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PubMed2006

Examination of the safety and use of apomorphine prescribed in general practice in England as a treatment for erectile dysfunction.

OBJECTIVE: To examine the safety and use of apomorphine as prescribed in general medical practice in England as a treatment for erectile dysfunction (ED). PATIENTS AND METHODS: Apomorphine hydrochloride (marketed as Uprima, Abbott Laboratories Ltd, UK) is licensed in the UK as a sublingual therapy for ED. It is the first treatment for ED with a central mode of action. This postmarketing observational cohort study was conducted using prescription-event monitoring (PEM) methods. Exposure information was obtained from dispensed prescription data for patients first prescribed apomorphine between October 2001 and December 2002. Outcome data were derived from Green-Form questionnaires posted to prescribing physicians > or = 6 months after the date of the first apomorphine prescription for each patient. The study cohort comprised 11 185 patients, 99.3% (11,111) of whom were men, with a median (interquartile range) age of 61 (54-68) years. RESULTS: The most frequently reported prescribing indication was ED and the most frequently reported reason for stopping apomorphine was that it was 'not effective'. In addition, the percentage of patients for whom apomorphine was reported to have been effective was relatively low. Headache was the most commonly reported adverse drug reaction, and the most frequently reported clinical condition occurring in the first month of observation. A small number of events (24) were reported that were not listed in the current Summary of Product Characteristics (SPC) and were considered by the prescribing general practitioner (GP) to be associated with apomorphine use. CONCLUSION: The proportion of patients for whom apomorphine was reported to be effective was low. Also, 'not effective' was the most frequently reported event and a high percentage of patients stopped apomorphine because it was 'not effective'. The most frequently reported clinical adverse events (headache and nausea) were those listed in the SPC. A small number of reports for unlabelled events were thought by prescribers to be related to apomorphine use. The confounding factors of patient age and coexisting disease should be considered when assessing data from this study.

Adult↗
PubMed2000

Acute challenge with apomorphine and levodopa in Parkinsonism.

BACKGROUND: The diagnosis of different parkinsonian syndromes and the ability to predict long-term drug efficacy constitute important clinical issues. DESIGN: Motor responses to the acute administration of levodopa and apomorphine were analyzed in a series of 134 parkinsonian patients, including 83 patients with a clinical diagnosis of idiopathic Parkinson's disease (PD), 28 patients with multiple-system atrophy (MSA), 6 with progressive supranuclear palsy, and 17 with an unclassified parkinsonian syndrome. METHODS: The patients received oral levodopa/carbidopa (250/25 mg) and subcutaneous apomorphine (1.5, 3 and 4.5 mg). Clinical variations of the Unified Parkinson's Disease Rating Scale (UPDRS) motor score were evaluated 1 h following levodopa administration or 20 min following apomorphine. The motor improvement produced by each acute challenge was matched with the clinical diagnosis and with the response to chronic levodopa treatment. The diagnosis was verified by repeated clinical assessments or by autopsy in 2 cases. A receiver operating characteristics curve was plotted comparing PD vs. non-PD, PD vs. MSA and chronic responders vs. nonresponders. Cutoff threshold improvement was defined as the value closest to the crossing point for 80% sensitivity and 80% specificity, corresponding to the best trade-off for a predictive evaluation. RESULTS: UPDRS motor score improvement was on average higher in PD than in non-PD patients (levodopa: 29.8 vs. 12.2%; apomorphine 1.5 mg: 27.1 vs. 10.5%; apomorphine 3 mg: 27.7 vs. 9.7%; apomorphine 4.5 mg: 28.8 vs. 11.8%; p < 0.01 with Student's t test). When PD patients were compared to non-PD patients, levodopa challenge had the best diagnostic accuracy with a threshold improvement of 16%. Apomorphine had the best diagnostic accuracy with a threshold improvement of 13.5% for 1.5 mg, 13% for 3 mg, and 16% for 4.5 mg. This meant that patients improving at least 16% in all tests had the highest probability of having PD. When PD patients were compared to MSA patients, levodopa acute challenge had the best diagnostic accuracy with a threshold improvement of 17%. Apomorphine had the best diagnostic accuracy with an improvement of 13% for 1.5 mg, 15% for 3 mg, and 18% for 4.5 mg. This meant that patients improving at least 18% in all tests had the highest probability of having PD rather than MSA. When patients who responded to chronic levodopa treatment were compared to those who did not, acute challenge with levodopa had the best predictive accuracy with a threshold improvement of 14.5%. Apomorphine had the best predictive accuracy with an improvement of 13% for 1.5 mg, and 14% for 3 and 4.5 mg. This meant that patients improving at least 14.5% in all tests had the highest probability of responding to chronic treatment. CONCLUSION: A good agreement was found between acute challenges with levodopa/carbidopa and apomorphine, and the use of both improved the reliability of the test. Different threshold improvements after acute challenges would support a diagnosis of PD or the exclusion of MSA, and would have a predictive value for subsequent response to chronic levodopa therapy.

