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PubMed1983

Increased paroxysmal activity of partial seizures in man by apomorphine.

In order to study the role of dopamine (DA) in the regulation of seizure mechanisms in man, a non-emetic dose of apomorphine, a direct stimulant of DA receptors, was administered to eight patients effected by different types of epilepsy. The EEG changes induced by apomorphine administration in comparison to those elicited by promazine or placebo were evaluated in a double blind cross-over study. Similarly to promazine treatment, apomorphine worsened the EEG recordings of some patients. The apomorphine-induced increase in paroxysmal activity was observed in patients affected by partial epilepsy and was not related to the sleep-inducing properties of the drug. This effect is interpreted as being the result of a stimulation of DA autoreceptors, mediating a decrease of dopaminergic activity in the central nervous system. The use of apomorphine as an EEG activating agent is suggested.

Adolescent↗
PubMed1985

Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage interval.

Administration of drugs that reduce the influence of dopamine at its receptor site can lead to postsynaptic supersensitivity, whereas treatment with dopamine (DA) agonists can cause postsynaptic subsensitivity. Both unaltered and enhanced postsynaptic responses to DA have been shown after pretreatment with DA agonists. In the present manuscript pretreatment with apomorphine, a dopaminergic agonist, is shown to induce either increased or reduced locomotor activity. When a drug-free period between successive injections was allowed, apomorphine induced an enhanced locomotor response, whereas a reduced response occurred when each dose was injected before the previous apomorphine dose had been completely metabolized. Pretreatment with both high (1 and 3 mg/kg) and low (0.05 mg/kg) apomorphine doses enhanced the response. Apomorphine treatment that caused enhanced locomotor responses did not modify the stereotypy response to the drug. Similar enhanced or reduced response were found in rats with partial lesions of the nigrostriatal system. These altered responses to DA agonists may have important clinical consequences. The present data also suggest the existence of a different DA systems for locomotor and stereotypy actions of dopaminergic agonists.

Animals↗
PubMed1979

Antagonism of apomorphine-induced hyperthermia in MAOI-pretreated rabbits as a sensitive model of neuroleptic activity.

Apomorphine induced dose-dependent hyperthermia when applied intravenously to rabbits pretreated with a monoamine oxidase inhibitor. Inhibition of the synthesis of catecholamines (by alpha-MT) did not influence on apomorphine-induced hyperthermia, whereas 5-HT synthesis inhibition (by PCPA) completely abolished the hyperthermic response. Some neuroleptics and a 5-HT receptor blocking agent inhibited the hyperthermia in very low doses. A highly significant correlation was registered between the antagonism of apomorphine hyperthermia of 15 neuroleptics and their clinically useful doses. It is concluded that apomorphine-induced hyperthermia most likely is a result of direct stimulation of dopamine receptors and release of 5-HT, and that abolition of this response represents a very sensitive in-vivo model for neuroleptic substances. Antagonism of apomorphine-induced hyperthermia may be achieved by either dopamine or 5-HT receptor blockade.

Animals↗
PubMed1982

Jumping behavior induced by thyrotropin releasing hormone in combination with apomorphine in mice.

Neuronal mechanisms involved in the jumping produced by thyrotropin releasing hormone (TRH) plus apomorphine were studied in mice. TRH (5--20 mg/kg IP) administered after apomorphine (0.25--2.0 mg/kg IP) elicited jumping behavior, the frequency of jumping being proportional to the dose of TRH but inversely related to the dose of apomorphine. Jumping behavior was also induced by TRH (20 mg/kg IP) administered after atropine (5 mg/kg IP) or clonidine (0.5 mg/kg IP). The jumping elicited by TRH (20 mg/kg IP) in combination with apomorphine (0.25 mg/kg IP) was decreased by pretreatment with haloperidol (1 mg/kg IP), physostigmine (0.2 mg/kg IP) or phentolamine (10 mg/kg IP), unaffected by propranolol (10 mg/kg IP), and markedly increased by atropine (5 mg/kg IP) or clonidine (0.5 mg/kg IP). The results suggest that TRH in combination with apomorphine, atropine or clonidine elicits jumping in which dopaminergic, cholinergic and noradrenergic functions are concomitantly involved.

Animals↗
PubMed1985

Experimental catalepsy is both enhanced and disrupted by apomorphine.

