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Anticipatory responding, exclusive drug-context pairing and conditioned effects in sensitization to apomorphine-induced climbing in mice.

1. The conditioning aspects of contextual sensitization were examined in the case of apomorphine-induced wall-climbing in mice, measuring onset latencies of the pharmacological response and controlling differential habituation to the test context during drug treatment. 2. Sensitization was generated in male out-bred mice which received intermittent i.p. injections of 0.4 mg/kg apomorphine over 9 daily sessions. On day 10, they were tested for contextual sensitization (all mice under apomorphine). On day 14, after 3 sessions of reinstatement, mice were tested for conditioned climbing (all mice under saline). 3. It was found that simultaneous exposure to both apomorphine and the test context facilitated the expression of a full-blown contextual sensitization (some non-contextual sensitization emerging too); importantly, sensitization was accompanied by a progressive shortening of the latencies to climb (before injections); conditioned climbing appeared only in mice pairing the drug with the test context, that response being absent in mice treated outside the context or never exposed to the context. 4. It is likely that contextual sensitization to apomorphine-induced climbing relies on Pavlovian conditioning processes rather than on habituation-related processes.

Animals↗

Brain activation patterns during video sexual stimulation following the administration of apomorphine: results of a placebo-controlled study.

OBJECTIVES: To evaluate the in vivo effect of apomorphine sublingual versus placebo on cortical and subcortical brain activation during video sexual stimulation. METHODS: Ten patients with psychogenic erectile dysfunction and six potent controls underwent functional magnetic resonance of the brain during video sexual stimulation after the administration of either apomorphine sublingual 4mg or placebo following a randomized, double blind design. Functional magnetic resonance sessions were performed with a 7-day interval. RESULTS: In potent controls, viewing erotic versus neutral films induced bilateral activations in a network of occipito-parietal and temporal inferior regions, in dorsolateral and premotor frontal cortex, in anterior temporal limbic areas and the thalamus, which were comparable to the patient activations during erotic stimulation in the placebo condition. However, a striking difference was found in patients, who demonstrated a significant and extended activation in the cingulate gyrus, frontal mesial and frontal basal cortex, bilaterally, in comparison with potent controls. These activated neural systems were modulated by apomorphine administration which produced a picture that was similar to the one seen in potent controls. In patients with spychogenic erectile dysfunction apomorphine sublingual caused an increase in the extension of the activated networks, plus additional activation foci in subcortical and deep structures, namely in the nucleus accumbens, hypothalamus and mesencephalon: this activation was greater than that seen with placebo. Interestingly, a down-regulation in the frontal basal and temporal limbic cortex was present as shown by a decrease of functional magnetic resonance imaging signal reflecting a deactivation of these regions. CONCLUSIONS: Apomorphine significantly enhances the activation of cortical and subcortical brain function during video sexual stimulation. Patients with psychogenic erectile dysfunction may have an underlying functional abnormality of the brain acting as a previously unrecognised aetiological factor.

Administration, Sublingual↗

Mechanisms underlying the cardiovascular responses to spinal dopamine receptor stimulation by apomorphine in anesthetized rats.

The present study investigated the mechanisms by which intrathecal (i.t.) apomorphine affects mean aortic pressure and heart rate in anesthetized rats. In saline-pretreated rats, upper thoracic (T2-T4) i.t. administration of apomorphine (48 microg/rat) induced immediate and significant hypotension and bradycardia. These responses were unaffected by intravenous (i.v.) methylatropine (1 mg/kg) or bilateral vagotomy, while they were prevented by i.t. lidocaine (25 microl at 1%) or i.v. hexamethonium (30 mg/kg). However, i.v. atenolol (1.5 mg/kg) suppressed the apomorphine-induced bradycardia without affecting the hypotension in either intact or bivagotomized rats. Bilateral adrenalectomy had no effect upon both maximal hypotensive and bradycardic responses to apomorphine (48 microg/rat at the T9-T10 level). These results suggest that hypotensive and bradycardic responses to i.t. apomorphine are due to an action in the spinal cord, presumably on sympathetic preganglionic neurons. These responses are dissociated and seem to result from withdrawal of sympathetic outflow to the vasculature and to the heart, respectively.

Adrenalectomy↗

Differential effect of sensitizing regimen on induction of Fos-protein and locomotor activity elicited by apomorphine in rats.

At doses that elicit behavioral activation, apomorphine does not induce Fos-protein in the nucleus accumbens of control animals but does under conditions of denervation supersensitivity. The purpose of this study was to determine whether apomorphine induces Fos-protein in animals sensitized by repeated treatment with apomorphine and whether the magnitude of such induction parallels the magnitude of behavioral response observed after different sensitizing paradigms. Apomorphine did induce Fos-protein expression in animals pretreated with apomorphine; however, the rats showing highest levels of induction were not those showing the largest behavioral responses.

