH 23390: evidence against the autoreceptor hypothesis.

The ability of apomorphine to induce yawning (YWG) in normal and reserpinized rats and its interaction with SCH 23390, a potent and specific D-1 receptor antagonist, was studied. Apomorphine was more potent in inducing YWG in reserpine-pretreated as compared to control rats. SCH 23390, in low doses (0.05 mg/kg SC), was able to significantly reduce the YWG evoked by apomorphine both in control and in reserpine-pretreated rats. The results indicate that D-1 receptors contribute to YWG elicited by apomorphine and contradict the idea that this effect is mediated by DA autoreceptors.

Animals↗

PubMed1978

A putative multipartite model of haloperidol interaction in apomorphine-disturbed behavior of the dog.

The interaction between various doses of apomorphine and haloperidol on intracranial self-stimulation in the dog was studied using a pradigm in which reinforcing brain-stimulation was controlled by a discriminative auditory stimulus. Reinforced lever-pressing was decreased by low doses of apomorphine and completely suppressed by stereotypogenic doses. At various doses of apomorphine, low doses of haloperidol either increased response inhibition by enhancing stereotypy, or increased lever pressing by reducing stereotypy while concomitantly increasing the number of nonreinforced responses. Intermediate to relatively high doses of haloperidol antagonized stereotypy and the response inhibition produced by apomorphine. High doses of haloperidol antagonized stereotypy but also suppressed self-stimulation. Thus, haloperidol is not only able to restore performance capability, but also disturbed reinforcing and discriminative stimulus control.

Animals↗

PubMed1984

Differential effects of apomorphine in 6-hydroxydopamine-treated and aged rats.

Effects of dopamine depletion and old age were tested on the ability of rats to discriminate the interoceptive cue produced by IP administered apomorphine. In Experiment 1, rats were administered IC injections of 6-hydroxydopamine or its vehicle at 5 days of age. Administration of this dopamine neurotoxin resulted in significant depletion of whole-brain dopamine to 27.2% of controls as indicated when the brains of littermate rats, killed at 35 days of age, were analyzed by high-pressure liquid chromatography. Although this dopamine depletion was significant, toxin-treated rats learned to discriminate 0.16 mg/kg apomorphine from saline at the same rate as control rats. However, the dose-response curve for apomorphine discrimination after doses of 0.04-0.24 mg/kg suggested hypersensitivity to the dopamine agonist in toxin-treated rats. In Experiment 2, senescent rats were similarly trained to discriminate apomorphine in the two-lever food-motivated operant task. Dose-response testing indicated hypersensitivity similar to that found in 6-OHDA-treated rats. This increased behavioral responsiveness of aged rats to dopamine agonists is discussed in relation to receptor supersensitivity, metabolic rates, and blood-brain barrier permeability.

Aging↗

PubMed1980

Suppression of REM and delta sleep by apomorphine in man: a dopamine mimetic effect.

Apomorphine, a direct stimulant of dopamine receptors, was given in nonemetic doses by continuous IV infusion for 180-240 min during night sleep in normal subjects. During apomorphine infusion, a significant reduction of stage (S)4 and an abolition of rapid eye movement (REM) sleep occurred. The percent duration of S2 was significantly increased. In the 240 min following interruption of 240-min infusion of apomorphine, a significant increase of S4 and REM percent duration was observed. The effect of apomorphine infusion on sleep was prevented by the administration of haloperidol or sulpiride, two dopamine receptor blocking agents. This suggests that it is due to a dopamine mimetic action.

Adult↗

PubMed1976

Effects of apomorphine and haloperidol on the acoustic startle response in rats.

A series of 3 experiments tested the effects of 0.01, 0.04, 0.19, 0.75, 3.00, and 6.00 mg/kg apomorphine and 0.13, 0.25, and 0.50 haloperidol on the acoustic startle response in rats. Apomorphine markedly facilitated startle amplitude for about 40 min after injection and then depressed startle over the next 40 min. Both the early facilitory and later inhibitory effects were directly related to the dose. Haloperidol (0.5 mg/kg--given 30 min before) completely blocked both the early facilitory and the later depressant effect of apomorphine (3 mg/kg). Haloperidol alone had only a slight depressant effect on startle. The data support the conclusion that DA receptor stimulation enhances acoustic startle amplitude and indicate that a previous report failed to find an effect of apomorphine on startle because startle was only measured 40 min after injection.

Acoustic Stimulation↗

PubMed1985

Effects of apomorphine and haloperidol on "spontaneous" stereotyped licking behaviour in the Cebus monkey.

Three recently arrived drug naive Cebus apella monkeys with "spontaneous" stereotyped oral movements were treated with apomorphine and haloperidol using a wide dose range. Low doses of apomorphine (0.05-0.1 mg/kg) suppressed the oral stereotypies without affecting normal behaviour such as grooming and scratching. Higher doses of apomorphine (0.25-1.0 mg/kg) and haloperidol (0.01-0.1 mg/kg) also decreased or abolished the oral stereotypies, but induced generalized stereotypies (apomorphine) or dystonia/parkinsonism (haloperidol), suppressing normal behaviour. The findings indicate that dopamine is involved in these presumably stress-induced (not drug-induced) stereotypies.

Animals↗

PubMed1983

Pharmacological characterization of the receptors involved in the apomorphine-induced polyphasic modifications of locomotor activity in mice.

Increasing doses of apomorphine elicited polyphasic changes in locomotor activity in mice, consisting of: (i) hypokinesia with a peak effect at 25 micrograms/kg, which was not antagonized by various neuroleptics used at the highest doses not changing spontaneous locomotor activity, except for haloperidol; (ii) a relative restoration of locomotor activity at 75 micrograms/kg; this effect was antagonized by all the neuroleptics tested (except clozapine) and was hardly affected by domperidone and sulpiride; this apomorphine-induced effect was markedly increased 12 days after ICV 6-hydroxydopamine, (iii) a further hypokinetic effect with a peak effect at 150 micrograms/kg-1 (occurring simultaneously with hypothermia) which was antagonized by all the neuroleptics tested (including sulpiride at low doses) except levomepromazine and clozapine, and was again hardly affected by domperidone; this hypokinesia was reduced after prior (24 h) administration of 5 mg/kg apomorphine, (iv) finally another restoration of locomotor activity was observed at doses of apomorphine above 200 micrograms/kg.

Animals↗