Age of Onset↗
PubMed1991

Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat.

Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.

Analysis of Variance↗
PubMed2000

Apomorphine: an underutilized therapy for Parkinson's disease.

Apomorphine was the first dopaminergic drug ever used to treat symptoms of Parkinson's disease. While powerful antiparkinsonian effects had been observed as early as 1951, the potential of treating fluctuating Parkinson's disease by subcutaneous administration of apomorphine has only recently become the subject of systematic study. A number of small scale clinical trials have unequivocally shown that intermittent subcutaneous apomorphine injections produce antiparkinsonian benefit close if not identical to that seen with levodopa and that apomorphine rescue injections can reliably revert off-periods even in patients with complex on-off motor swings. Continuous subcutaneous apomorphine infusions can reduce daily off-time by more than 50% in this group of patients, which appears to be a stronger effect than that generally seen with add-on therapy with oral dopamine agonists or COMT inhibitors. Extended follow-up studies of up to 8 years have demonstrated long-term persistence of apomorphine efficacy. In addition, there is convincing clinical evidence that monotherapy with continuous subcutaneous apomorphine infusions is associated with marked reductions of preexisting levodopa-induced dyskinesias. The main side effects of subcutaneous apomorphine treatment are related to cutaneous tolerability problems, whereas sedation and psychiatric complications play a lesser role. Given the marked degree of efficacy of subcutaneous apomorphine treatment in fluctuating Parkinson's disease, this approach seems to deserve more widespread clinical use.

Antiparkinson Agents↗
PubMed2002

Apomorphine monotherapy in the treatment of refractory motor complications of Parkinson's disease: long-term follow-up study of 64 patients.

Continuous subcutaneous infusion of apomorphine is now increasingly recognized as an effective treatment for refractory off periods and peak-dose dyskinesias in Parkinson's disease. We have reviewed our experience with apomorphine infusions, after a strategy decision in 1995 based on emerging preclinical data, to treat all patients with steady-state plasma levels of apomorphine throughout the waking day, minimizing additional pulsatile stimulation either by oral dopaminergic medication or bolus parenteral injections of apomorphine. Sixty-four patients have been treated with apomorphine pumps and 45 of these successfully converted to monotherapy, managing to discontinue all other forms of dopaminergic stimulation during the daytime treatment period with apomorphine. Patients were followed up for a mean of 33.8 months (range, 4-108 months) and clinical data analyzed retrospectively. The mean maintenance dose of apomorphine was 98 mg per 24 hours (monotherapy group: 103 mg/24 hours; polytherapy group: 93 mg/24 hours), which did not significantly increase at final follow-up. There was a mean maximum dyskinesia reduction of 64% (S.D. = 20) in the monotherapy group, compared to 30% (S.D. = 33) in those continuing on polytherapy (P < 0.001), despite a maintained increase in on time (monotherapy group: 55%, P < 0.005; polytherapy group: 50%, P = 0.05). Fifteen patients failed to successfully convert to monotherapy but benefited nonetheless, and only 3 failed apomorphine infusional therapy altogether. Reasons for failure were mixed, including difficulty with compliance and adverse effects such as daytime somnolence, skin complications, and painful dystonias. There was a significantly higher success rate in patients able to manage the treatment either independently or with the help of their caregiver. These results confirm that subcutaneous apomorphine monotherapy can reset peak-dose dyskinesia threshold in levodopa-treated patients and further reduce off-period disability after all available forms of oral medication, including long-acting dopamine agonists, have been tried.