Animals↗

Expression of c-Fos, Fos B, Jun B, and Zif268 transcription factor proteins in rat barrel cortex following apomorphine-evoked whisking behavior.

Apomorphine-evoked expression of transcription factor proteins: c-Fos, Fos B, Jun B, and Zif268 (also named Krox-24, NGFI-A, Egr-1), was investigated in rat somatosensory (barrel) cortex. The effect of the N-methyl-D-aspartate receptor antagonist MK-801 on their expression was also analyzed. Apomorphine is a dopamine receptor agonist, eliciting motor activity, including enhanced whisking leading to the activation of vibrissae representation in the barrel cortex. Rats had their whiskers clipped on one side of the snout. The Zif268 levels were markedly reduced by this procedure alone. In contrast, apomorphine (5.0 mg/kg) evoked marked c-Fos elevation, less pronounced changes in Jun B and Zif268 and no change in Fos B. The greatest apomorphine-evoked c-Fos accumulation was observed in layers IV and V/VI of non-deprived barrel cortex and was not significantly influenced by MK-801 injection at 0.1 mg/kg. A higher dose of MK-801 (1.0 mg/kg) produced abnormalities in locomotor behavior and diminished c-Fos levels on the non-deprived side to the ones observed in the sensory stimulus-deprived cortex. We conclude that the response of the somatosensory cortex is selective with respect to both the gene activated and its cortical layer localization. Furthermore, sensory stimulation provides a major but not the only component to apomorphine-evoked barrel cortex gene activation.

Afferent Pathways↗

Prenatal corticosterone treatment induces long-term changes in spontaneous and apomorphine-mediated motor activity in male and female rats.

The potential influence of glucocorticoids on fetal brain development was investigated after corticosterone administration via pellets to pregnant rats during the last trimester of gestation. We examined both spontaneous motor activity and dopamine-mediated motor responses to apomorphine, a D1, D2 and D3 receptor agonist, given at a postsynaptic dose (1 mg/kg, s.c.) to both prepubertal and adult male and female offspring. Prenatal corticosterone was found to produce the following alterations in the offspring. (1) Prepubertal stage: Male offspring: a statistically significant (P < 0.05) increase was observed in spontaneous rearing, motility and locomotion (activity measured during the first 30 min) without changes in apomorphine-induced motor responses. Female offspring: a reduction (P < 0.05) only in spontaneous rearing activity was observed during the exploratory phase (activity measured during the first 10 min) without significant changes in apomorphine-induced motor responses. (2) Adult stage: Male offspring: the exploratory activity to the novel environment was increased (P < 0.05) without significant changes in apomorphine-induced motor activity. Female offspring: an increase (P < 0.05) in spontaneous locomotion was observed during the first 30 min of testing without significant changes in exploratory activity to the novel environment. However, the apomorphine-induced motility and locomotion were reduced (P < 0.05) during the first 30 min. These observations indicate that prenatal corticosterone induces both short-term and long-term changes in spontaneous motor activity as well as long-lasting alterations in dopamine receptor response in the motor network mechanisms controlled by DA receptors. These changes are in part age and sex-dependent. The possible relationship between prenatal programming of the mesolimbic and nigrostriatal dopaminergic pathways by corticosterone and the observed changes in motor function is discussed.

Animals↗

A clinical comparison of syrup of ipecac and apomorphine use in adults.

A prospective, randomized study was performed to compare syrup of ipecac to apomorphine as the emetic of choice in poisoning cases. Of the 28 adults studied, 15 patients (54%) received 30 ml of ipecac orally and 13 received 0.1 mg/kg apomorphine subcutaneously. Emesis was successfully induced with initial therapy in 13 of 15 (87%) ipecac-treated patients and 10 of 13 (77%) apomorphine-treated patients. In the ipecac group the mean latency period before onset of vomiting was 11.6 minutes (range 4 to 26 min) and in the apomorphine group, 5.3 minutes (range 2 to 13 min) (P less than .01). In the ipecac group, one patient suffered moderate central nervous system (CNS) depression. No hypotension or respiratory depression was observed in this group. In the apomorphine group significant CNS depression developed in eight patients (62%), hypotension developed in five (38%) and respiratory depression in one. There was no consistent relationship between type of poison ingested and occurrence of side effects.

Adolescent↗

Increased dopamine D2 receptor binding and enhanced apomorphine-induced locomotor activity in mu-opioid receptor knockout mice.

Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the mu-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2mg/kg, i.p.) for a period of 90min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [3H] SCH23390 and [3H] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated mu-opioid receptor knockout mice between 5 and 40min after administration. The results obtained also show that the binding of D2 dopamine receptor in mu-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in mu-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated mu-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking mu-opioid receptor genes.

Analysis of Variance↗

Variation in hippocampal dynorphin b-immunoreactive mossy fiber terminal fields of apomorphine-(un)susceptible rats.

The size of distinct hippocampal sub-fields were measured in the apomorphine-susceptible and apomorphine-unsusceptible rat lines. Mossy fiber terminal fields were delineated using dynorphin B immunoreactivity and area measurements were taken from (1) the supra-pyramidal mossy fiber terminal field; (2) the intra- and infra-pyramidal mossy fiber terminal field; (3) the hilus of the fascia dentata (4) the non dynorphin B immunoreactive area of the regio inferior and fascia dentata and (5) the total area of regio inferior and fascia dentata. The data indicate that statistically significant differences in the morphometry of the hippocampal subfields of the apomorphine susceptible and unsusceptible rats are confined to the intra- and infra terminal field: the relative size of the left and right intra- and infra terminal field of apomorphine unsusceptible rats are significantly larger than those of the apomorphine susceptible rats. These data explain at least in part the differential response of these rats to novelty.

Animals↗

Perioperative problems in Parkinson's disease and their management: apomorphine with rectal domperidone.

OBJECTIVE: To present guidelines on the use of apomorphine in combination with rectal domperidone in Parkinson's disease (PD) patients undergoing abdominal surgery and to review the perioperative problems encountered in such patients. BACKGROUND: PD patients undergoing abdominal surgery present a major therapeutic challenge. Because most antiparkinsonian medications must be withheld until the patient is able to resume oral intake, resulting rigidity and akinesia as well as alterations in gastrointestinal motility, respiratory function and swallowing mechanisms predispose these patients to numerous serious postoperative complications. We have found that parenteral apomorphine in combination with rectal domperidone markedly facilitates the care of these difficult patients. METHODS: Presentation of two illustrative cases with review of the literature. RESULTS: A standardized protocol using subcutaneous apomorphine and rectal domperidone was used in two PD patients who underwent abdominal surgery. Excellent control of parkinsonian symptomatology was obtained without side effects. The simplicity of the protocol was emphasized in our second patient who required urgent reoperation; the surgery nursing staff was able to restart the apomorphine immediately without having to wait for neurological follow-up assessment. CONCLUSIONS: The use of parenteral apomorphine with rectal domperidone in the immediate postoperative period for patients unable to take oral antiparkinson drugs increases patient comfort, facilitates nursing care and may reduce serious postoperative complications.

Administration, Rectal↗

Iontophoretic delivery of apomorphine. II: An in vivo study in patients with Parkinson's disease.

PURPOSE: Transdermal transport rates of the dopamine agonist R-apomorphine were determined in patients with idiopathic Parkinson's disease (IPD). Apomorphine was applied by iontophoresis at two current densities. METHODS: In ten patients apomorphine was applied passively for one hour. Thereafter, in the first five patients, a current density of 250 microA.cm-2 was applied for one hour and a current density of 375 microA.cm-2 in the second group. The individual pharmacokinetic parameters were obtained separately following a 15-minute zero-order intravenous infusion of 30 micrograms.kg-1. Skin resistance was measured during current delivery. Current-induced irritation was measured by Laser Doppler Flowmetry (LDF). The pharmacodynamics were quantified by a unilateral tapping score. Qualitative clinical improvements (decreased tremor, rigidity or cramp) were also recorded. RESULTS: In all patients increasing plasma concentrations of R-apomorphine were found during the interval of current application. The maximum concentrations that were attained were related to the applied current density: 1.3 +/- 0.6 ng.ml-1 at 250 microA.cm-2 and 2.5 +/- 0.7 ng.ml-1 at 375 microA.cm-2. When the current was switched off all concentrations returned to baseline values in about 90 minutes. By mathematical deconvolution of the profiles it was shown that steady-state fluxes were reached within the one-hour interval of current driven transport Steady-state fluxes were calculated to be 69 +/- 30 nmol.cm-2.h-1 at 250 microA.cm-2 and 114 +/- 34 nmol.cm-2.h-1 at 375 microA.cm-2. Individual drug input rates were inversely related to the overall resistance. Significantly elevated LDF values were found after patch removal, indicating mild current induced erythema. Only subtherapeutic plasma concentrations were obtained in all patients except for one. CONCLUSIONS: The results show that current-dependent delivery of apomorphine is possible in vivo at acceptable levels of skin irritation. Excellent correlation was found between the calculated in vivo transport rates and the rates that were previously obtained in vitro.

