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PubMed1995

Apomorphine continuous stimulation in Parkinson's disease: receptor desensitization as a possible mechanism of reduced motor response.

Apomorphine is a potent nonselective agonist at D1 and D2 dopamine receptors. The utility of apomorphine in Parkinson's disease (PD) is well asserted but its clinical use is reduced because of its short half-life and numerous side-effects. The disabling "on-off" fluctuations are among the most frequent and troublesome complications of chronic levodopa therapy in PD. Apomorphine is effective to reverse refractory L-dopa induced "off" periods, but a reduced motor response after repeated administrations has also been described with this drug. The loss of response to apomorphine, when the drug is administered repeatedly, is well fitted by the processes of receptor phosphorylation and down regulation. Elucidation of the molecular bases of dopaminergic receptors desensitization may lead to a better understanding of the mechanisms of dopaminergic regulation, and to a more appropriate treatment of PD.

Antiparkinson Agents↗
PubMed1995

Pharmacokinetics of apomorphine in Parkinson's disease.

The pharmacokinetic properties of apomorphine in patients with Parkinson's disease are described. Apomorphine is lipophilic; it has a large volume of distribution and is rapidly cleared from plasma, with an elimination half life of 33 minutes. It is rapidly absorbed following subcutaneous injection, with peak levels achieved within 5-10 minutes in most patients. There is a large variation in absorption between patients but is more constant within patients following repeated dosing. Apomorphine rapidly equilibrates between plasma and brain. Like levodopa, the response tends to be largely "all or none"; larger doses produce a longer duration of effect within a 30-90 minute range. Apomorphine may be administered intranasally and sublingually; of these routes, the former is more quickly and completely absorbed. Other routes of administration, including rectally, are not as well absorbed but may also be used effectively.

Antiparkinson Agents↗
PubMed1995

Changes in the amplitude of the N30 frontal component of SEPs during apomorphine test in parkinsonian patients.

Somatosensory evoked potentials (SEPs) to median nerve stimulation have been performed before and after apomorphine-test in 10 parkinsonian patients. Latency and amplitude of the P14-N20 parietal complex and of the P20-N30 frontal complex were evaluated. The N30 amplitude was significantly reduced before apomorphine administration (p < 0.001) with a consequent increase of the N20/N30 amplitude ratio (p < 0.001). Eight patients clinically improved after Apomorphine. Following Apomorphine there was no change in the amplitude of the parietal complex P14-N20. On the other hand the frontal complex P20-N30 showed a significant amplitude potentiation (p < 0.005), with a reduction of the N20/ N30 amplitude ratio (ns). This finding was almost constant among the 8 responder patients. These results suggest the utility of combining clinical and neurophysiological data to assess the responsiveness to dopaminergic treatment.

Adult↗
PubMedDate not supplied

The effect of lesions of dopaminergic and serotonergic systems on apomorphine-induced hypothermia in the rat.

Bilateral lesion of caudate nucleus or substantia nigra as well as brain transsection between telencephalon and diencephalon potentiates the body temperature fall produced by apomorphine (5 mg/kg). A lesion of nucleus accumbens septi did not prevent the hypothermia, but slightly shortened its duration. Electrolytical and chemical (with 5,6-dihydroxytryptamine) lesions of both dorsal and medial raphe nuclei alleviated the hypothermia produced by apomorphine. The lesion of medial raphe nucleus did not affect, while the lesion of dorsal raphe nucleus prevented the hypothermia induced by apomorphine or piribedil (25 mg/kg). The results show that dopaminergic neurons of telencephalon are not involved in the mechanism of induction of apomorphine hypothermia, while the neurons of dorsal raphe nucleus participate in it.

5,6-Dihydroxytryptamine↗
PubMed1998

[Reduction of apomorphine-induced rotation in rats with additional destruction of the pedunculopontine nucleus contralateral to the unilateral nigrostriatal lesion].

Pedunculopontine nucleus (PPN) has been proposed to be one of the responsible sites for dopamine agonist induced contraversive rotation in rats with unilateral dopaminergic denervation. However, previous experiments have not confirmed possible participation of PPN in this rotational behavior. To determine whether contralateral side of the PPN plays a vital role in this rotation, we investigated apomorphine induced rotation in rats with further destruction of unilateral PPN contralateral to the nigrostriatal lesion. First, rats with unilateral PPN lesioned with N-methyl-D aspartic acid (NMDA) showed contralateral rotation when they were injected with apomorphine 0.5 mg/kg s.c. Second, rats with right substantia nigra previously lesioned with 6-hydroxydopamine were microinjected with NMDA (PPN lesion group) or vehicle (sham lesion group) into the contralateral (left)side of the PPN. Contraversive rotation induced by apomorphine 0.05 mg/kg s.c. did not show any significant change in PPN lesion group as compared with sham lesion group. Whereas such rotation induced by apomorphine 0.5 mg/kg s.c. significantly reduced to 61% in PPN lesion group as compared with that in sham lesion group. These results could be interpreted as a partial cancellation of rotational activity to the contralateral side (left) by the potential rotational activity toward the opposite side (right) in rats with additional contralateral PPN lesion. Although PPN might not serve as an output route for the dopaminergic neurotransmission in the basal ganglia, PPN itself could rather induce some movement affecting the basal ganglia.

