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PubMed1986

Effects of neuroleptic drugs on the inhibition of exploratory behaviour induced by a low dose of apomorphine: implications for the identity of dopamine receptors.

Apomorphine in low doses inhibits spontaneous exploratory behaviour in rats. This effect is commonly referred to as an expression of selective stimulation of dopaminergic autoreceptors. The aim of the present study was to investigate the influence of neuroleptic drugs with different pharmacological profiles on this apomorphine induced inhibition of exploration using techniques for detailed recording of behaviour and multivariate statistical analysis of the results. By comparison with dose response analyses of apomorphine it was possible to determine whether a neuroleptic specifically antagonised the apomorphine effect or if the pattern of behaviour was qualitatively changed in some way. Apomorphine (0.05 mg/kg) was tested against cis-flupenthixol (0.01-0.5 mg/kg), haloperidol (0.01-0.1 mg/kg), metoclopramide (0.2-5 mg-kg), sulpiride (0.5-50 mg/kg) and SCH 23390 (0.005-0.05 mg/kg). Metoclopramide and haloperidol had weak antagonising effects against apomorphine while cis-flupenthixol and SCH 23390 was completely inefficient in this respect. The multivariate analysis indicated that the effects of haloperidol was restricted to only some aspects of the behavioural effects of apomorphine. Only sulpiride did selectively and dose-dependently antagonise the apomorphine induced behavioural suppression. The data provide evidence for a functional subdivision of dopamine receptors at the behavioural level.

Animals↗
PubMed1986

Behavioral deficits induced by low doses of apomorphine in rats: evidence for a motivational and cognitive dysfunction which discriminates among neuroleptic drugs.

In order to further assess the alterations (motor, motivational or cognitive) that might underlie animal behavioral deficits associated with a reduced dopamine transmission, the effects of apomorphine at doses thought to stimulate dopaminergic autoreceptors were studied on rat operant behavior. Apomorphine (30 micrograms/kg SC) decreased the number of food rewards obtained, when rats trained on a continuous reinforced schedule were shifted to schedules of fixed ratio higher than 2:FR3, FR4, and FR8. In rats shifted to a FR4 schedule, apomorphine (7.5, 15, 30, 60 micrograms/kg SC) dose-relatedly reduced the number of rewards obtained. In rats subjected to previous extinction sessions, apomorphine (30 micrograms/kg) did not affect lever pressing reinstated on presentation of primary reinforcers but inhibited responding renewed on presentation of secondary reinforcers. Under a FR(3 + 1) schedule where the last (rewarded) response was distinct from the initial (non-rewarded) responses, the detrimental effect of apomorphine on response rates was considerably weaker than under a conventional FR4 schedule. The reward deficits caused by apomorphine under the FR4 schedule were dose-dependently and completely reversed by amisulpride (0.125, 0.25, 0.5, 1 and 2 mg/kg), pimozide (0.125 mg/kg), sulpiride (8, 16, 32 and 64 mg/kg), but not by conventional neuroleptics (namely chlorpromazine, fluphenazine, haloperidol, metoclopramide and thioridazine). It is suggested that behavioral deficits associated with a reduced dopamine transmission such as that caused by low doses of apomorphine involve motivational and cognitive dysfunctions rather than motor impairments. In account of its differential sensitivity to neuroleptic drugs, apomorphine-induced deficit might have some relevance for a further delineation of the mechanisms of action of these compounds.

Animals↗
PubMed1987

Repeated low dose apomorphine induced subsensitivity of presynaptic dopamine receptors.

The influence of repeated administration of a low dose of apomorphine on presynaptic dopamine (DA) receptors was examined. (1) Male ddY mice were given a low dose of apomorphine (0.2 mg/kg) for 7 days. Following 2 drug-free days they were given apomorphine (0.2 mg/kg, IP), after which cage climbing behavior and the level of 3-methoxytyramine (3MT) in striatum was measured. Mice became tolerant to apomorphine's activity-depressing effect and 3MT-decreasing effect. (2) Mice were given haloperidol (1 mg/kg) for 7 days. Then after 2 drug-free days they were given 0.2 or 1.0 mg/kg of apomorphine, after which cage climbing behavior was measured. One mg/kg of apomorphine significantly increased cage climbing behavior, indicating that supersensitivity of postsynaptic DA receptors was induced by haloperidol, but the activity-depressing effect of 0.2 mg/kg of apomorphine was not modified. The results suggest that subsensitivity of presynaptic DA receptors participates in the tolerance to the activity-depressing effect of a low dose of apomorphine.