In mice that were scored for the length of time they remained immobile in awkward postures (cataleptic) on an inclined wire grid, a large IP dose of pilocarpine (80 mg/kg) caused a clear catalepsy, which was prevented by both dopamine agonists that were tested, apomorphine (4 or 8 mg/kg, IP) and bromocriptine (8 mg/kg, IP). In other experiments, haloperidol (2.5 mg/kg) caused mild catalepsy. As expected, neither 4 nor 8 mg/kg apomorphine caused much effect when given alone, but both doses produced profound and long-lasting catalepsy in the haloperidol-treated animals. Bromocriptine also had little effect when given alone, and neither 4 nor 8 mg/kg enhanced the haloperidol catalepsy. Apomorphine alone produced catalepsy at low doses. Repeated testing after a low (0.3 mg/kg) dose of apomorphine showed that catalepsy was most profound at 5 min postinjection, with progressive decline thereafter. Apomorphine, but not bromocriptine, thus can produce catalepsy under certain conditions of DA receptor blockade or in low dose. Catalepsy, and perhaps other forms of hypomotility, appear to be differentially mediated by a subclass of dopaminergic receptors.

Animals↗
PubMed1989

Studies on the discriminative stimulus properties of apomorphine in rhesus monkeys.

Four rhesus monkeys were trained to discriminate the effect of apomorphine (0.1 mg/kg IM) from that of saline injections. The discriminative stimulus (DS) effect of apomorphine generalized to the dopamine D2 receptor agonist quinpirole. The D1 dopamine receptor agonist SKF 38393 elicited responses only on the saline-appropriate lever. Stimulus generalization of the dopamine autoreceptor agonist 3-PPP exhibited stereospecificity favoring the (+) over the (-) isomer. d-Amphetamine, phencyclidine, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and clonidine did not share the DS effect of apomorphine. The D2-selective antagonists sulpiride and metoclopramide reversed both the DS effect and the response rate reduction produced by the training dose of apomorphine. Chlorpromazine and the D1 antagonist Sch 23390 also antagonized the DS effect, but the antagonism was accompanied by a further rate reduction. Haloperidol and clozapine antagonized the DS effect incompletely. The DS effect produced by apomorphine in this study appears to be mediated predominantly by post-synaptic D2 receptor activation, with contribution also from the D1 receptor.

Animals↗
PubMed1989

Appearance of a stereotyped apomorphine-induced climbing in unresponsive DBA2 mice after subchronic manipulations of brain dopamine transmission.

DBA2 mice show an erratic spontaneous climbing which is reduced by increasing doses of direct dopamine agonists (apomorphine up to 5 mg/kg, piribedil up to 20 mg/kg). Sustained stereotyped climbing occurs when animals are treated with L-dopa plus benserazide and dexamphetamine. In this strain, which is spontaneously insensitive to apomorphine-induced climbing, this behaviour progressively appeared in a stereotyped manner after repeated administrations of apomorphine (5 mg/kg). The sensitization to apomorphine-induced climbing is long-lasting (more than 15 days). A similar sensitization may be induced by repeated administrations of either piribedil or of the dopamine uptake inhibitor GBR 12783. The semichronic reduction in dopaminergic transmission induced by four administrations of haloperidol (2 mg/kg at 2-day intervals) or by pretreatment with reserpine (3 mg/kg) induced sensitization to apomorphine-induced climbing. These results are discussed in terms of modifications in the sensitivity of two types of dopamine receptors exerting opposite effects on climbing behaviour.

Animals↗
PubMed1984

Inhibition of striatal tyrosine hydroxylase by low concentrations of apomorphine.

The inhibitory effect of apomorphine on tyrosine hydroxylase (TH) was tested using enzyme preparations from rat striatum, neuroblastoma clone N1E-115 and pheochromocytoma clone PC-12. When the striatal enzyme preparation was incubated at pH 7.2 with (6R,S)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) as cofactor (100-1,000 mumol/l), the IC50 for apomorphine was found to be in the 0.1-1 mumol/l range depending on the BH4-concentration used. Changing the incubation medium to pH 6.0 yielded an IC50 of about 2.5 mumol/l (BH4 = 100 mumol/l). Apomorphine was even less effective when 2-amino-4-hydroxy-6,7-dimethyl-5,6,7,8-tetrahydropteridine (100 mumol/l) was used as cofactor (IC50 approximately 10 mumol/l). Similar results were obtained with the enzyme preparations of the two cell clones. These experiments show that, even in low concentrations, apomorphine inhibits TH directly, provided more physiological test conditions are used. The relevance of these results for the autoreceptor-mediated mechanism of the apomorphine action on catecholamine synthesis is discussed.

Animals↗
PubMed1976

Therapeutical efficacy of a combination of apomorphine with sulpiride or metoclopramide in Parkinsonism.