Administration, Cutaneous↗

Pretreatment with a water-based surfactant formulation affects transdermal iontophoretic delivery of R-apomorphine in vitro.

PURPOSE: To further increase the transdermal transport rate of R-apomorphine, a nonocclusive pretreatment with an aqueous surfactant formulation in combination with iontophoresis was explored in vitro. METHODS: The human stratum corneum was pretreated nonocclusively with formulations composed of laureth-3 oxyethylene ether (C12EO3), laureth-7 oxyethylene ether (C12EO7), and cholesterol sulfate (CSO4) prior to iontophoresis. The effect on the flux of the following parameters was examined: the composition, the charge, and the applied amount of surfactant formulations. RESULTS: The iontophoretic flux of R-apomorphine was appreciably increased by pretreatment with surfactant formulations. A formulation containing C12EO3/C12EO7/CSO4 at a molar ratio of 70:30:5 was very stable and increased the iontophoretic flux of R-apomorphine from 92.2 +/- 13.9 nmol/cm2 x h to 181.5 +/- 22.6 nmol/cm2 x h. When further increasing the negative charge of this formulation the iontophoretic transport rate was slightly inhibited. A dose of 40 microL/cm2 of the formulation with a total surfactant concentration of 5% (w/w) was sufficient for a maximum enhancing effect. CONCLUSIONS: The results obviously show that nonocclusive pretreatment with the surfactant formulation enhances the iontophoretic transport of R-apomorphine, and is a promising approach to achieve therapeutic concentrations of R-apomorphine.

Adjuvants, Pharmaceutic↗

Effects of different periods of lithium pretreatment and aminoglycoside antibiotics on apomorphine-induced yawning in rats.

Interactive effects of intracerebroventricular administration of the aminoglycoside antibiotics, amikacin and gentamicin, and different duration of lithium pretreatment on apomorphine-induced yawning were investigated in male rats. The study was designed to investigate whether the hypothesis that the aminoglycoside antibiotics, amikacin and gentamicin, via their effects on phosphoinositide pathways and calcium channel might influence dopaminergic mechanisms as manifested in the yawning effect. Lithium is known to interact with phosphoinositide metabolism and was also tested after chronic studies on the apomorphine yawning model. Subcutaneous administration of apomorphine (0.1, 0.2 and 0.4 mg/kg) to rats induced yawning in a biphasic manner. However the maximum response was obtained by 0.2 mg/kg of the drug. Intracerebroventricular administration of aminoglycoside antibiotics amikacin (25 microg/rat) increased and gentamicin (10 and 20 microg/rat) decreased apomorphine-induced yawning. Pretreatment of animals with lithium (600 mg/l) in drinking water for 7, 14 and 21 days reduced yawning induced by apomorphine. Administration of lithium for 28 days did not induce any significant effect on yawning response. Amikacin and gentamicin function via the same mechanism on phosphoinositide cascade. Since amikacin and gentamicin did not affect the yawning response similarly, they apparently do not involve inositol trisphosphate level in the alterations of dopaminergic-induced yawning. Probably, the effect of lithium pretreatment on the number of yawns is also time-dependent and some tolerance to the inhibitory effect of lithium might occur after 28 days' treatment.

Amikacin↗

Role of the lateral parabrachial nucleus in apomorphine-induced conditioned consumption reduction: cooling lesions and relationship of c-Fos-like immunoreactivity to strength of conditioning.

The following experiments were designed to determine whether the lateral parabrachial nucleus (lPBN) mediates acquisition of conditioned consumption reduction induced by apomorphine, an agent that also has reinforcing properties. Temporary cooling lesions of the PBN blocked acquisition of apomorphine-induced conditioned consumption reduction. In addition, both apomorphine and LiCl activated c-Fos-like immunoreactivity (c-FLI) in the central, external, and crescent lPBN, and there was a strong correspondence between amount of c-FLI expression and strength of conditioned consumption reduction in these subnuclei. Taken together, these results support the hypothesis that the lPBN mediates apomorphine-induced conditioned consumption reduction, as is true for LiCl. Furthermore, they raise the possibility that the specific part of the lPBN mediating this conditioning effect of apomorphine and LiCl is 1 of the 3 subnuclei.

Animals↗

Time course of tolerance to apomorphine in parkinsonism.

