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PubMed1996

A study of tolerance to apomorphine.

1. The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2. Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 micrograms kg-1, i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloralose-anaesthetized dogs. 3. The first administration of apomorphine induced a significant decrease in blood pressure and rectal temperature, a marked rise in heart rate with no change in noradrenaline plasma levels or respiratory rate. Emesis occurred in 71% of the animals. 4. A second administration of apomorphine 30 min later failed to modify blood pressure or heart rate. In contrast, the magnitude of apomorphine-induced changes in blood pressure and heart rate was similar to that observed after the first administration when apomorphine was given 120 or 720 min later. 5. The apomorphine-induced decrease in rectal temperature evoked by a second dose of apomorphine was less marked when given 30 and 120 min after the first dose and unchanged when given 720 min later. 6. The number of animals exhibiting retching and vomiting was lower when apomorphine was reinjected after 30 min than when the time between two successive injections of apomorphine was 120 or 720 min. 7. These results show that tolerance to apomorphine involves its cardiovascular, hypothermic and emetic effects. The time course of tolerance to repeated injections of apomorphine is longer for its hypothermic than for its hypotensive or emetic effects. This suggests a tissue-specific regulation of D2 dopamine receptors to repeated injections of apomorphine.

Animals↗
PubMed2004

Subcutaneous apomorphine : an evidence-based review of its use in Parkinson's disease.

Apomorphine, a short-acting dopamine D1 and D2 receptor agonist, was the first dopamine receptor agonist used to treat Parkinson's disease. Subcutaneous apomorphine is currently used for the management of sudden, unexpected and refractory levodopa-induced 'off' states in fluctuating Parkinson's disease either as intermittent rescue injections or continuous infusions. Other indications include the challenge test for determining the dopaminergic responsiveness and finding the appropriate dose of the drug in intermittent subcutaneous administration. Except for a rapid on- and offset of the antiparkinsonian response with subcutaneous apomorphine, the magnitude and pattern of the motor response to single dose of subcutaneously administered apomorphine is qualitatively comparable to that of oral levodopa. Seventy-five percent of patients achieve a clinically significant improvement with a dose of apomorphine 4mg. The efficacy of intermittent subcutaneous apomorphine injections as an add-on to levodopa therapy in advanced Parkinson's disease was explored in one short-term, randomised, double-blind, placebo-controlled trial, one short-term and six long-term, open-label, uncontrolled studies, including a total of 195 patients. These studies provide evidence that this mode of administration was successful in aborting 'off' periods and improving Parkinson's disease motor scores, but tended to increase dyskinesias. No levodopa-sparing effect was observed. Eleven long-term, open-label, uncontrolled studies, including a total of 233 patients evaluated the efficacy of continuous subcutaneous apomorphine infusions in monotherapy or as an add-on to levodopa therapy in advanced Parkinson's disease. These studies proved that subcutaneous apomorphine infusions are successful in aborting 'off' periods, reducing dyskinesias and improving Parkinson's disease motor scores with the added benefit of a substantial levodopa-sparing effect. The apomorphine challenge test has at least 80% overall predictive ability to clinically diagnose Parkinson's disease across the different stages of the disease and parkinsonian syndromes. Similarly, those data also indicate that the apomorphine challenge test has a >80% ability to predict dopaminergic responsiveness across all stages of Parkinson's disease. Adverse events are usually mild and consist predominantly of cutaneous reactions and neuropsychiatric adverse effects. The incidence of adverse effects is higher in patients receiving continuous infusion than in those receiving intermittent pulsatile administration. Based on the results of these studies it is recommended that subcutaneous apomorphine either as intermittent injections or continuous infusions should be offered to any suitable Parkinson's disease patient who has difficulties in his/her management with conventional therapy. Low-dose levodopa therapy in combination with waking-day hours subcutaneous apomorphine infusion would probably be the most efficient treatment. Continuous subcutaneous apomorphine infusions should be evaluated before more invasive measures or neurosurgical interventions are contemplated.

