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At least 793 records · Page 44Linked to original sources
PubMed2003

Endomorphin-1, an endogenous mu-opioid receptor agonist, improves apomorphine-induced impairment of prepulse inhibition in mice.

The present study was designed to examine the effects of the endogenous mu-opioid receptor agonist endomorphin-1 on prepulse inhibition (PPI) in mice. Although apomorphine (1mg/kg) produced a marked decrease in PPI, endomorphin-1 (17.5 microg) had no marked effects on PPI or startle amplitude in normal mice. Endomorphin-1 (17.5 microg) inhibited the apomorphine (1mg/kg)-induced decrease in PPI. beta-Funaltrexamine (5 microg), a mu-opioid receptor antagonist, did not significantly antagonize the effects of endomorphin-1 (17.5 microg). Naloxonazine (35 mg/kg), a mu(1)-opioid receptor antagonist, antagonized the effects of endomorphin-1 (17.5 microg) on the apomorphine (1mg/kg)-induced decrease in PPI, whereas naloxonazine (35 mg/kg) itself was without significant effects on the apomorphine (1mg/kg)-induced decrease. These results suggest that endomorphin-1 alleviates the impairment of PPI resulting from the hyperactivity of dopaminergic neurotransmission through the mediation of mu(1)-opioid receptors.

Animals↗
PubMed2000

Apomorphine-induced aggressive behaviour and post-mortem monoamine content in male Wistar rats.

The aim of this study was to investigate the monoamine content in post-mortem brain samples of control, apomorphine-aggressive, and apomorphine-non-aggressive adult male Wistar rats. The repeated apomorphine (1.0 mg/kg, (s.c.) once daily during 2 weeks) gradually induced aggressive behaviour in 18 animals out of 24. No unidirectional changes in the brain monoamine contents in four regions (frontal cortex, striatum, hippocampus, and hypothalamus) were detected as measured by high pressure liquid chromatography-electrochemical detection. In conclusion, our present experiment demonstrates that the development and intensity of apomorphine-induced aggressive behaviour do not correlate with the brain post-mortem monoamine content.

Aggression↗
PubMed2003

Enhanced hypotensive response to intravenous apomorphine in chronic spinalized, conscious rats: role of spinal dopamine D(1) and D(2) receptors.

Intravenous (i.v.) treatment with apomorphine (0.3 mg/kg) in conscious rats with chronic spinal cord transection (at T5-T7) induced a significant hypotension, which was greater than that in sham-operated rats. The present study examined whether such an amplification results from an enhanced spinal dopamine D(1) and/or D(2) receptor-mediated depressor effect. Intrathecal (i.t.) pretreatment with domperidone (40 microg/rat at T9-T10), a dopamine D(2) receptor antagonist that does not cross the blood-brain barrier, blocked nearly 35 and 56% of the maximal apomorphine-induced hypotension in control and spinal rats, respectively. The remaining hypotension after i.v. domperidone (0.5 mg/kg) pretreatment (i.e. the spinal component of the response) was significantly greater in spinal rats than in controls. In the latter animals, apomorphine-induced hypotension was fully abolished by metoclopramide (5 mg/kg, i.v.). However, in spinal rats, the hypotension was only abolished by combined pretreatment with i.v. metoclopramide and i.t. SCH 23390 (27 microg/rat at T9-T10). The results suggest that the enhancing hypotensive effects of i.v. apomorphine by spinal cord section are related to increased spinal dopamine D(1) and D(2) receptor-mediated depressor effects.

Animals↗
PubMed1997

MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice.