Adult↗
PubMed1991

Absorption of apomorphine by various routes in parkinsonism.

We wanted to determine the absorption and clinical effect of sublingual (SL) and transdermal apomorphine in parkinsonism. Patients received single SL apomorphine doses (N = 7) and the absorption was compared with parenteral (N = 5) and oral (N = 4) doses. One patient received a transdermal dose of apomorphine. The relative bioavailability of SL apomorphine ranged from 10 to 22% of a parenteral apomorphine dose. Oral apomorphine was less than 4% bioavailable, and the transdermal dose did not produce detectable plasma levels. Three patients with motor fluctuations responded to SL apomorphine, with a latency to effect of 20-40 min and a duration of effect of 15-100 min. One patient used SL apomorphine as an adjunct with levodopa, and during 1 month reported a large decrease in "off" periods. We conclude that apomorphine is effectively absorbed by the sublingual route.

Absorption↗
PubMed1995

Peripheral and central pharmacokinetics of apomorphine and its effect on dopamine metabolism in humans.

Apomorphine is a dopamine receptor agonist increasingly used in the treatment of Parkinson's disease (PD). In the present study, we examined the plasma and ventricular cerebrospinal fluid (CSF) pharmacokinetics of apomorphine as well as its effects on dopamine metabolism in six patients (one woman and five men, mean age 79.5 years) without evidence of PD who underwent 48-h intracranial pressure monitoring for suspected normal pressure hydrocephalus. Maximal plasma apomorphine concentration (25.04 ng/ml) is found 20 min after subcutaneous injection (50 micrograms/kg), and the mean area under the curve is 1,439.37 ng/ml for 120 min. In contrast to plasma values, the maximal ventricular CSF apomorphine concentration (1.08 ng/ml) is found 30 min after injection and the mean area under that curve is 7% of that of plasma (96.69 ng/ml for 120 min). Apomorphine administration causes a significant reduction in ventricular CSF concentrations of dopamine and of its major metabolites sulfoconjugated dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). This effect starts 10 min after the injection of apomorphine, is maximal after 30 min (free dopamine, -30%; sulfoconjugated dopamine, -28%; HVA, -21%; DOPAC, -31%) and is still present, although to a lesser extent (-5 to -10%), 120 min after the injection of apomorphine. This study shows that in humans a dose of apomorphine commonly used in PD causes significant inhibition of dopamine metabolism lasting > 120 min. In addition to their symptomatic effects, dopamine agonists such as apomorphine may play a role in preventing or slowing the neurodegeneration in PD by autoreceptor-mediated inhibition of dopamine metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1999

Apomorphine has a potent antiproliferative effect on Chinese hamster ovary cells.