Antiparkinson Agents↗
PubMed1997

Stimulus and response factors affecting the development of behavioral sensitization to apomorphine.

The present study was designed to assess the role of stimulus and response factors in the context-dependency of behavioral sensitization to the direct dopamine agonist apomorphine. In two experiments, male Wistar rats were given repeated injections of the direct dopamine agonist, apomorphine (5 mg/kg, s.c.), or vehicle at 24- to 72-h intervals and tested for locomotor activity for 30 min in either an openfield activity drum or a running wheel. In experiment 1, after eight activity sessions in either the activity drum or running wheel, one-half of the rats in each drug condition (apomorphine or vehicle) were tested in the alternate activity test environment. In both activity test environments, apomorphine produced progressively greater levels of locomotor activity with repeated treatment (i.e., sensitization). Moreover, sensitization to apomorphine transferred completely across test environments. That is, rats given apomorphine associated with one test environment (e.g., wheel) displayed equivalent sensitization when tested in the alternate environment (e.g., drum). Thus, changing external stimulus cues associated with repeated drug exposure did not affect the expression of sensitization. In experiment 2, rats were given either apomorphine or vehicle daily and tested for activity in a running wheel. For one-half the rats in each drug condition, the running wheel was free to move, but for the remainder the wheel was immobilized. After nine training sessions, all rats were given an apomorphine challenge injection and tested in a mobile wheel. After the challenge injection of apomorphine, rats previously treated with apomorphine and trained in the mobile wheel were significantly more active than rats previously treated with vehicle. In contrast, rats given equivalent apomorphine treatments and trained in the immobile wheel did not differ in activity from rats previously given only vehicle. Since the external stimulus cues associated with drug exposure for the mobile and immobile wheel groups were the same, this finding suggests that environmental factors affecting response expression are critical to the development of behavioral sensitization to apomorphine.

Animals↗
PubMed1987

Evidence that the stimulus properties of apomorphine are mediated by both D1 and D2 receptor activation.

Male and female rats were trained to discriminate between the stimulus properties of apomorphine (0.16 mg/kg i.p.) and saline in a two-lever, food-motivated operant procedure. Apomorphine, at doses different than the training dose, produced a similar dose-dependent relationship in both sexes. Consistent with the hypothesis that the behavioral effects of apomorphine are mediated by D2 activation, the apomorphine interoceptive cue generalized to bromocriptine, a drug considered to be a preferential D2 agonist. In addition, the dose-response curve after 5-15 mg/kg bromocriptine administration was parallel to that of apomorphine. Consistent with the biochemical evidence that apomorphine's effects are mediated, to a lesser extent, by D1 activation, the apomorphine cue partially generalized to the selective D1 agonist SKF 38393. Furthermore, the apomorphine cue was not blocked by the selective D1 antagonist SCH 23390. Somewhat surprising was the partial generalization of the apomorphine cue to SCH 23390. However, this is not the first time that the administration of SCH 23390 has resulted in unexpected behavioral responses. Other novel findings include the lack of sex differences in acquisition training to the apomorphine cue and in the generalization tests to the selective agonists. The behavioral results are consistent with previous biochemical evidence that the effects of apomorphine are mediated by both D1 and D2 activation and is further behavioral support that apomorphine's effects are not the result of D2 activation alone, as previously hypothesized.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Conditioned locomotion induced by unilateral intrastriatal administration of apomorphine: D(2) receptor activation is critical but not the expression of the unconditioned response.