Intraperitoneal administration of MK-801 (0.1 mg/ kg), an N-methyl-D-aspartate (NMDA) receptor antagonist, before and during methamphetamine treatment inhibited methamphetamine-induced conditioned place preference (CPP) in mice. Behavioral sensitization to a dopamine (DA) receptor agonist apomorphine that developed in methamphetamine-induced CPP mice was also inhibited by MK-801. Furthermore, MK-801 inhibited apomorphine-induced postsynaptic dopaminergic action, cage-climbing behavior. Therefore, the present studies suggest that methamphetamine-induced behaviors, such as CPP and behavioral sensitization, may be closely related to the dopaminergic activation mediated via the NMDA receptor. The behavioral sensitization to apomorphine may be a possible underlying mechanism of methamphetamine-induced CPP, because behavioral sensitization developed in methamphetamine-induced CPP mice, as well as apomorphine-induced climbing behavior in mice, were inhibited by MK-801.

Animals↗
PubMed1998

Endogenous opioids and ATP-sensitive potassium channels are involved in the mediation of apomorphine-induced antinociception at the spinal level: a behavioral study in rats.

The effects of intrathecally (i.t.) administered glibenclamide, a blocker of adenosine triphosphate-sensitive potassium (K(ATP)) channels, or naloxone on the antinociception produced by i.t. apomorphine or morphine were observed and analyzed in rats by tail-flick (TF) test. The results showed that: (1) i.t. apomorphine produced a significant and dose-dependent antinociception, (2) the antinociception produced by i.t. apomorphine could be blocked dose-dependently by i.t. glibenclamide or naloxone, (3) the antinociception produced by i.t. morphine could also be blocked dose-dependently by i.t. glibenclamide. The results suggest that endogenous opioids and ATP-sensitive potassium channels might be involved in the mediation of apomorphine-induced antinociception at the spinal level.

Adenosine Triphosphate↗
PubMed1999

Involvement of endogenous opioids and ATP-sensitive potassium channels in the mediation of apomorphine-induced antinociception at the spinal level: a study using EMG planimetry of flexor reflex in rats.

The effects of intrathecally (i.t.) administered naloxone or glibenclamide, a blocker of adenosine triphosphate-sensitive potassium (KATP) channels, on the antinociception produced by i.t. apomorphine were observed by an integrated electromyogram measurement of hindlimb flexor reflex in lightly pentobarbital-anesthetized rats. The results showed that i.t. apomorphine produced a significant and dose-dependent antinociception and that the antinociception produced by i.t. apomorphine could be blocked dose dependently by i.t. naloxone or glibenclamide. The results suggest that endogenous opioids and ATP-sensitive potassium channels might be sequentially involved in the mediation of apomorphine-induced antinociception at the spinal level.

Adenosine Triphosphate↗
PubMed2001

Transdermal permeation of apomorphine through hairless mouse skin from microemulsions.

The in vitro transdermal absorption of apomorphine from microemulsions was studied using the skin of the hairless mouse as a membrane. Two microemulsions (no. 1 and 2) were prepared and thickened both containing 3.9% of apomorphine hydrochloride. The lipophilicity of the drug was increased by forming apomorphine-octanoic acid ion-pairs. The fluxes of the drug from the microemulsions through hairless mouse skin were 100 microg h(-1) cm(-2) from no. 1 and 88 microg h(-1) cm(-2) from no. 2. Apomorphine in microemulsions, protected from light with antioxidants, showed no degradation for up to 6 months.

Administration, Cutaneous↗
PubMed1997

Determination of apomorphine in human plasma by alumina extraction and high-performance liquid chromatography with electrochemical detection.

Apomorphine is a powerful agonist of dopaminergic receptors which several years ago was introduced into the therapy of Parkinson's Disease. The pharmacological activity of apomorphine already appears significant at low doses. Unfortunately, the difficulty in determining the drug in plasma at low concentrations hampers the completion of accurate pharmacokinetic studies in humans. Considering the analogy of apomorphine with the molecular structure of catecholamines, the extraction of the drug from plasma was optimized by using adsorption on alumina, a technique widely used for noradrenaline and adrenaline analysis in clinical chemistry laboratories. This method proved particularly efficient and selective in apomorphine extraction from plasma prior to high-performance liquid chromatographic analysis. After pretreatment of 200 microliters of plasma sample with 40 mg of alumina and 10 microliters of tris buffer (pH 8.6), the drug was eluted with 200 microliters of an acidic-organic solution. One volume of the supernatant was mixed with two volumes of phosphate buffer (pH 3.6), and 100 microliters of the obtained mixture were injected into the HPLC system. The chromatograph was equipped with a C18 reversed-phase column and with an electrochemical coulometric detector fitted with a high-sensitivity cell (first electrode 0.00 volts, second electrode +0.35 volts). Sensitivity (20 pg of injected drug), precision (CV within assay and between assays of 3.7% and 5.6%, respectively) and accuracy were comparable to more complex analytical procedures. The miniaturisation of the entire sample pretreatment proved very advantageous for pharmacokinetics studies and, in principle, for therapeutic drug monitoring and toxicological investigations.