Apomorphine is a potent non selective agonist at the D1 and D2 dopamine receptors acting both pre- and post-synaptically. In this report we describe a novel function of apomorphine, independent from its dopaminergic activity. Apomorphine inhibits Chinese hamster ovary (CHO)-K1 cell proliferation in a dose-dependent manner. The EC50 of apomorphine-induced inhibition of CHO-K1 cell proliferation determined by cell counting was 3.24 +/- 0.07 microM. Remarkably, the dose-response curve obtained by measuring the incorporation of [3H]thymidine was practically identical to the previous one giving an EC50 of 3.52 +/- 0.04 microM. The dopaminergic antagonists SCH23390 and spiperone at a concentration of 10 microM (well beyond their Kd values for the dopamine D1- and D2-like receptors respectively) were not able to antagonize the effect of apomorphine on CHO-K1 cell proliferation. Apomorphine exerts its effect early during incubation; CHO-K1 cells exposed to apomorphine for a period as short as 1 h and then allowed to grow for three days were significantly reduced in number with respect to untreated control cells. After four hours of exposition to apomorphine (10 microM) the antiproliferative effect was similar to that seen when this compound was present in the bath for all three days. Concentrations of apomorphine higher than 10 microM induced cell death, and the colony was completely destroyed at 50 microM. Cytometric analyses showed a significant accumulation of CHO-K1 cells in the G2/M phase.

Animals↗
PubMed1986

Apomorphine response plasticity in lesioned rats: supersensitivity dependency and lack of drug- or non-drug-associated environmental cuing.

Low doses of apomorphine can induce biphasic, contralateral circling behaviour in rats having unilateral, 6-hydroxydopamine lesions of the substantia nigra. The present studies examined the extent to which this is linked to the supersensitive state, the possible contribution of apomorphine's actions in the intact striatum, and the extent to which response differentiation might be linked to drug- or non-drug-associated environmental cuing. In the first instance, weekly administration of 0.4 mg/kg SC apomorphine to "normosensitive" rats having electrolytic ablation of one caudate failed to result in biphasic circling, whereas clear biphasic responses developed in supersensitive, 6-hydroxydopamine lesioned animals receiving 0.05 mg/kg SC apomorphine at weekly intervals. In the second instance, 6-hydroxydopamine-lesioned animals exhibiting biphasic responses after three exposures to apomorphine continued to do so after additional electrolytic ablation of the contralateral caudate, indicating a primary role for apomorphine's interaction within the denervated striatum. In studying the possible role of drug- or non-drug-associated environmental cuing effects it was found that repeated exposure of 6-hydroxydopamine-lesioned rats to 0.05 mg/kg SC apomorphine at 2-h intervals failed to elicit biphasic responses, although these were evident when the same animals were tested 1 and 2 weeks later. However, studies combining weekly exposure to the test cages with saline or apomorphine administration failed to reveal a role of drug- or nondrug-associated environmental cuing in response differentiation. The latter findings are supported by those from supplementary studies employing opaque contact lenses, in which lesioned animals continued to respond biphasically to apomorphine when deprived of visual input.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Responses to apomorphine of pigs with different coping characteristics.

RATIONALE: Classification of pigs based on the degree of resistance they display in a so-called "backtest" seems, to a certain extent, predictive for their coping strategy. OBJECTIVE: The present study examined whether, as found in rodents, the behavioral response to apomorphine of pigs relates to individual coping characteristics. METHODS: During the suckling period pigs were subjected to the backtest. In this test, each pig is restrained on its back for 1 min and the resistance (i.e. number of escape attempts) is scored. Pigs classified as low-resisting (LR, n=10) or high-resisting (HR, n=10) were selected. At 17-18 weeks of age they received a saline and an apomorphine injection (0.2 mg/kg SC) on 2 consecutive days in a balanced design. Behavior was recorded until 120 min after injection. RESULTS: Apomorphine increased locomotion in all pigs and reduced standing, standing alert and defecating. In addition, apomorphine induced the occurrence of some peculiar activities, rarely seen in saline-treated pigs, which seemed to represent either a transition between different postures or a conflict between hind- and forelimb activities. Apomorphine-treated LR pigs performed significantly more of these activities than HR pigs. However, snout contact with the floor, an oral stereotypy, was significantly increased in apomorphine-treated HR pigs, but not in apomorphine-treated LR pigs. CONCLUSIONS: In conclusion, the response to apomorphine of pigs relates to their behavioral response, high-resisting (HR) versus low-resisting (LR), in the backtest. The contrasts in behavioral response to apomorphine suggest a difference in the dopaminergic system between HR and LR pigs.