The present study examined the role of D(1) and D(2) receptors in the conditioning of apomorphine-induced locomotor behavior. A Pavlovian conditioning protocol was used in which rats received 5 daily intrastriatal apomorphine treatments paired or unpaired to an open-field environment followed, 2 days later, by a saline test for conditioning. In the conditioning induction phase, the intrastriatal apomorphine treatment increased locomotor activity expressed as an increased number of sectional crossings and rearings. In the conditioning test, the apomorphine-paired group had significantly higher locomotor activity than the unpaired and vehicle groups, consistent with the development of a conditioned locomotor response. The concomitant blockade of D(1) and D(2) receptors with D(1) (SCH23390) and D(2) (sulpiride) antagonists prevented the apomorphine-induced behavioral response during the induction phase and in the conditioning test. Pretreatment with the D(1) antagonist SCH 23390 also blocked the apomorphine-induced behavioral response during the induction phase but did not block the apomorphine conditioned response. Pretreatment with the selective D(2) antagonist sulpiride blocked the apomorphine behavioral response during the induction phase and in the conditioning test. Altogether, these results indicate that antagonism of either the D(1) or D(2) receptors in the dorsal striatum can block apomorphine-induced locomotor activation but that D(2) but not D(1) antagonism can prevent the development of the apomorphine conditioned response. Altogether, these findings indicate a key role for the D(2) receptor site in the mediation of apomorphine conditioned behavior; and, in addition, that apomorphine conditioned locomotor response can develop without the expression of the locomotor stimulant response during the induction phase of conditioning.

Animals↗
PubMed1984

Pharmacological studies on the antagonism by antidepressants of the hypothermia induced by apomorphine.

In male Swiss mice, the hypothermia induced by apomorphine (10 mg/kg) was completely blocked by administration of haloperidol and d-butaclamol, but not by l-butaclamol, phenoxybenzamine, clozapine or propranolol. This substantiated the dopaminergic nature of the hypothermia induced by apomorphine. Desipramine, imipramine, chlorimipramine, fluoxetine and mazindol produced a dose-dependent blockade of apomorphine-induced hypothermia, their ED50S being 0.313, 0.733, 1.88, 6.04 and 0.0033 mg/kg, respectively. Iprindole failed to block the hypothermia induced by apomorphine. Because chlorimipramine and fluoxetine, which are relatively more selective and more potent blockers of the uptake of serotonin (5-HT) than is desipramine, were considerably less effective than the latter in antagonizing hypothermia induced by apomorphine, it was concluded that the property of blocking uptake of 5-HT alone does not contribute to the antagonism to apomorphine exhibited by the classical antidepressants. Quipazine, a 5-HT agonist, blocked the hypothermia induced by apomorphine, this effect developed tolerance on repeated administration. However, no cross-tolerance between quipazine and the antidepressants could be demonstrated. This finding provided further support for the non-involvement of 5-HT in the antagonism to apomorphine. No correlation existed between the potencies of these antidepressants to block the reuptake of norepinephrine (NE) in brain and their relative potencies to block the hypothermia induced by apomorphine. Moreover, selective depletion of high affinity binding sites for [3H]desipramine and [3H]-NE, achieved by treatment with DSP-4, failed to reduce the effectiveness of desipramine in blocking the hypothermia induced by apomorphine. Hence, inhibition of uptake of NE does not account for the antagonism by the antidepressants of apomorphine-induced hypothermia. A possibility was considered that certain antidepressants selectively blocked the hypothalamic DA receptors, thereby antagonizing the hypothermic effects of apomorphine, leaving the extra-hypothalamic dopaminergic responses of this DA agonist unaffected.

Animals↗
PubMed1999

Effect of nicotine on apomorphine-induced licking behaviour in rats.

In the present study, the dopaminergic receptor agonist apomorphine (0.1, 0.25 and 0.5 mg/kg) induced a dose-dependent licking in rats. Nicotine administration (0.025-250 microg/kg) altered the apomorphine-induced licking. The lower doses of nicotine (0.05 and 0.5 microg/kg) increased while the higher dose of the drug (250 microg/kg) reduced the apomorphine response. The antimuscarinic drug atropine (2.5 and 5 mg/kg) reduced the effects of apomorphine or nicotine plus apomorphine. The central nicotinic receptor antagonist mecamylamine (0.05, 0.25 and 0.5 mg/kg) also reduced the response induced by apomorphine or nicotine plus apomorphine. However, the peripheral nicotinic receptor antagonist hexamethonium (2.5, 5 and 10 mg/kg) reduced the response induced by nicotine plus apomorphine but not that elicited by apomorphine alone. The results indicate that the nicotinic receptor mechanism(s) may interact with apomorphine-induced licking in rats. Although central nicotinic and cholinergic mechanisms may be involved in the licking induced by apomorphine, peripheral nicotinic mechanism may be involved in the nicotine-induced increased apomorphine effect.