Adsorption↗
PubMed2002

Effects of yohimbine and apomorphine on the male sexual behaviour pattern of the golden hamster (Mesocricetus auratus).

It has been reported that the copulatory pattern of male hamsters differs from that displayed by most rodents. Besides mount, intromission and ejaculatory patterns, male hamsters display a peculiar copulatory pattern known as long intromission (LI). This peculiar behavioural pattern emerges after the male has been allowed to ejaculate repeatedly. Although LIs have been linked to sexual exhaustion, their functional meaning and their pharmacological regulation have not yet been elucidated. In this study, the sexual behaviour pattern of male golden hamsters was analysed after the administration of yohimbine and apomorphine, drugs that selectively acts on the noradrenergic and dopaminergic system, respectively. Both drugs have proved effective in inducing facilitation of masculine sexual behaviour in several species, including rodents. Results showed that, as in rats, the administration of yohimbine and apomorphine in male hamsters seems to have a stimulatory effect on masculine sexual behaviour, although their effects differ in characteristics and in intensity. In particular, after yohimbine administration, the onset of LIs appears sooner than in control subjects and it seems that they are linked to the number of ejaculations. In addition, sexual activity seems increased after the onset of LIs, including an increase in ejaculations and in the number of LIs. On the other hand, apomorphine administration induced just a slight stimulatory effect limited to ejaculatory latency and postejaculatory interval. Concerning LIs, apomorphine induced a complete disappearance of LIs in 60% of the subjects. The full significance of these findings remains to be elucidated.

Adrenergic alpha-Antagonists↗
PubMed1999

Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits.

PURPOSE: The purpose of this study was to investigate both the in vitro and in vivo release of apomorphine from mucoadhesive powder formulations of Carbopol 971P and polycarbophil. METHODS: The in vitro drug release from the mucoadhesive formulations was studied using a modified USP XXII rotating basket. The pharmacokinetics of apomorphine given as a solution was determined after subcutaneous and intranasal administrations to rabbits. The animals also received intranasally the mucoadhesive dosage forms and immediate release lactose powder mixture. Comparisons were made between the salient pharmacokinetic parameters of the different dosage forms. RESULTS: Sustained in vitro drug release was obtained from the mucoadhesive formulations. Apomorphine was absorbed more rapidly in rabbits when administered intranasally than as a subcutaneous injection. The mucoadhesive formulations both gave sustained plasma drug concentrations and bioavailabilities comparable to subcutaneous injections. The times taken to achieve peak plasma drug concentrations from these mucoadhesive formulations were more than three-fold that of lactose. With these mucoadhesive formulations apomorphine lasted longer in the blood. It could be detected for up to 6-8 h compared to approximately 3 h for the other forms of administration. CONCLUSIONS: The nasal bioavailability of powders is higher than that of solutions. Drug release from the mucoadhesive powders was sustained and there was no significant difference between Carbopol 971P and polycarbophil.

Acrylic Resins↗
PubMed2003

Acute low single dose of apomorphine reduces periodic limb movements but has no significant effect on sleep arousals: a preliminary report.