Adaptation, Psychological↗
PubMed1985

Low doses of apomorphine elicit two opposing influences on dopamine cell electrophysiology.

Dopamine (DA) cells are known to be very sensitive to direct acting DA agonists, and inhibition of DA cell firing by low doses of DA agonists is generally considered to be an action of these agonists on DA cell autoreceptors. During intracellular recording from spontaneously discharging DA cells in vivo, intravenous administration of apomorphine (20 micrograms/kg i.v.) elicited a hyperpolarization and an increase in input resistance. The calculated reversal potential of the apomorphine effect was approximately -40 mV. However, in non-firing DA cells the reversal potential of these effects was significantly different (P less than 0.01), being close to the reversal potential of responses induced by stimulation of striatonigral pathways (i.e. -67 mV). In addition, haloperidol (0.01 mg/kg i.v.) reversed the hyperpolarization produced by apomorphine but not the increase in input resistance. Transection of striatonigral pathways eliminated most of the increase in input resistance accompanying apomorphine administration, and shifted the apomorphine reversal potential to a value positive to 0 mV. Low doses of apomorphine were also found to affect a class of zona reticulata (ZR) interneurons. Apomorphine caused decreases in ZR cell firing rate, which were abolished by striatonigral pathway transection. Thus, the following mechanism is proposed for the electrophysiological actions of autoreceptor-selective doses of apomorphine on DA cells: (1) apomorphine directly inhibits spontaneous DA cell discharge by inhibiting the slow depolarization preceding action potentials and thereby hyperpolarizes the DA cell, (2) decreased DA cell firing disinhibits GABAergic striatal cells, whose increased firing preferentially (3) inhibits GABAergic ZR interneurons, and thus (4) removes an inhibitory input to DA cells, resulting in an increase in input resistance.

Animals↗
PubMed1984

Evidence that apomorphine and pergolide induce rotation in rats by different actions on D1 and D2 receptor sites.

Apomorphine and the ergot derivative pergolide induced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation of the ascending dopamine pathways. This was interpreted as an action on supersensitive receptors. However, large differences were found when comparing apomorphine and pergolide dose-response curves as well as the patterns of rotational behaviour the compounds elicited. Pergolide had a steep dose-response curve, while apomorphine had a flatter curve reaching a plateau at the dose of 1 mg/kg s.c. In doses higher than 1 mg/kg, apomorphine induced self-mutilation, while this was infrequent after pergolide. Apomorphine induced a two-peak pattern of rotation that never occurred when the same rats were tested with the ergot derivative. Both drugs induced dose-dependent ipsilateral rotation in animals with unilateral striatal kainic acid lesions but at doses 100 times higher. This effect was interpreted as an action on normosensitive receptors situated on the intact side. The differences between apomorphine and pergolide may be explained in terms of actions on different dopamine receptors, since the agonists were differently inhibited by neuroleptics acting on D1- or D2-type receptors. The D1/D2 antagonist cis-flupenthixol blocked both apomorphine and pergolide with similar potency, while sulpiride, a substituted benzamide devoid of any effect on D1 receptors, was a poor inhibitor of the apomorphine response. In contrast, sulpiride blocked pergolide rotation at doses 1000 times lower than those needed to block apomorphine rotation. Our results suggest the existence of functionally distinct sites related to the D1/D2 receptor classification.

Animals↗
PubMed1985

Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists.

The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.

Adrenergic alpha-Antagonists↗
PubMed1994

Dorsal striatal mechanisms involved in the dopamine D2 receptor-mediated potentiation of apomorphine-induced jaw movements.