In healthy volunteers the emetic effect of apomorphine (5-10 mg, i.m.) was prevented by haloperidol (2 mg), metoclopramide (10 mg) and sulpiride (100 mg), injected intramuscularly. In parkinsonian patients, apomorphine (1 mg) given alone ameliorated the neurological symptoms (30% improvement in the disability score), but the improvement was accompanied by nausea, vomiting, sedation or sleepiness. Haloperidol (2 mg) prevented not only the emetic effect of apomorphine (10 mg), but also its therapeutic efficacy in parkinsonism. Indeed, the disability score was worsened by the drug combination in some patients. Moreover, after haloperidol, apomorphine produced deep sedation and sleep. By contrast, in parkinsonian patients pretreated with metoclopramide (10 mg) or sulpiride (100 mg), apomorphine (10 mg) markedly diminished tremor and rigidity and failed to produce nausea, vomiting and sleepiness.

Adult↗
PubMed1988

Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses.

Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0-50.0 micrograms/ul), contralateral rotation. However, while apomorphine produced ipsilateral rotation in rats with unilateral striatal kainic acid lesions, a response considered to be dependent upon normosensitive dopamine receptors, neither caffeine nor theophylline produced rotational responses. As for apomorphine, the rotational behaviour elicited by caffeine (15.0 mg/kg SC) and theophylline (25.0 mg/kg SC) was inhibited by the dopamine antagonists cis-(Z)flupentixol, haloperidol and sulpiride. Nevertheless, despite the fact that cis-(Z)flupentixol was the most potent inhibitor of the caffeine response, no more than 50% inhibition was produced with doses as high as 1.0-10.0 mg/kg SC of cis-(Z)flupentixol. Pretreatment with alpha methyl-p-tyrosine inhibited the rotational response produced by caffeine in 6-OHDA-lesioned animals, but did not significantly modify the apomorphine response. Furthermore, the benzodiazepine diazepam produced a dose-dependent inhibition of the caffeine rotation, but again, the apomorphine response, although qualitatively modified, was not significantly inhibited.

Animals↗
PubMed1977

Effect of apomorphine on schizophrenic symptoms.

The effects of apomorphine on psychotic symptoms were evaluated in chronic schizophrenic patients using double-blind placebo controlled procedures. Although on the basis of dopamine theory of schizophrenia, apomorphine was expected to increase schizophrenic symptoms, in this study apomorphine substantially reduced psychotic symptoms in some chronic schizophrenic patients. No patient showed the substantial increase in psychotic symptoms previously demonstrated after the administration of IV methylphenidate. These clinical effects of apomorphine in schizophrenia may be relevant to recent pharmacological research which has indicated that apomorphine also has potent effect on presynaptic dopamine neurons, in addition to its previously described postsynaptic receptor stimulation.

Apomorphine↗
PubMed1994

Naloxone does not prevent apomorphine-induced emesis or hypotension in dogs.

Previous data have shown that apomorphine-induced respiratory depression can be reversed by the opiate antagonist, naloxone. The present study investigates the influence of naloxone on cardiovascular changes and vomiting elicited by apomorphine in dogs. In chloralose-anaesthetized animals, naloxone (0.02 mg/kg i.v.) failed to modify either the decrease in blood pressure and the biphasic changes (bradycardia followed by a long-lasting tachycardia in heart rate or the characteristics (occurrence, latency, duration) of the emesis elicited by apomorphine (200 micrograms/kg i.v.). In contrast, in conscious animals, naloxone (0.02 mg/kg i.v.) increased both the number and the duration (but not latency) of vomiting induced by a lower dose of apomorphine (30 micrograms/kg i.v.). These data show that apomorphine-induced vomiting and arterial hypotension do not involve opiate receptors.

Anesthetics↗
PubMed1990

Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains.

Apomorphine disruption of prepulse inhibition (PPI) has been proposed as an animal model of sensorimotor gating deficits exhibited by schizophrenics. The effects of apomorphine on PPI of the acoustic startle reflex in male rats of Wistar and CD (Sprague-Dawley derived) strains were compared under identical test conditions. In Wistar rats, subcutaneous administration of 0.25-1.0 mg/kg apomorphine blocked PPI without affecting startle amplitude. In CD rats, apomorphine (0.3-3.0 mg/kg, SC) had no effect on PPI, but increased startle amplitude. Therefore, choice of rat strain is an important factor in the design of experiments studying apomorphine effects on PPI.

Acoustic Stimulation↗
PubMed1995

Effects of adenosine agents on apomorphine-induced yawning in rats.