We sought to determine if tolerance developed to the antiparkinsonian effects of apomorphine and, if so, what temporal factors influenced its development. Seven patients with parkinsonism and motor fluctuations received short (6-hour) and long (22- to 31-hour) apomorphine infusions. Tolerance was evaluated by comparison of the responses to test doses of apomorphine that were administered before and after each infusion. The responses to the test doses that followed either infusion were reduced by 35% after the short infusion and by 68% after the long infusion, although plasma apomorphine levels were similar to or higher than levels achieved with preinfusion test doses. The duration of improvement in parkinsonism after discontinuation of the long infusion was briefer than that after the short infusion. We conclude that tolerance to apomorphine occurs in parkinsonism, and the loss of response is greater after longer periods of drug administration.

Aged↗

The effect of apomorphine, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) and placebo on smooth pursuit gain and corrective saccades in normal subjects.

The effects of apomorphine (0.01 mg/kg SC) a direct-acting dopamine (DA) agonist, MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine) (20 mg PO), a direct-acting serotonin (5-HT) agonist, and placebo on smooth pursuit eye movements were evaluated in 10 to 12 normal volunteers. Smooth pursuit was tested just prior to administration of either apomorphine, MK-212, or placebo (on separate days), and then repeatedly tested at 30 min intervals for two hours after dose administration. The smooth pursuit targets were a series of predictable, constant velocity ramps with velocities of 5 degrees/sec (slow target) and 20 degrees/sec (fast target). Eye movements were recorded with infrared oculography, and the following six measures were obtained; steady-state gain (slow-target-gain; fast-target-gain), corrective catch-up saccade (CUS) rate (slow-target-CUS-rate; fast-target-CUS-rate), and CUS amplitude (slow-target-CUS-amplitude; fast-target-CUS-amplitude). The placebo test yielded a statistically significant monotonic decrease over time in slow-target-gain and corresponding increase in slow-target-CUS-rate, but no effects of placebo were noted for the fast target. Apomorphine injection produced a marked reduction in both slow-target-gain and fast-target-gain at 30 min, returning to baseline thereafter. Apomorphine injection also produced a statistically significant increase in slow-target-CUS-amplitude. Ingestion of MK-212 produced a statistically significant increase in slow-target-gain and fast-target-gain as well as a corresponding decrease in slow-target-CUS-rate and fast-target-CUS-rate at 90 min or 120 min. There was evidence that the decline in slow-target-gain after apomorphine was associated with side-effects such as sleepiness, but the decline in fast-target-gain was not related to side-effects. The improved smooth pursuit performance after MK-212 was not related to side-effects. The data suggest that serotoninergic stimulation can improve smooth pursuit performance, whereas dopaminergic stimulation worsens this performance.

Adult↗

Nicotine blocks apomorphine-induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic alpha7 receptors.

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05-1 mg kg(-1), s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5-5 mg kg(-1), s.c.), an alpha(7) nicotinic receptor antagonist, nor dihydro-beta-erythroidine (0.5-2 mg kg(-1), s.c.), an alpha(4)beta(2) nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01-0.2 mg kg(-1), s.c.) dose-dependently reversed the disruption of PPI induced by apomorphine (1 mg kg(-1), s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg(-1), s.c.). The reversal of apomorphine-induced PPI disruption by nicotine (0.2 mg kg(-1)) was eliminated by mecamylamine (1 mg kg(-1), i.p.), but not by hexamethonium (10 mg kg(-1), i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine-induced PPI disruption was dose-dependently blocked by methyllycaconitine (1 and 2 mg kg(-1), s.c.). However, dihydro-beta-erythroidine (1 and 2 mg kg(-1), s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine-induced PPI through central alpha(7) nicotinic receptors.

Acoustic Stimulation↗

The apomorphine test in heroin addicts.

Chronic administration of opiates to laboratory animals induces supersensitivity of the dopamine receptors in the cerebral areas innervated by the mesotelencephalic dopamine pathways. In humans, the in vivo study of the sensitivity of the dopamine neurotransmitter system in Parkinson's patients can be done by means of the apomorphine test, which consists of measuring the number of yawns induced by the subcutaneous administration of low doses of apomorphine (0.005 mg/kg). If chronic opiate use in humans, as in experimental animals, results in supersensitivity of the dopamine systems, the apomorphine test could differentiate between heroin addicts and healthy volunteers, with the former showing greater number of yawns. In order to test this hypothesis we carried out the apomorphine test in two groups of subjects: a group of male heroin addicts attending our Addiction Treatment Centre for detoxification and the other group consisting of healthy volunteer male university students. Results showed that subcutaneous apomorphine administration induced a greater number of yawns (p < 0.05) in the group of heroin addicts as compared with the group of healthy volunteers, suggesting that heroin addicts present an enhanced sensitivity of the dopamine nuerotransmitter system.

Adolescent↗