The role of dorsal striatal mechanisms in the regulation of apomorphine-induced jaw movements was studied. Jaw movements induced by apomorphine (0.2 mg/kg i.v.) were potentiated by quinpirole (10 micrograms/0.2 microliter) injected into the dorsal part of the striatum 10 min before apomorphine. Quinpirole injection into the ventral part of the striatum did not affect the effects of apomorphine. the quinpirole-induced potentiation in the dorsal striatum was prevented by l-sulpiride (25 ng), nemonapride (1 microgram), SCH23390 (1 microgram) or methylscopolamine (1 microgram), but not muscimol (50 ng), co-administered with quinpirole. Injection of these drugs alone 10 min before apomorphine failed to alter the effects of apomorphine. l-Sulpiride (25 ng) injected into the dorsal striatum 60 min before apomorphine increased the frequency of jaw movements induced by apomorphine (0.2 mg/kg). The l-sulpiride-induced potentiation was prevented by methylscopolamine (0.1 microgram) or l-sulpiride (25 ng) injected into the dorsal striatum 10 min before apomorphine; we had already found that this potentiation was also blocked by SCH23390. It is suggested that a synergistic dopamine D1/D2 receptor interaction underlies both the quick-onset potentiation by quinpirole and the delayed-onset potentiation by l-sulpiride.

Animals↗
PubMed1984

Interpretation of changes in apomorphine-induced stereotyped behaviour in rats receiving continuous administration of trifluorperazine for 15 months.

Rats treated continuously with trifluoperazine dihydrochloride (4.4-4.9 mg/kg per day) for 15 months showed an exaggerated stereotyped response to large doses of apomorphine (1.0 mg/kg, s.c.), but inhibition of stereotyped behaviour by a small dose of apomorphine (0.125 mg/kg, s.c.) as compared to responses obtained in age-matched control animals. Apomorphine (0.03-1.0 mg/kg, s.c.) produced more hyperactivity in trifluoperazine-treated rats than in control animals. After withdrawal of the drug for a period of 2 weeks or more, the stereotyped responses to all doses of apomorphine (0.0625-0.5 mg/kg, s.c.) were exaggerated in animals treated with trifluoperazine compared with age-matched control rats. Acute administration of trifluoperazine (4.5 mg/kg, p.o., 3 hr previously) to animals withdrawn from trifluoperazine abolished the stereotyped behaviour induced by a small dose of apomorphine (0.125 mg/kg) but a maximal response still was obtained with large doses (1.0 mg/kg). In contrast, acute challenge with trifluoperazine (4.5 mg/kg, p.o.) in control animals inhibited the stereotyped behaviour at virtually all doses of apomorphine, as compared with the responses to apomorphine in both animals withdrawn from trifluoperazine, given the same treatment, and naive control rats. Administration of trifluoperazine (0.28 and 0.56 mg/kg, p.o.) inhibited stereotypy induced by small doses of apomorphine (0.125 mg/kg, s.c.) in control animals but the response in animals withdrawn from trifluoperazine was exaggerated. Larger doses of trifluoperazine (1.125-4.5 mg/kg) totally inhibited apomorphine-induced (0.125 mg/kg, s.c.) stereotypy in both groups. These findings do not support the concept of separate mechanisms controlling low grade and high grade stereotyped behaviour during chronic treatment with neuroleptics.

Animals↗
PubMed1982

Circadian variation in methamphetamine- and apomorphine-induced increase in ambulatory activity in mice.