Animals↗
PubMed1988

Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice.

The effects of apomorphine (0.0125-1 mg/kg, SC), a dopamine (DA) agonist, on passive avoidance learning were assessed in mice which received brief and long foot-shocks in a training test. At low doses, apomorphine stimulates DA autoreceptors. With a shock of brief duration, apomorphine at a low dose (0.05 mg/kg), enhanced the avoidance learning when it was administered 20 min before the training test or the retention test. At high doses, apomorphine stimulates postsynaptic DA receptors. With a shock of long duration, apomorphine at a high dose (1 mg/kg), impaired the avoidance learning when it was administered 20 min before the training test or the retention test. However, apomorphine (0.05 and 1 mg/kg) given immediately after the training test did not have any effect on the avoidance behavior with shocks of either brief or long durations. Apomorphine-induced enhancement of passive avoidance learning was antagonized by sulpiride, but not by haloperidol. These results show that apomorphine induced the opposite effects on the passive avoidance learning depending on the dose or on the reinforcement intensity and suggest that the central DA system may play an important role in modulating memory processes.

Animals↗
PubMed1994

Conditioned apomorphine-induced turning in 6-OHDA-lesioned rats.

Apomorphine-induced turning has been used to evaluate the extent of unilateral nigrostriatal denervation after 6-hydroxydopamine (6-OHDA) lesions and subsequent functional striatal reinnervation by catecholaminergic grafts. It has been noted that the pregraft rotational pattern is usually double peaked and that fetal ventral mesencephalic grafts or dopaminergic drugs will alter the second peak but leave the first relatively unchanged. We hypothesized that the first peak may be the result of factors extrinsic to the nigrostriatal dopamine system, specifically a conditioned turning response, and would, therefore, be unperturbed by the above treatments which increase dopaminergic (DA) inputs. This was investigated by injecting 6-OHDA, unilaterally, into the nigrostriatal pathway of several groups of young Fisher 344 rats. One experimental group was repeatedly tested with 0.05 mg/kg apomorphine and the rotations quantified. A second group received similar injections of apomorphine but were prevented from rotating. Vehicle control animals were also studied for both of the above experimental groups. Subsequent to the above treatment, all animals were tested unrestrained repeatedly on apomorphine. Our results support the conditioned response hypothesis in that the first peak is not present with the initial unrestrained apomorphine behavioral trial but is present upon the second and subsequent unrestrained trials. Moreover, the restrained but apomorphine-injected rats, as well as the control animals, manifest no first peak upon their first freely moving apomorphine test; the second and subsequent unrestrained apomorphine trials, in these groups, do manifest a first peak.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Vacuous jaw movements induced by acute reserpine and low-dose apomorphine: possible model of parkinsonian tremor.

Coadministration of the monoamine-depleting agent reserpine with a low dose of apomorphine has been shown to result in high levels of vacuous jaw movements in rats. Two experiments were conducted to study the pharmacologic and motoric characteristics of the vacuous jaw movements induced by 5.0 mg/kg reserpine plus 0.1 mg/kg apomorphine. The first experiment was undertaken to determine whether the vacuous jaw movements induced by reserpine plus apomorphine could be reduced by coadministration of the muscarinic antagonist scopolamine. Injections of scopolamine produced a dose-related decrease in vacuous jaw movements induced by reserpine plus apomorphine, with the two highest doses (0.5 and 1.0 mg/kg scopolamine) producing significant differences relative to the control group that received reserpine plus apomorphine. In the second experiment, a slow-motion videotape system was used to study the temporal characteristics of the vacuous jaw movements induced by reserpine and apomorphine, and to study the effects of 1.0 mg/kg scopolamine on these movements. Most of the vacuous jaw movements shown by rats treated with reserpine and apomorphine occurred in rapid bursts of jaw movement. Analysis of the interresponse times (i.e., time between each jaw movement) showed that most of the jaw movements had a local frequency in the range of 2.86-6.67 Hz. Cotreatment with scopolamine significantly affected several measures of jaw movements. Thus, the vacuous jaw movements induced by reserpine plus apomorphine can be reversed by anticholinergic treatment, and these movements tend to occur as periodic oscillations of the lower jaw with a frequency of 3-7 Hz. Vacuous jaw movements in rats share some characteristics with parkinsonian symptoms and may represent an animal model of parkinsonian tremor.