STUDY OBJECTIVES: To investigate the effects of apomorphine on the frequency of periodic limb movements during sleep (PLMS) and on sleep architecture. DESIGN: Nine patients presenting PLMS (including eight patients with restless legs syndrome) underwent three consecutive night sleep recordings. They received a single dose of 0.5 mg subcutaneous apomorphine at bedtime the third night. RESULTS: When computing PLMS during four 2-h periods of sleep, a significant period by apomorphine-effect was demonstrated, with a marked reduction of PLMS during the first 4 h post-injection (P < 0.01). No significant differences were found in sleep macroarchitecture between the three recorded nights, excepted a slight reduction in sleep latency during the third night (P < 0.05). Despite the decreased number of PLMS after apomorphine injection, there were significant changes neither in the total number of arousals nor in the index of arousals per hour of sleep. CONCLUSION: Our results add further support to the dopaminergic hypothesis in the generation of PLMS. The persistence of arousals suggests that they are not simply the consequence of PLMS but a primary phenomenon, not related with the dopaminergic system.

Apomorphine↗
PubMed2002

Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the 'indirect pathway'.

OBJECTIVES: Previous studies suggested that the hypo-activity of the external pallidus (GPe) might drive the hyper-activity of subthalamic neurons, which underlies the cardinal symptoms of Parkinson's disease. We have challenged this view, based on the so-called 'indirect pathway', by recording apomorphine effects from both structures of parkinsonian patients, at rest and during passive movements. METHODS: We performed single-unit recordings from external pallidus (GPe), internal pallidus (GPi) and subthalamic nucleus (STN) during the stereotactic neurosurgery aimed to implant deep brain stimulating electrodes in GPi or STN. First, we verified the firing frequency of each structure in off-state conditions. Then, therapeutic, subdyskinetic concentrations of the dopaminergic agonist apomorphine was delivered to assess each nucleus response. RESULTS: The firing rate of STN averaged about 40 Hz; a large proportion (75%) of STN units exhibited marked responsiveness to passive movements. Apomorphine reduced the firing discharge of parkinsonian STN in all cells, although electrophysiological recovery was usually incomplete. Movement-related activity was also dramatically reduced. In contrast, apomorphine failed to modify the firing frequency of GPe, despite the amelioration of hypo-kinetic symptoms and the simultaneous inhibition of GPi firing discharge. CONCLUSIONS: We demonstrate that part of the models on basal ganglia circuitry needs to be revised. The re-balancing of STN hyper-activity, when patients benefit from dopaminergic therapy, is not due to an increased input from GPe, but, instead, due to changes in STN intrinsic firing properties and/or modulation of glutamatergic inputs.

Adult↗
PubMed1976

Diester derivatives as apomorphine prodrugs.

A series of diesters of apomorphine was synthesized to serve as prodrugs. They were converted in vivo to free apomorphine, which could be detected in the brain. Stereotyped gnawing behavior and unilateral rotation similar to that produced by apomorphine were induced by all of the diesters but the time course of action of the latter was prolonged. The duration of action generally increased with the size of the ester substituent and appeared to correlate inversely with the rate of hydrolysis of the esters by liver extracts. It is concluded that the diesters serve as prodrugs of apomorphine and their prolonged duration is partly explained by a decreasing rate of hydrolysis attributable to increased steric hindrance at the acyl carbon atoms.

Animals↗
PubMed1997

Iontophoretic delivery of apomorphine. I: In vitro optimization and validation.

PURPOSE: To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. METHODS: In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. RESULTS: Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37 degrees C the steady-state flux was increased by a factor of 2.3 and the lag time decreased to +/- 3 minutes. No effect of osmolarity and buffer strength and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. CONCLUSIONS: The results obtained in vitro indicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.

Antiparkinson Agents↗
PubMed1990

Altered pharmacokinetics and dynamics of apomorphine in the malnourished rat: modeling of the composed relationship between concentration and heart-rate response.