Animals↗
PubMed2005

Effects in vitro and in vivo by apomorphine in the rat corpus cavernosum.

The study was performed to clarify if apomorphine at the level of the rat corpus cavernosum can produce erectile responses or interfere with nerve-induced penile erection. Apomorphine (10(-9)-10(-4) M) exhibited a 10-fold higher potency to relax phenylephrine (Phe)- than endothelin-1 (ET-1)-induced contractions. Relaxant effects of apomorphine in Phe-activated corpus cavernosum did not change tissue levels of cyclic nucleotides, and were unaffected by inhibition of the synthesis of nitric oxide, or by inhibition of the soluble guanylate cyclase. Relaxations by apomorphine of ET-1-contracted rat corpus cavernosum were not influenced by alpha2-adrenoceptor blockade (yohimbine, 10(-7) M), or by the dopamine D1-like receptor antagonist SCH 23390 (10(-6) M). Clozapine (10(-6) M), a proposed dopamine D2-like receptor antagonist, partly reduced apomorphine-induced relaxations, and significantly altered the -log IC50 value for apomorphine. Nerve-induced contractions of the rat corpus cavernosum were attenuated by apomorphine in a concentration-dependent and biphasic manner. Yohimbine (10(-7) M) abolished the biphasic concentration-response pattern. SCH 23390 (10(-6) M) attenuated the inhibitory effects of apomorphine on contractions, and significantly altered the -log IC50 value for the compound. In anesthetized rats (50 mg kg(-1) pentobarbital sodium, 10 mg kg(-1) ketamine), intracavernous apomorphine (100, 300, or 1000 nmol) did not have effects on basal cavernous pressure under resting conditions, and did not affect filling or emptying rates, or peak pressures of the rat corpus cavernosum during submaximal activation of the cavernous nerve. In awake rats, apomorphine produced a maximal number of erections at 300 nmol kg(-1). In the rat isolated corpus cavernosum, pre- and postjunctional effects of apomorphine appear to involve dopamine D1- and D2-like receptors, as well as alpha-adrenoceptors. At relevant systemic doses of apomorphine, peripheral effects of the compound are unlikely to contribute to its proerectile effects in rats.

Animals↗
PubMed1982

Behavioral and neurochemical effects of apomorphine in the cat.

Administration of apomorphine (2-10 mg/kg i.p.) elicited a number of behaviors, such as limb flicking, abortive grooming, investigatory and hallucinatory-like responses, head and body shakes, and excessive grooming, which we have previously proposed as an animal model for studying the actions of LSD and related hallucinogens. Repeated administration of apomorphine resulted in a significant tolerance, which occurred within 2 h of the initial injection, and completely dissipated within 24 h. A pronounced LSD-apomorphine cross tolerance was observed; however, there was no significant apomorphine-LSD tolerance. Apomorphine-induced behavioral changes were blocked by prior treatment with haloperidol, but were unchanged by pretreatment with L-DOP[A. Administration of L-DOPA, in combination with a peripheral decarboxylase inhibitor, did not elicit these characteristic behavioral changes. Increasing synaptic serotonin levels by monoamine oxidase inhibition, precursor administration, or reuptake blockade in general did not alter the behavioral response to apomorphine. Similarly, pretreatment with serotonin receptor blockers produced no large changes in apomorphine-induced behaviors. Prior serotonin depletion with chronic p-chlorophenylalanine administration, however, potentiated certain apomorphine-induced behaviors. Neurochemical studies revealed that apomorphine administration increased striatal dopamine, and decreased dopamine metabolites. Norepinephrine levels were generally decreased throughout the CNS by apomorphine treatment. Administration of apomorphine increased CNS serotonin and 5-hydroxyindoleacetic acid levels, while tryptophan levels were unchanged. The biological bases of the limb flick model is discussed in the context of these pharmacological and neurochemical studies.