The existence of circadian variation in methamphetamine- and apomorphine-induced change in ambulatory activity in mice was investigated. Adult male mice of dd strain, which had been housed on a 12 hr light-dark schedule (light period; 6:00-18:00) for 4 weeks, received injections of either methamphetamine HCl 1 or 2 mg/kg SC at one of six times of day (3:00, 7:00, 11:00, 15:00, 19:00 and 23:00), or apomorphine HCl 0.5 or 1 mg/kg SC at one of six times of day (3:30, 7:30, 11:30, 15:30, 19:30 and 23:30). The control animals were administered a physiological saline vehicle alone at the corresponding times of day. The ambulatory activity of each mouse was measured by a tilting-type activity cage for 3 hr after methamphetamine, and for 1 hr after apomorphine. A circadian variation in the ambulatory activity was observed after the administration of the saline, methamphetamine and apomorphine. Here, the highest activity counts were found when the saline, methamphetamine and apomorphine were administered during the late dark period (3:00 or 3:30), while the lowest activity counts were found when the saline and apomorphine 1 mg/kg were administered during the mid light period (11:00 or 11:30), and methamphetamine 1 and 2 mg/kg and apomorphine 1 mg/kg were administered during the late light period (15:00 or 15:30). The circadian variation in methamphetamine-induced increase in the activity was abolished by a pretreatment with reserpine 2 mg/kg SC 4 hr before, but that of apomorphine was maintained even by the pretreatment with reserpine. The present results suggest that the methamphetamine- and apomorphine-induced increase in the ambulatory activity in mice is dependent on the time-of-day of the drug administration, and the occurrence is mainly due to a circadian variation in activity of the catecholaminergic systems in the brain.

Animals↗
PubMed1987

Reversal by cholecystokinin of apomorphine-induced inhibition of dopamine release in the nucleus accumbens of the rat.

In vivo electrochemical techniques were used to study the effects of the sulfated (CCK8-S) and unsulfated (CCK8-US) forms of cholecystokinin octapeptide on apomorphine-induced inhibition of dopamine (DA) release in the nucleus accumbens of the anesthetized rat. A dose-dependent inhibition of DA release was observed with intravenous (i.v.) injections of apomorphine. CCK8-S administered i.v. at the nadir of the apomorphine-induced inhibition of DA release produced a transient and dose-dependent increase followed by a prolonged decrease in DA release CCK8-US was ineffective in altering apomorphine's inhibitory effects on DA release. The CCK receptor antagonist proglumide injected i.v. 10 min after apomorphine administration had no effect on apomorphine-induced inhibition of DA release, but blocked the effects of CCK8-S on this inhibition. Given that apomorphine may inhibit DA release by a direct hyperpolarizing action on DA neurons, the observation that CCK8-S temporarily reverses apomorphine-induced effects and further inhibits DA release suggests that CCK8-S exerts its inhibitory effects via a process of depolarization block in DA neurons. These findings indicate that apomorphine and CCK8-S may inhibit DA release in vivo by opposite effects on DA cell membrane potentials and suggest that endogenously released CCK may serve to modulate mesolimbic DA neurotransmission.

Animals↗
PubMed1995

Effects of chronic lithium pretreatment on apomorphine-induced penile erection.

1. The effects of chronic lithium pretreatment (600 mg/l in drinking rats, 30 days) on penile erection (PE) induced by apomorphine were investigated in rats. This treatment resulted in a serum Li concentration after 30 days of 0.31 +/- 0.01 mmol/l. 2. Subcutaneous (s.c.) administration of mixed D1/D2 dopamine receptor agonist apomorphine (0.05-0.5 mg/kg) induced PE in a biphasic manner. The maximum effect was obtained with 0.1 mg/kg of the drug while the response decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg. 3. Pretreatment of animals with 0.0125-0.1 mg/kg of D1 dopamine receptor antagonist SCH 23390 or D2 dopamine receptor antagonist sulpiride (12.5-100 mg/kg) decreased apomorphine-induced PE. Combination of SCH 23390 (0.025 mg/ kg) with sulpiride (12.5 mg/kg) caused a stronger inhibitory effect on apomorphine response. This indicates that both D1 and D2 dopamine receptors may be involved in PE induced by apomorphine. 4. The response induced by apomorphine (0.05-0.05 mg/kg) was decreased in animals pretreated with chronic lithium. The inhibitory effect of sulpiride on apomorphine response, increased in animals pretreated with lithium, in contrast the inhibitory effect of SCH 23390 did not change in this condition. However, a combination of SCH 23390 with sulpiride increased inhibitory effect on apomorphine response in lithium pretreated rats. 5. It is concluded that chronic lithium inhibits PE induced by dopaminergic mechanism(s).

Animals↗