Animals↗
PubMed1984

Indirect effects of apomorphine on serotoninergic neurons in rats.

We have studied the effects of apomorphine on central serotoninergic system by using fluorescence histochemistry and high performance liquid chromatography coupled with electrochemical detection. Apomorphine has been shown selectively to elevate intracellular serotonin fluorescence in dorsal raphe neurons and serotonin and/or 5-hydroxyindoleacetic acid concentrations in the major terminal area of the dorsal raphe, the striatum. Apomorphine has no effect on serotonin neurons in the median raphe or its corresponding projection site, the hippocampus. In the present study, intraventricular 6-hydroxydopamine, when administered together with desimipramine and pargyline, antagonized the apomorphine-induced elevations of serotonin fluorescence in the dorsal raphe and serotonin and 5-hydroxyindoleacetic acid levels in the striatum. This antagonism was found when 6-hydroxydopamine was given either 3 or 10 days before 3 mg/kg apomorphine. Apomorphine also elevated extraperikaryal serotonin fluorescence and catecholamine fluorescence in the dorsal raphe selectively and these effects were also blocked by 6-hydroxydopamine. Additionally, 6-hydroxydopamine accelerated striatal serotonin turnover when it was given 10 days prior to death. This phenomenon probably reflects some compensatory change of mesostriatal serotonin neurons in response to the prolonged depletion of brain dopamine. The above results suggest that the observed effects of apomorphine on the serotoninergic system are mediated indirectly through dopaminergic neurons and that postsynaptic dopamine receptors are probably not responsible for apomorphine's effects.

Animals↗
PubMed2004

Apomorphine prevents myocardial ischemia/reperfusion-induced oxidative stress in the rat heart.

This study examined the hypothesis that low-concentration apomorphine improves postischemic hemodynamic and mitochondrial function in the isolated rat heart model by attenuating oxidation of myocardial proteins. Control and apomorphine-treated hearts were subjected to 35 min of perfusion, 25 min of normothermic global ischemia, and 60 min of reperfusion. Apomorphine (2 microM) was introduced into the perfusate for 20 min starting from the onset of reperfusion. Apomorphine significantly (p <.05) improved postischemic hemodynamic function: work index of the heart (product of LVDP and heart rate) was twice as high in apomorphine-treated hearts compared to controls at the end of reperfusion (p <.01). After isolation of cardiac mitochondria, the respiratory control ratio (RCR) was calculated from the oxygen consumption rate of State 3 and State 4 respiration. Apomorphine significantly improved postischemic RCR (87% of preischemic value vs. 39% in control, p <.05). Using an immunoblot technique, carbonyl content of multiple unidentified myocardial proteins (mitochondrial and nonmitochondrial) was observed to be elevated after global ischemia and reperfusion. Apomorphine significantly attenuated the increased protein oxidation at the end of reperfusion. These results support the conclusion that apomorphine is capable of preventing ischemia/reperfusion-induced oxidative stress and thereby attenuating myocardial protein oxidation and preserving mitochondrial respiration function.

Animals↗
PubMed2000

Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat.

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.

Animals↗
PubMed1998

Differences in pre- and post-synaptic sensitivity to apomorphine between saline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mice as reflected in climbing activity.

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.

Animals↗
PubMed2000

Glucuronidation of apomorphine.

Apomorphine, a dopaminergic receptor agonist, is largely used in the therapy of Parkinson's disease. In this study, we characterized the glucuronidation of apomorphine and other catechols in rat liver and brain microsomes, using UDP-[U-14C]glucuronic acid and separation of the glucuronides formed by a thin layer chromatographic method. rat liver microsomes glucuronidate apomorphine at a significant rate, that was increased in the presence of dithiothreitol. Two apomorphine glucuronides were separated by high pressure liquid chromatography. We showed by electrospray mass spectrometry that both products were monoglucuronides. Other catechols were also glucuronidated in liver microsomes at various rates, and among them, 4-nitrocatechol was the most efficiently conjugated. in rat brain microsomes, only 4-nitrocatechol was significantly glucuronidated, suggesting that in the liver, several uridine-diphosphate glucuronosyltransferase (UGT) isoforms participate to the conjugation of catechols. To determine which isoforms catalyze apomorphine glucuronidation, two recombinant enzymes expressed in V79 cells were used. The isoform UGT1A6 was unable to glucuronidate apomorphine, but we observed a significant activity catalyzed by the isoform UGT2B1. These results provide, to our knowledge, the first demonstration of apomorphine conjugation by recombinant UGT2B1, and the first evidence of the lack of apomorphine glucuronidation in the rat brain.