Animals↗
PubMedDate not supplied

Time-dependent effects of antidepressant drugs on the low dose of apomorphine-induced locomotor hypoactivity in rats.

In the present study the hypothesis of antidepressant-induced subsensitivity of presynaptic dopamine receptors was readdressed. We used the behavioral model of low dose of apomorphine-induced locomotor hypoactivity in rats. Indeed, repeated administration of imipramine and citalopram attenuated the effect of low dose of apomorphine. However, the most interesting finding of the present study was the observation that similar and even stronger attenuation of low dose of apomorphine-induced hypoactivity was obtained by the acute treatment with imipramine, citalopram and amitriptyline, followed by 14 drug free days. That means that the acute antidepressant drug treatment seems to be sufficient to trigger the changes at the level of dopamine D2 presynaptic receptors and/or signal transduction mechanisms as a function of time, regardless of whether the drug is again administered. On the other hand, such the effect of time was not observed in the experiments using D-amphetamine as a motor stimulant. Only the repeated administration of antidepressant drugs enhanced the locomotor hyperactivity induced by D-amphetamine. Acute treatment, neither 2 h nor 14 days after the last dose, changed the D-amphetamine-induced hyperactivity. Such a difference in the time-dependent effects of antidepressant drugs on the locomotor activity induced by either the low dose of apomorphine or D-amphetamine may possibly result from the different mechanisms involved in the regulation of the biosynthesis of dopamine presynaptic and postsynaptic receptors in the rat brain.

Amitriptyline↗
PubMed1998

Dose response and concentration response relationship of apomorphine in patients with Parkinson's disease and end-of-dose akinesia.

The motor response and the PK-PD relationship of the dopamine agonist, apomorphine, after ascending single doses (0.5, 1, 2, 4 mg s.c.), was investigated in 10 patients with advanced Parkinson's disease presenting end-of-dose motor fluctuations. Aim of the study was to investigate the exact pharmacodynamic effects of different apomorphine doses on the magnitude and duration of motor responses in parkinsonian fluctuators. The average improvement in the magnitude of the motor response (% change of baseline score in the Columbia University Rating Scale) elicited by apomorphine was negligible with 0.5 mg, 10% after the 1 mg dose, 22% after 2 mg, and 25% after 4 mg. If a 20% improvement is considered clinically relevant, a response was seen in 0/10 patients (0.5 mg), 2/10 patients (1 mg), 6/10 patients (2 mg), and 6/8 patients (4 mg). The duration of response was about 0.25 h (1 mg), 0.58 h (2 mg), and 0.72 h (4 mg). An explorative analysis of individual plasma concentration vs. effect curve, yielded a steep, sigmoidal concentration effect relationship with fast equilibrium at the effect site. The EC50 of the individual curves averaged 20 pMol/ml. However, several curves exhibited proteresis, making the application of a PK-PD model impossible. The reason for proteresis is not clear, it might indicate acute tolerance as well as a redistribution of apomorphine from the effect site.

Adult↗
PubMed1976

[Nigrostriatally induced motor reactions in the rat. I. Rotational behavior and posture asymetry after intracerebral injection of apomorphine and dopamine].

Using a rotameter described by Ungrstedt, the influence of pretreatment with 6-hydroxy-dopamine and transections of the Capsula interna on the asymmetry of the animal's poise and movement following systemic and intracerebral administration of dopamine and apomorphine was studied. After lesion of the nigrostriatal tract, i.p. administered apomorphine caused the animals to rotate towards the damaged side. After injection of apomorphine in the Nucleus caudatoputamen of healthy animals, initial rotations towards the injection side with subsequent opposite rotation were observed, whereas dopamine injected into the Nucleus caudatoputamen and the Substantia nigra initiated rotations in contralateral direction only. Pretreatment with haloperidole nullified the effect of apomorphine. The results have proved the effectiveness both in the Nucleus caudatoputamen and the Substantia nigra of drugs stimulating the dopamine receptors. With intact rats, the two sides of the nigrostriatal system are functionally asymmetric, which is reflected by the quantitative differences of responses following stimulation of dopamine-sensitive receptors and the individually different preference of one rotational direction. These individual behavioural patterns are modified by experimental influences.