Animals↗
PubMed1994

The angiotensin converting enzyme inhibitors captopril and enalapril inhibit apomorphine-induced oral stereotypy in the rat.

The possible functional interaction between angiotensin and dopamine mechanisms in the rat was investigated by examining the effects of the angiotensin converting enzyme inhibitors captopril and enalapril on apomorphine-induced stereotypy. Apomorphine-induced behaviour was observed, and recorded using a keypad linked to a microcomputer. In agreement with previous findings, low doses of apomorphine induced a syndrome of vacuous mouth movements, penile grooming, yawning and immobility whereas at higher doses the yawning syndrome disappeared to be replaced with sniffing, licking and gnawing. Two antagonism studies were carried out. In the first the effects of captopril on apomorphine-induced behaviour were compared with those of the classical neuroleptic haloperidol, and in the second dose-response curves for the effects of captopril and enalapril on apomorphine-induced behaviour were determined. Captopril had no effect on the apomorphine-induced yawning syndrome whereas this was blocked by haloperidol. In contrast, both captopril and haloperidol blocked oral stereotypy (licking and gnawing) induced by apomorphine but had no effect on sniffing induced by the dopamine agonist. Selective blockade of apomorphine-induced oral stereotypy by angiotensin converting enzyme inhibition was confirmed in the second study in which both captopril and enalapril were observed to antagonize apomorphine-induced gnawing. The inhibition of apomorphine-induced gnawing by enalapril correlated with inhibition of brain angiotensin converting enzyme, but not lung angiotensin converting enzyme, by the drug as assessed by ex vivo penetration studies. These data suggest that angiotensin converting enzyme inhibition modulates the expression of apomorphine-induced oral stereotypy, a response that is thought to be mediated by postsynaptic dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

A comparative review of apomorphine formulations for erectile dysfunction : recommendations for use in the elderly.

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men worldwide. First-line oral therapy for ED includes the use of phosphodiesterase type 5 inhibitors (sildenafil, tadalafil and vardenafil) and sublingual apomorphine. Apomorphine is a dopamine D(1) and D(2) receptor agonist that has been approved for marketing in Europe. Different apomorphine formulations have been tested, such as sublingual, subcutaneous and intranasal. However, the sublingual formulation has shown the best results in terms of efficacy, safety and tolerability, especially the 2mg and 3mg doses. Although clinical studies of the efficacy and tolerability of apomorphine sublingual (SL) have included older patients, who are more likely to have ED, no study has specifically assessed the efficacy and tolerability of different doses of apomorphine SL in aging men. Therefore, a MEDLINE search was conducted from January 1987 to November 2005 to identify studies of the efficacy, safety (in particular cardiovascular safety) and tolerability of different apomorphine formulations and doses as treatments for ED in the subcohort of aging men. On the basis of the most recent peer-reviewed publications, the first part of this article critically evaluates data regarding the epidemiology of ED in the aging population. The second part of the article focuses on the mechanism of action and pharmacokinetics of apomorphine both in the general and the elderly population. Finally, a critical analysis of the efficacy and safety of different apomorphine formulations and doses for the treatment of ED is reported. Apomorphine represents a first-line oral treatment for ED. Available formulations include only sublingual administration. Few studies have assessed the efficacy and safety of apomorphine in the elderly population. However, in clinical practice, older patients with multiple vascular risk factors and systematic vascular damage show poor overall response to apomorphine SL for the treatment of ED.

Aged↗
PubMed1999

Pharmacokinetic-pharmacodynamic relationships of apomorphine in patients with Parkinson's disease.