The impact of malnutrition on the pharmacokinetics and pharmacodynamics (change in heart rate) of apomorphine was studied in the rat. One group of rats received a low-protein diet (0.5%) ad libitum to produce prekwashiorkor. The control group received commercial food pellets. In the first experiment, the two groups received a 2 mg/kg iv bolus dose of apomorphine to determine any differences in the basic pharmacokinetic parameters. The pharmacodynamic characteristics in each group were studied at different steady-state plasma levels, achieved by iv infusions with continuous measurements of the heart rate. There was an almost twofold decrease in the plasma clearance in the malnourished rats compared with controls. A pronounced change in the pharmacodynamic response was also observed in the malnourished group. In the control group, apomorphine produced bradycardia at low concentrations and tachycardia at high concentrations, while only bradycardia was registered in the malnourished group, with maximum effects at steady-state plasma concentrations of 50 ng/ml and a return to baseline at higher concentrations. The effects in control and malnourished rats were fitted simultaneously to the sum of two Hill equations with a nonlinear regression program, and the fits were compared by means of an F test. The maximum pure tachycardia obtainable differed significantly in the prekwashiorkor group compared to the control group. These results suggest a selective down regulation/desensitization only of the receptors responsible for the tachycardia produced by apomorphine during malnutrition.

Animals↗
PubMed1987

Effects of apomorphine and haloperidol on response suppression learning of young chicks.

In four experiments, the effects of augmenting or blocking dopamine receptor activity on response suppression learning of Colburn X Colburn chicks were determined. In each experiment, 4-day-old chicks were trained to key peck for heat reward and then tested for response suppression learning by using either a response-contingent punishment or an extinction-punishment task. Before response suppression testing, different groups of chicks were injected ip with apomorphine (1.0, 2.0, or 4.0 mg/kg) either alone or after pretreatment with haloperidol (0.5 or 1.0 mg/kg). Regardless of the response suppression task used, chicks injected with apomorphine had difficulty inhibiting their responding; whereas, chicks injected with haloperidol, either alone or before apomorphine treatment, responded on fewer trials than saline-treated chicks. During extinction testing, 4-day-old chicks given only apomorphine showed the typical suppressive effect of punishment on responding rather than the paradoxical punishment-induced increase in responding found in normal 1-day-old chicks. These results indicate that activation of dopamine receptors retards response suppression learning of the 4-day-old chick, but functional changes in central dopaminergic mechanisms are not primarily responsible for the normal age-dependent improvement in response suppression learning of the young chick.

Age Factors↗
PubMed1999

Conditioning of and contextual sensitization to apomorphine-induced climbing in mice: evidence against the habituation hypothesis.

Several predictions of the habituation hypothesis of conditioned drug effects were tested by looking at contextual sensitization to apomorphine-induced climbing in mice (Mus musculus). Mice were first sensitized to that effect after 9 daily injections of 0.4 mg/kg apomorphine in the test context. Other mice received the same treatment outside the test context. On Day 10, all mice were challenged with either saline (conditioned drug effects test) or apomorphine (contextual sensitization test). On both tests, the levels of climbing of mice that received apomorphine paired with the test context during the intermittent treatment were significantly higher than those of mice that were experiencing the test context for the first time (unexposed mice). Also, the rate of extinction in conditioned mice did not parallel the rate of habituation in the unexposed mice. Results contradict the habituation hypothesis of conditioned drug effects and contextual sensitization.

Animals↗
PubMed2002

Genetic differences in startle gating-disruptive effects of apomorphine: evidence for central mediation.

Strain differences in sensitivity to dopamine agonist-induced disruption of prepulse inhibition (PPI) may be a useful model for the genetics of PPI deficits in neuropsychiatric disorders. Compared with Long-Evans (LE) rats, Sprague-Dawley (SD) rats are more sensitive to the PPI-disruptive effects of the DA agonist apomorphine. The authors tested the hypothesis that this strain difference reflects brain function rather than peripheral physiology. Significant SD > LE PPI-disruptive effects of apomorphine were observed despite equal apomorphine levels in SD and LE rats in forebrain regions that regulate PPI. SD > LE PPI-disruptive effects of apomorphine were also independent of peripheral versus central route of administration. This model for PPI genetics is sensitive to differences in central rather than peripheral substrates.

Animals↗