Animals↗
PubMed1998

Extracellular dopamine in the anterior nucleus accumbens is distinctly affected by ventral tegmental area administration of cholecystokinin and apomorphine: data from in vivo voltammetry.

The interaction of cholecystokinin (CCK) and dopamine (DA) in the mesolimbic system was investigated. The study focused on DAergic cells not containing colocalized CCK projecting from the ventral tegmental area (VTA) to the anterior nucleus accumbens (NA). Differential pulse voltammetry in pargyline pretreated and anesthetized rats was used to measure extracellular DA in the anterior NA following microinjection of apomorphine either alone or in combination with CCK-8s into the VTA. In agreement with an earlier study there was a dose-dependent increase in the DA signal in the anterior NA after microinjection of CCK-8s into the VTA. Apomorphine microinjected into the VTA produced a biphasic effect on extracellular DA in the anterior NA with an increase from basal levels of approximately 50% by 1 ng, whereas 10 ng was ineffective and 100 ng apomorphine caused a slight decrease in the DA signal. Apomorphine (1 ng) microinjected together with 1 ng CCK-8s produced an increase in the DA signal to approximately 180% of the baseline value, whereas the combination of 1 ng apomorphine and 100 ng CCK-8s was ineffective. When 100 ng apomorphine were microinjected in combination with either 1 ng or 100 ng CCK-8s, the DA signal in the anterior NA was unchanged. These results suggest that low doses of apomorphine injected into the VTA synergistically influence the effects of CCK-8s on extracellular DA in the anterior NA, whereas higher doses of apomorphine suppress the effect of CCK-8s on DAergic cells projecting to the anterior NA.

Anesthesia↗
PubMed1997

Apomorphine priming alters the response of striatal outflow pathways to D2 agonist stimulation in 6-hydroxydopamine-lesioned rats.

Chronic treatment with dopaminergic agonists is associated with response fluctuations to L-dihydroxyphenylalanine in Parkinson's disease and enhanced motor activity to D1 and D2 dopamine agonists in rats with 6-hydroxydopamine lesions of the nigrostriatal pathway. In dopamine-depleted rodents this phenomenon has been referred to as "priming" or reverse tolerance. The neurochemical changes that underlie "priming" of dopaminergic agonist responses are poorly understood. Some aspects of priming of D1 agonist-mediated rotation in the 6-hydroxydopamine-lesioned rat have been characterized, but priming of D2-agonist-dependent motor responses has been less thoroughly studied. In this study, examination of rotational behaviour and induction of Fos-like immunoreactivity were used to investigate changes in the striatal outflow systems in response to treatment with the D2 agonist quinpirole in 6-hydroxydopamine-lesioned rats that had been primed with apomorphine. Administration of apomorphine (0.5 mg/kg; three injections at three to six day intervals) permitted an otherwise inactive dose of quinpirole (0.25 mg/kg) to produce robust contralateral rotation and to induce the expression of Fos in striatal neurons belonging to the striato-nigro-entopeduncular ("direct") pathway. The increase in contralateral rotation and ipsilateral striatal Fos expression following administration of quinpirole to apomorphine-primed rats was mediated by a D2-like receptor and did not appear to be due to a change in sensitivity of D2 receptors. Apomorphine priming also enhanced the ability of quinpirole to induce Fos expression in the globus pallidus, a target of the striatopallidal ("indirect") pathway. Western blot analysis confirmed that treatment with quinpirole induced the expression of c-Fos protein with no change in the expression of 35-37,000 mol. wt Fos-related antigens in apomorphine-primed rats treated with water or quinpirole. Induction of Fos expression in the striatum generally results from blockade of D2 receptors and the striato-nigro-entopeduncular pathway preferentially expresses D1 receptors. Thus, the quinpirole-dependent induction of striatal Fos in apomorphine-primed 6-hydroxydopamine-lesioned rats represents a qualitative alteration in striatal outflow. These studies demonstrate that pretreatment of 6-hydroxydopamine-lesioned rats with apomorphine increases the activity of the "direct" and "indirect" striatal outflow pathways in response to D2 receptor stimulation. These changes have the net result of enhancing thalamocortical activity and likely underlie the enhanced contralateral rotation produced by quinpirole in apomorphine-primed rats. Changes in striatal outflow, particularly in the striato-nigro-entopeduncular pathway, may contribute to alterations in D2-dependent motor responses observed after chronic dopaminergic stimulation in the dopamine-depleted striatum.