In the present work, adenosine agonists and antagonists on apomorphine-induced yawning in rats was investigated. Subcutaneous (SC) injection of apomorphine (0.02, 0.05 and 0.1 mg/kg) induced dose-dependent yawning behaviour in rats. Intracerebroventricular (ICV) administration of different doses of the drug (1, 3, 5 micrograms/rat) also caused a dose-related yawning. ICV administration of the adenosine receptor agonists 5-N-ethylcarboxamidoadenosine (NECA) and N6-cyclohexyladenosine (CHA) decreased apomorphine-induced yawning. The response induced by the adenosine agonists was reduced by 8-phenyladenosine (8-PT) pretreatment. The yawning induced by SC and ICV administration of apomorphine was decreased by ICV or IP injection of theophylline, respectively. It is concluded that at least A1 adenosine receptors may exert negative influence on the apomorphine-induced yawning. However, the exact mechanism(s) of adenosine receptors in this behaviour remain to be established.

Adenosine↗
PubMed1995

Free radical scavenging properties of apomorphine enantiomers and dopamine: possible implication in their mechanism of action in parkinsonism.

The influence of R(-) apomorphine, S(+) apomorphine and dopamine on the oxidation kinetics of two polyunsaturated fatty acids (PUFA) (cholesteryl linoleate (CL) and Trilinolein (TL)) was investigated. The oxidation was initiated by free radicals generated through thermal decomposition of 2.2'-Azobis(2-methyl-propionitrile) (AMPN) in phosphate buffer (pH 7.4) thermostated at 50 degrees C. The hydroperoxides formed were determined by iodine titration using a diode array spectrophotometer at 290nm. Both enantiomers of apomorphine as well as dopamine exerted an inhibitory effect. Tocopherol (alpha-tocopherol) and ascorbic acid were used as controls. The former inhibited while ascorbic acid facilitated the oxidation reaction. These results are discussed in relation with the possible role of oxidative injury in parkinsonism and the usefulness of apomorphine in elevating "on-off" episodes. On this basis, the non-dopaminergic enantiomer of apomorphine (S(+)-isomer) is put foward to test the importance of its radical scavenging properties in parkinsonism which could eventually lead to a therapeutic alternative with less side effects.

Apomorphine↗
PubMed1988

Apomorphine anorexia: the role of dopamine receptors in the ventral forebrain.

The inhibition of feeding following the administration of apomorphine, systemically or directly into the nucleus accumbens/ventral striatum, was studied using a microstructural analysis paradigm. On systemic administration, apomorphine reduced food consumption, eating rate and eating time; the effects were blocked by sulpiride but not by SCH-23390. Two doses of apomorphine were administered centrally. Both doses reduced total food intake and eating rate; only the higher dose also reduced eating time; all of these effects were blocked by sulpiride pretreatment. Only the lower dose reduced locomotor activity and rearing in the open field. The results suggest that apomorphine reduces eating rate by an action on dopamine (DA) axon terminal autoreceptors. We have previously demonstrated that apomorphine reduces eating time by an action on DA cell body autoreceptors. Therefore, the two populations of DA autoreceptors appear to be differentially involved in behaviour.

Animals↗
PubMed2001

NMDA-type glutamatergic modulation in dopaminergic activation measured by apomorphine-induced cage climbing behaviors.

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced dopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). I.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic stimulation, but not AMPA/Kainate and mGlu type glutamate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Apomorphine-induced disruption of prepulse inhibition that can be normalised by systemic haloperidol is insensitive to clozapine pretreatment.

RATIONALE: Prepulse inhibition (PPI) of startle refers to the phenomenon in which a weak prepulse attenuates the startle response to a succeeding intense stimulus. PPI can be disrupted by systemic apomorphine in animals, and reduced PPI has been consistently reported in schizophrenia patients. The ability of the atypical antipsychotic clozapine to reverse apomorphine-induced PPI deficit has been demonstrated in the rat, but has not yet been tested in the mouse. The present study was designed to fill this gap. OBJECTIVE AND RESULTS: We investigated the efficacy of clozapine in reversing apomorphine-induced (2.0 or 2.5 mg/kg, s.c.) PPI deficit in C57BL6 mice. Clozapine failed to restore PPI disruption in apomorphine-treated mice in two independent laboratories across two dose ranges (1-3 mg/kg, i.p., or 3-30 mg/kg, p.o.), whereas the typical antipsychotic haloperidol (1 mg/kg, i.p.) completely normalised PPI performance. CONCLUSIONS: Unlike the rat, apomorphine-induced PPI disruption in mice might be instrumental in distinguishing between typical and atypical antipsychotic drugs. This also lends further support to the suggestion that the neuropharmacology of PPI is not identical in the two rodent species.

Animals↗