In the treatment of patients with Parkinson's disease, apomorphine has an established place as a back-up therapy if other antiparkinsonian drugs, such as levodopa and oral dopamine agonists, have not controlled the existing response fluctuations. Apomorphine is a synthetic derivative of morphine, with a totally distinct pharmacological profile. It is a very lipophilic compound which is easily (auto)oxidised. This (auto)oxidation is the main metabolic route besides glucuronidation and sulphation, which are both responsible for about 10% of the metabolic transformation. Apomorphine quickly passes the nasal and intestinal mucosa as well as the blood-brain barrier (depending on the administration route). Many routes of administration have been explored, but subcutaneous, sublingual, nasal and rectal administration are used in clinical practice. The volume of distribution varies between 1 and 2 times bodyweight. The elimination half-life is very short (30 to 90 min) depending on the type of parenteral administration. Apomorphine is a high clearance drug (3 to 5 L/kg/h) and is mainly excreted and metabolised by the liver. Only 3 to 4% is excreted unchanged in the urine. The clinical effect of apomorphine can be linked directly to its concentration in the cerebrospinal fluid. Consequently, a 2-compartment model can be used to predict the clinical effects of apomorphine. The pharmacokinetic-pharmacodynamic data reflect the clinical observations of steep dose-effect curves if apomorphine is used in patients with random 'on-off' fluctuations. These dose-effect curves are less steep in stable or 'wearing-off' (end-of-dose deterioration) patients. Intravenous infusions of apomorphine in combination with timed motor assessments can be used clinically to characterise the therapeutic window of a particular patient if dyskinesia persists after single injections of apomorphine. If more population data become available, the population pharmacokinetics-pharmacodynamics of apomorphine could be helpful in predicting the clinical effects of apomorphine in the several subgroups of patients with Parkinson's disease.

Antiparkinson Agents↗
PubMed2002

Nicotine alters striatal glutamate function and decreases the apomorphine-induced contralateral rotations in 6-OHDA-lesioned rats.

The overall goal of this study was to determine the effects of subchronic nicotine (0.4 mg/kg) treatment for 7 or 14 days on striatal glutamate function in both naïve and in 6-hydroxydopamine (6-OHDA)-treated rats in which the nigrostriatal dopamine pathway was lesioned. In lesioned animals, the effect of nicotine on apomorphine-induced contralateral rotations was also assessed. In naïve rats, once daily nicotine administration for 7 or 14 days resulted in a decrease and then an increase, respectively, in the basal extracellular level of striatal glutamate compared to the saline-treated group. Ultrastructurally, 14-day treatment with nicotine resulted in an increase in the density of striatal glutamate immunolabeling within nerve terminals making an asymmetrical synaptic contact compared to the saline-treated group. In 6-OHDA-lesioned animals, coadministration of nicotine with apomorphine or nicotine alone for 7 days resulted in an increase in the density of nerve terminal glutamate immunolabeling, compared to the apomorphine- or saline-treated groups. However, coadministration of nicotine with apomorphine for 14 days resulted in a decrease in the density of nerve terminal glutamate immunolabeling compared to the nicotine-treated group. Following subchronic treatment of 6-OHDA-lesioned rats with apomorphine for 7 or 14 days, there was an increase in the number of apomorphine-induced contralateral rotations compared to the saline treated group. There was a decrease in the number of apomorphine-induced contralateral rotations in the group coadministered nicotine with apomorphine for 7 or 14 days compared to the apomorphine treated group. The data suggests that in this 6-OHDA lesion model of Parkinson's disease, treatment with nicotine may be useful in counteracting the increased behavioral effect (i.e., contralateral rotations) observed after treatment with a dopamine agonist, such as apomorphine.

Animals↗
PubMed1995

Role of N-methyl-D-aspartic acid and cholecystokinin receptors in apomorphine-induced aggressive behaviour in rats.