Animals↗
PubMed2000

Nasal toxicological investigations of Carbopol 971P formulation of apomorphine: effects on ciliary beat frequency of human nasal primary cell culture and in vivo on rabbit nasal mucosa.

OBJECTIVE: The objective of this study was to investigate the nasal toxicity of a mucoadhesive Carbopol 971P formulation of apomorphine. MATERIALS AND METHODS: The effects of different concentrations of Carbopol 971P and apomorphine on ciliary beat frequency (CBF) were studied in suspension cultures of human nasal epithelial cells. The rabbit nasal mucosal tolerance of the formulation and its components were investigated using light microscopy. Different groups of the rabbits received twice daily, air puffs, glucose, glucose/apomorphine, Carbopol 971P or Carbopol 971P/apomorphine for 1 week (glucose-treated rabbits) or 1, 2 and 4 weeks (other treatments). RESULTS: Both Carbopol 971P and apomorphine showed both concentration- and time-dependent inhibitory effects on the CBF. The effects on CBF were: apomorphine, 1.0% w/v, irreversible ciliostasis; 0.1 and 0.5% w/v, reversible cilio-inhibition; 0.01%w/v, irreversible cilio-stimulation; and Carbopol 971P, 0.1 and 0.25% w/v, partially-reversible cilio-inhibition. Glucose and glucose/apomorphine physical mixture caused mild inflammation. Carbopol 971P (both with and without apomorphine) caused severe inflammation, which increased with duration of treatment. Necrosis, squamous metaplasia or ciliary degeneration was not observed. CONCLUSIONS: Due to the severe inflammation caused by Carbopol 971P with and without apomorphine, we conclude that this polymer is not a suitable carrier for intranasal administration of apomorphine. This is in spite of the reversible effects of Carbopol 971P (0.1 and 0. 25% w/v) and apomorphine (0.1 and 0.5% w/v) on CBF.

Acrylates↗
PubMed1993

The effect of the dopamine agonist, apomorphine, on regional cerebral blood flow in normal volunteers.

Apomorphine, a non-selective dopamine agonist, has been used as a pharmacological probe for investigating central dopaminergic neurotransmission in psychiatric illness. In this study repeated measurements of regional cerebral blood flow (rCBF) were made in normal volunteers before, and after, the administration of apomorphine (5 or 10 micrograms/kg), or placebo. The difference in rCBF, before and after drug (apomorphine versus placebo), was used to identify brain areas affected by apomorphine. Compared to placebo, both doses of apomorphine increased blood flow in the anterior cingulate cortex. Apomorphine 10 micrograms/kg also increased prefrontal rCBF (right > left). No decreases in rCBF were noted following either dose of apomorphine. Apomorphine-induced increases of anterior cingulate blood flow might serve as an in vivo index of central dopamine function. Such an approach would complement established neuroendocrine challenge paradigms for investigating central dopamine neurotransmission in psychiatric illness.

Adult↗
PubMed2001

Spinal proerectile effect of apomorphine in the anesthetized rat.