Animals↗
PubMed1995

A comparison of different sensory stimuli in producing conditioned apomorphine effects.

In previous studies, it was shown that apomorphine-induced stereotyped behaviour could be conditioned when apomorphine was repeatedly paired with sensory stimuli (CS). Since in these experiments, the sum of various sensory stimuli were applied, it seemed of interest to use each sensory stimulus separately in order to evaluate the relevance of each of the stimuli for the development of the conditioned responses (CRs). Therefore, apomorphine (0.5mg/kg s.c.) was repeatedly (six times) paired either with an auditory, an olfactory, a tactile or a compound (auditory + olfactory + tactile) stimulus. On the seventh (drug-free test) day, the rats were injected with solvent in the presence of the CS previously applied. It was shown that the olfactory stimulus alone when used as CS produced similar CRs (in particular, stereotyped sniffing and licking) as the compound stimulus, whereas the other stimuli applied did not noticeably contribute to the development of the CRs. Furthermore, similarly to the compound stimulus, the olfactory stimulus, but not the auditory or tactile one, enhanced the apomorphine-induced stereotypies in the presence of the CS. This result suggests that the application of olfactory stimuli might be of particular relevance for the development of conditioned dopaminergic responses.

Journal Article↗
PubMed1978

Apomorphine hydrochloride-induced improvement in Huntington's chorea: stimulation of dopamine receptor.

Four patients affected by Huntington's chorea (HC) with a well defined family history of the disease were injected intramuscularly with apomorphine hydrochloride in nonemetic doses, ranging from 1 to 4 mg. Soon after treatment, all patients showed a marked decrease in abnormal involuntary movements. Pretreatment with haloperidol (2 mg intramuscularly) or sulpiride (100 mg intramuscularly) 30 minutes prior to apomorphine treatment, prevented the therapeutic effect of this compound. It is suggested that apomorphine-induced improvement in Huntington's Chorea is mediated by the stimulation of a special kind of dopamine receptor, leading to inhibition of the activity of dopaminergic neurons.

Adult↗
PubMed1984

Growth hormone and prolactin response to apomorphine in schizophrenia and the major affective disorders. Relation to duration of illness and depressive symptoms.

The responses of serum prolactin (PRL) and growth hormone (GH) to the dopamine agonist apomorphine hydrochloride (0.75 mg subcutaneously) were studied in a large group of unmedicated hospitalized patients with functional psychoses. There were no differences in the GH response in various diagnostic groups. The PRL response was greater in patients with affective disorders. The GH response was inversely related to total duration of illness in the entire sample of patients, but this correlation was independent of age effect only in the group of patients with major depression. In schizophrenics, the effect of the two factors, age and duration of the illness, could not be separated. The apomorphine-induced GH response was significantly correlated with psychosis ratings and negative symptom scale scores. The apomorphine-induced PRL suppression correlated significantly with various measures of depression across diagnostic groups.

Adolescent↗
PubMed1984

Apomorphine and schizophrenia. Treatment, CSF, and neuroendocrine responses.

Previous studies have variably reported the efficacy of apomorphine in treatment of schizophrenia and tardive dyskinesia. Stimulation of dopamine neuron autoreceptors is the presumed mode of action. Low-dose apomorphine (0.75 mg subcutaneously) and placebo were administered to 25 male schizophrenics to evaluate the drug's effect on psychotic and tardive dyskinetic symptoms. No significant improvement or deterioration was seen. Concomitant measurements of plasma prolactin and growth hormone levels and CSF homovanillic acid level indicated that the dose used was centrally active. These results indicate that an active though nonsedating dose of apomorphine does not ameliorate symptoms of schizophrenia or tardive dyskinesia.

Adult↗
PubMed1999

Apomorphine and levodopa challenge in patients with a focal midbrain lesion.

Three patients who presented with parkinsonian signs resulting from a focal midbrain lesion are reported. In all patients parkinsonian features occurred acutely and improved following acute challenge with apomorphine but not with levodopa. Remission of parkinsonian signs occurred spontaneously to a different degree. Inconsistent clinical response following administration of levodopa has been well documented in patients with focal midbrain lesions associated with parkinsonian signs; however, the efficacy of apomorphine has not been tested before. Anatomic or etiologic features do not allow us to predict in which cases parkinsonian signs secondary to a midbrain lesion would respond to levodopa or to dopamine agonists. A trial with apomorphine is warranted in all such cases.

Adult↗
PubMed1994

Tactile sensory input regulates basal and apomorphine-induced immediate-early gene expression in rat barrel cortex.