We studied the aggressive behaviour induced by repeated treatment with apomorphine, a dopamine agonist (0.5 mg/kg s.c. twice daily, 10 days), in rats. The first signs of defensive aggressiveness appeared on the third day of apomorphine treatment and were generally seen on the 7th day. Aggressiveness induced by a challenge dose of apomorphine (0.5 mg/kg s.c.) on the 11th day was antagonized by haloperidol (0.05 and 0.1 mg/kg i.p.) and clozapine (10 mg/kg i.p.). An antagonist of N-methyl-D-aspartate (NMDA)-gated channels, dizocilpine (MK-801), also blocked the aggressive behaviour at 0.25 and 0.5 mg/kg i.p. but caused ataxia. When dizocilpine (0.25 mg/kg i.p.) and apomorphine were coadministered for 10 days, aggressive behaviour did not develop. At 0.025 mg/kg i.p., dizocilpine even accelerated the appearance of apomorphine-induced aggressive behaviour, which manifested on the 3rd day in all rats. In a separate study, a 7-day treatment with dizocilpine (0.25-1 mg/kg i.p.) of rats, sensitized by a prior 10-day apomorphine treatment, did not reverse the established aggressive behaviour. The coadministration of apomorphine and cholecystokinin (CCK) -A or -B antagonists, devazepide or L-365,260 (0.01-2.5 mg/kg i.p.) respectively, neither affected development of apomorphine-induced aggressive behaviour nor intensity of aggressiveness in the sensitized rats. In binding studies neither density nor affinity of striatal dopamine D2 receptors was changed by acute or chronic apomorphine treatment. The number of [3H]pCCK-8 binding sites in the frontal cortex increased already after a single injection of apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1991

Effects of selective D1 and D2 dopamine antagonists on the development of behavioral sensitization to apomorphine.

The objective of the present study was to determine whether the development of behavioral sensitization to apomorphine could be blocked by either D1 or D2 selective dopamine antagonists. In three experiments, male rats received 10-21 daily injections of a selective D1 (SCH 23390; 0 or 0.5 mg/kg IP) or D2 (sulpiride; 0, 30, or 100 mg/kg IP) antagonist followed by an apomorphine (0 or 1.0 mg/kg SC) injection. In two experiments, the rats were tested for locomotor activity in photocell arenas after the daily injections. In all experiments, the rats were tested for sensitization to apomorphine following the training phase. The results indicated that apomorphine produced a progressively greater increase in locomotor activity with each injection, and this apomorphine-induced increase in activity was completely blocked by both sulpiride and SCH 23390 treatments. However, although both sulpiride and SCH 23390 blocked apomorphine-induced activity, only SCH 23390 injections prevented the development of sensitization to apomorphine. That is, rats pretreated with sulpiride and apomorphine displayed significant sensitization when subsequently tested with a challenge dose of apomorphine alone. These findings suggest that the development of behavioral sensitization to apomorphine is related specifically to the stimulation of dopamine D1 receptors.

Analysis of Variance↗
PubMed2005

[Apomorphine in the treatment of Parkinson's Disease].

Apomorphine has long been used in many medical specialties. It is a highly potent D2-, D3- and D4-dopamine receptor agonist with a particularly high D1-dopamine receptor affinity. Due to its almost complete inactivation during liver passage it is usually applied subcutaneously. After rapid onset its effect is waning after about one hour. Apomorphine's action is not dependent on enteral dopamine resorption and on praesynaptic dopamine storage and dopamine secretion mechanisms. When applied subcutaneously its most common side effect is cutaneous nodules at the injection sites. Peripheral dopaminergic side effects, such as nausea and orthostatic hypotension, usually occur only during therapy initiation and respond well to domperidone. Hallucinations occur less frequently than with other dopamine receptor agonists. The apomorphine test determines the levodopasensitivity of a parkinsonian syndrome by application of an apomorphine bolus to distinguish between idiopathic Parkinson's disease and atypical parkinsonian syndromes. It indicates a levodopasensitivity in about 90% of the patients tested. False-negative results can occur in mild parkinsonian syndromes. A meta analysis indicates that intermittent subutaneous apomorphine applications (intermittent apomorphine therapy) with a self application device can reduce the daily duration of unpredictable off-phases by 48.8+/-8.7%. For this an average of 3.7+/-1.1 x 2.9+/-0.8 mg apomorphine has to be applied per day. Continuous subcutaneous apomorphine application with an extracorporal pump (continuous apomorhine therapy) during the wake phase reduces the duration of daily off-phases by 64.8+/-13.5% and the additional levodopa dose by 30.3+/-31.1%. 24-hour application reduces the daily duration of the off-phases by 63.5+/-19.1% and the additional levodopa dose by 65.5+/-21.9%. Levodopa-induced dyskinesias are also substantially reduced. A gradual conversion to an apomorphine monotherapy is possible. Even after prolonged treatment times no significant loss of efficacy occurs. With this profile apomorphine is a highly successful treatment option for off-phases and levodopa-induced dyskinesias in advanced cases of idiopathic Parkinson's disease which should be used before more invasive approaches are considered.