Considering the presence of dopaminergic receptors in the lumbosacral spinal cord, we tested whether apomorphine could exert a proerectile effect by acting at the spinal level. Intracavernous (ICP) and blood pressures (BP) were measured in anesthetized rats. ICP rises were quantified (duration, percentage of ICPmaximum/meanBP (ICPmax/BPx100), area under ICP curve (AUC/BP) and sum of AUC/BP after intravenous (i.v.) and intrathecal (i.t.) injections of apomorphine alone or in presence of i.t. oxytocin (10 ng). Both 10 and 30 microg i.v. apomorphine dosings elicited erectile events evidenced by ICP rises. Upon the 30 microg i.v. injection, duration of ICP rises were increased from 25+/-10 to 69+/-18 s (P<0.001), ICPmax/BPx100 from 21+/-3 to 50+/-14% (P=0.001), AUC/BP from 3+/-1 to 14+/-6 s (P=0.002) and sum of AUC/BP from 5+/-7 to 34+/-35 s (P=0.021). Upon 30 microg i.t. injections of apomorphine at the lumbosacral level, the number of ICP rises was increased from 0.2+/-0.4 to 3.0+/-1.5, ICPmax/BPx100 from 16+/-9 to 43+/-12 and sum of AUC/BP from 1+/-3 to 31+/-15 s compared to vehicle injection (P<0.05 for all parameters). Injection of 30 microg i.v. or i.t. apomorphine non-significantly enhanced the number and amplitude of the ICP rises induced by 10 ng i.t. oxytocin. However, the enhancement of the amplitude of the ICP rises elicited by i.t. oxytocin was more pronounced with i.t. apomorphine than with i.v. apomorphine. These results suggest the existence of a spinal site of action for apomorphine which may (1) participate to generation of erection and (2) exerts a facilitator effect on erection of supraspinal origin.

Animals↗
PubMed2004

A comparative, crossover study of the efficacy and safety of sildenafil and apomorphine in men with evidence of arteriogenic erectile dysfunction.

The aim of the study was to establish and compare the efficacy and safety of sildenafil and apomorphine in men with arteriogenic erectile dysfunction (ED). In all, 43 men with ED and postinjection max penile systolic velocity <25 cm/s in repeated Doppler ultrasonography were included. Of these, 24 men started on apomorphine 2 mg and 19 on sildenafil 50 mg, the doses titrated up to 3 and 100 mg according to effectiveness and tolerability. Safety was evaluated according to adverse events (AEs) and patient withdrawal. Efficacy was the percentage of attempts resulting in erections firm enough for intercourse, based on event log data. The incidence of AEs with apomorphine 3 mg was higher than with sildenafil 100 mg. Two men on apomorphine 3 mg discontinued treatment due to AEs. The overall success rate of sildenafil was 63.7% compared to 32.1% of apomorphine (Pearson chi(2), P<0.01). Of all men, 25 (58.1%) responded to sildenafil 50 mg without the need for dose increase, while only one responded to apomorphine 2 mg. The response to sildenafil 50 mg was age related (analysis of variance, p=0.04). Satisfaction was reported by 76.75 and 13.95% of patients for sildenafil and apomorphine, respectively, but 20.9% were not satisfied with any of the two drugs. In conclusion, this study provides clear evidence that sildenafil, even at 50 mg dose, is more effective than apomorphine 3 mg in men with arteriogenic ED. The fact that one out of five patients is not satisfied with the above-studied drugs shows that new oral agents need to be evaluated for the treatment of this disorder.

Apomorphine↗
PubMed2002

Apomorphine induces trophic factors that support fetal rat mesencephalic dopaminergic neurons in cultures.

Apomorphine, the catechol-derived dopamine D1/D2 receptor agonist, is currently in use as an antiparkinsonian drug. It has previously been reported that apomorphine was able to elicit expression of the enzyme tyrosine hydroxylase, a marker for DA neurons, in the fetal rat cerebrocortical cultures whilst in the presence of brain-derived neurotrophic factor. The present study demonstrated that treatment of fetal rat ventral mesencephalic cultures with apomorphine caused a marked increase in the number of dopaminergic neurons. The action of apomorphine can be mimicked by dopamine receptor (D1 and D2) agonists or blocked by preincubation with D1/D2 receptor antagonists. Incubation of recipient mesencephalic cultures with the conditioned medium derived from apomorphine-stimulated donor mesencephalic cultures elicited a 3.72-fold increase in the number of TH-positive neurons. Increased mRNA expression levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were also found in the apomorphine-treated mesencephalic cells along with concomitant protein expression increases in the conditioned medium. Moreover, the trophic activity observed could be partially neutralized by antibodies against either brain-derived neurotrophic factor or glial cell line-derived neurotrophic factor. Cultured fetal striatal cells, but not hippocampal cells, also responded to apomorphine treatment. The membrane filtration studies revealed that both <30 kDa and >50 kDa fractions contained trophic activities. The latter characterization distinguishes them from most known neurotrophic factors. These results suggest that the apomorphine-modulated development of dopaminergic neurons may be mediated by activation of the dopamine receptor subtypes D1 and D2 thereby increasing the production of multiple growth factors.

Animals↗