Clipping of mystacial vibrissae on one side of the rat's snout results in sensorimotor asymmetries in normal behavior and in behavior induced by the dopamine receptor agonist, apomorphine. Immediate-early gene expression, a marker for short-term changes in neuron function, was used to examine whether this sensory deprivation leads to functional changes in the somatosensory barrel cortex under experimental conditions which reveal behavioral asymmetries. The expression of c-fos and zif268 immediate-early genes was assessed with in situ hybridization histochemistry. Four hours after unilateral clipping of the mystacial vibrissae, the level of zif268 mRNA was reduced in the corresponding part of the contralateral barrel field. Injection of apomorphine (5 mg/kg) resulted in increased expression of both c-fos and zif268 immediate-early genes in cortex and striatum. This apomorphine-induced increase was blocked in the sensory-deprived somatosensory cortex. Laminar analysis of gene regulation showed that vibrissae removal affected immediate-early gene expression in all layers of the barrel cortex. These results demonstrate that: (1) basal zif268 gene expression in neurons of the somatosensory cortex is dependent on sensory input, (2) cortical immediate-early gene expression is increased after dopamine receptor activation, and (3) in the barrel cortex, this increase is also dependent on sensory input. We suggest that the observed reduction in gene expression after vibrissae removal reflects decreased activation of neurons in the barrel column by removal of sensory input.

Animals↗
PubMed2005

Development of a gas chromatographic/mass spectrometric method to quantify R(-)-apomorphine, R(-)-apocodeine and R(-)-norapomorphine in human plasma and urine.

A method was developed and validated for the analysis of R(-)-apomorphine, (R-)-apocodeine and R(-)-norapomorphine in human plasma and urine with N-propylnorapomorphine as internal standard using gas chromatography/mass spectrometry (GC/MS) and single-ion monitoring after a single liquid-liquid extraction and silylation of compounds. The quantification limits were 1 ng/ml for apomorphine and apocodeine and 25 ng/ml for norapomorphine. Calibration curves were linear, within the range 1-100 ng/ml. Variation in intraday and interday precision was below 10%. This method was applied to study apomorphine bioavailability in nine patients with Parkinson's disease before and after coadministration of a catechol-O-methyl transferase inhibitor.

Apomorphine↗
PubMed1976

Derivatives of apomorphine and of other N-substituted norapomorphines.

Derivatives of apomorphine and of N-n-propylnorapomorphine were prepared to obtain modified pharmacological activity and enhanced chemical stability. Mouse profile and dog emesis screens were performed, and the activity of various N-substituted derivatives and their esters was evaluated and compared to the parent compounds. The N-n-propyl diacetate derivative and N-methyl and N-n-propyl ascorbate salts were remarkably stable to air: apomorphine etherate was no more stable than the free base. The dimers, the major products formed during the acid-catalyzed rearrangement of morphines to apomorphines, were all potent emetics. Additionally, two showed a significant antagonism to morphine in mice and dogs.

Animals↗
PubMed1993

Relief of akinesia by apomorphine and cerebral metabolic changes in Parkinson's disease.

The cerebral metabolic rate of glucose was measured in 14 Parkinson's disease patients with severe on-off fluctuations. Two positron emission tomography (PET) scans with [18F]fluorodeoxyglucose were performed, one after a challenge of subcutaneous apomorphine at a dose able to relieve akinesia within 15 min and the other with the vehicle. Apomorphine reduced glucose utilization by 4-6% in the lenticular nuclei and the occipital cortex and by 6-9% in the thalamic nuclei, but this effect was not statistically significant. Thus, central stimulation of dopamine receptors by apomorphine in advanced Parkinson's disease is not associated with cerebral metabolic changes as assessed by PET. Despite a dramatic improvement of the motor state, the global neuronal activity in the striatum and its downstream projections remains stable, suggesting an equilibrium between excitatory and inhibitory dopaminergic activities.

Aged↗
PubMed1998

Confirmation of the antidyskinetic effect of posteroventral pallidotomy by means of an intraoperative apomorphine test.

We present a series of six consecutive Parkinson's disease patients undergoing posteroventral pallidotomy (PVP), who received an apomorphine injection after thermolesioning the posteroventral region of the internal globus pallidus (GPi) to evaluate the effect of the lesion on drug-induced dykinesias and therefore to proceed with further lesions or to conclude the surgery. Five of six patients failed to present dykinesias or did so to a significantly lesser degree (F [2,10] 42.6; p < 0.0001) so that surgery was concluded. One patient continued having contralateral dyskinesia despite an improvement in rigidity and bradykinesia, therefore, a new track was performed followed by a new lesion. No differences were found between intrasurgical and 1-month postoperative apomorphine test values. This report indicates that the use of an apomorphine test after thermolesioning may provide a reliable tool to check lesion efficacy on dyskinesia. The development of techniques that provide additional clinical information to the electrophysiological recording could help improve the outcome of patients undergoing pallidotomy.

Aged↗