Antiparkinson Agents↗
PubMed2004

A 10 year retrospective audit of long-term apomorphine use in Parkinson's disease.

OBJECTIVES: Apomorphine is a potent dopamine agonist useful in the treatment of Parkinson's disease patients with disabling motor fluctuations and 'off' periods, not responding to oral medication. It can also be of benefit in reducing dyskinesia by providing more constant dopaminergic stimulation and permitting lower levodopa dosage. However, there is a paucity of information on long-term benefits of apomorphine, including no large-scale phase III trial. We have examined our experience of apomorphine over the last 10 years, to assess indications, pattern of use, efficacy, and side effect profile. METHODS: All patients requiring apomorphine were identified through the Parkinson's disease Nurse Specialist's records. An audit form was produced so that the same information was gathered from all case-notes. RESULTS: There were 107 patients (61 males and 46 females). Mean age of disease onset was 50.9 years, SD+/-9.3 (range 29-78). The mean duration of disease at start of apomorphine treatment was 10 years (SD+/-4.8, range 2-29). The most common indications for apomorphine were severe unpredictable 'off' periods (75.7 %), motor fluctuations (18.7 %) and dyskinesia (5.6 %). Most patients (63.6 %) used both intermittent subcutaneous injections and infusion via pump; 25.2% were on intermittent injection, and 11.2 % infusion alone. Mean dose per injection was 3.7 mg. Mean infusion dose 69.8 mg, running over a mean of 13.5 hours. The mean duration of intermittent apomorphine use was 48.2 months. The mean duration of infusion was 25.1 months. Complications included skin problems in 16 patients, 2 had symptomatic hypotension, 2 worsening confusion, 1 new confusion and 5 new hallucinations (after sometime on apomorphine). Sixteen patients have stopped using apomorphine completely. Thirteen have stopped the pump, but continue on intermittent injections. CONCLUSION: Subcutaneous apomorphine is easy for patients to use, is well tolerated and has a low incidence of side effects, especially confusion.

Adult↗
PubMed2000

Effects of apomorphine on visual functions in Parkinson's disease.

The effect of apomorphine on visual functions in Parkinson's disease (PD) was evaluated by use of a static contrast sensitivity test (VCTS charts), a colour discrimination test (Farnsworth-Munsell 100 Hue test) and the examination of achromatic and chromatic contour perception. 31 patients (14 male, 17 female; mean age 60.9 +/- 9.2 years) with idiopathic PD were tested before and after an individual dosage of subcutaneously applied apomorphine showing a significant effect on motor function during the whole experiment. The achromatic spatial contrast sensitivity improved significantly after apomorphine injection with respect to all spatial frequencies. The improvement of colour discrimination after apomorphine application was minimal and not statistically significant. The small advantage of apomorphine with respect to colour discrimination may be explained by negative cognitive side-effects of apomorphine interfering with the test performance. The achromatic contour perception before and after apomorphine injection was unaltered. The contour fusion latency for the green stimulus was shortened, the latency for the rest of the examined coloured stimuli was delayed (= normalized) after apomorphine application. We conclude that apomorphine may be used as a test-drug for the examination of the dopaminergic response of the visual system in patients with PD. The improvement of basal visual functions by dopaminergic stimulation with apomorphine underlines the role of dopamine deficiency for visual dysfunction in PD.

Aged↗