Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Apomorphine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2004

Levodopa treatment does not affect low-dose apomorphine test in patients with Parkinson's disease.

Challenge with low-dose apomorphine causes a significant rise in growth hormone (GH) in patients with Parkinson's disease (PD) compared to controls and patients with multiple system atrophy (MSA) who have not previously received dopaminergic treatment. To date, it has not been demonstrated whether an apomorphine-induced rise in GH can still be detected in PD patients who are currently treated with levodopa. We investigated whether an ongoing treatment with levodopa influences the GH response to subcutaneously applied low-dose apomorphine in PD patients. We studied 44 patients with idiopathic PD using the low-dose apomorphine test. Twenty-three patients were under treatment with levodopa and 21 patients were without any dopaminergic therapy. GH and cortisol levels were analyzed at time of injection and 45 minutes and 60 minutes after subcutaneous apomorphine injection. Forty-five minutes after apomorphine injection, there was no significant difference between the mean rise in plasma GH in untreated PD patients compared with levodopa-treated patients (P = 0.235). There was no increase of cortisol levels in each treatment group. Age, sex, duration, and severity of the disease did not show a covariate effect with GH levels. A small group of PD patients (n = 8) treated with dopamine agonists and a small group of patients with MSA (n = 5) as well as patients with vascular parkinsonism (n = 5) did not show any increase of GH. Our data suggest that the apomorphine-induced rise in GH does not depend on previous levodopa treatment in PD patients but, as expected, is blocked by dopamine agonists and is not present in patients with other than idiopathic parkinsonian syndrome. Thus, the low-dose apomorphine test may also be a useful biological marker in the early differential diagnosis of PD patients who have already received levodopa treatment.

Adult↗
PubMed2005

Continuous subcutaneous apomorphine therapy improves dyskinesias in Parkinson's disease: a prospective study using single-dose challenges.

Continuous subcutaneous (SC) infusion of the dopamine agonist apomorphine was shown in retrospective studies to improve drug-induced dyskinesias in Parkinson's disease (PD). We prospectively assessed the antidyskinetic effect of continuous SC apomorphine therapy using subjective and objective measures, and sought to determine whether any observed dyskinesia reduction could be corroborated using single-dose dopaminergic challenges. Twelve PD patients with on-off fluctuations and disabling dyskinesias who were scheduled to start apomorphine pump treatment underwent acute levodopa and apomorphine challenges at baseline and 6 months later. Video recordings involving motor tasks were rated blindly by two independent raters using modified AIMS and Goetz dyskinesia scales. At 6 months, mean apomorphine dose was 75.2 mg per day and the mean L-dopa dose had been reduced by 55%. Daily off time in patients' diaries was reduced by 38% (2.4 hours). The L-dopa challenges showed a reduction of 44% in AIMS and 40% in Goetz scores (both P < 0.01). Apomorphine challenges showed a reduction of 39% in AIMS and 36% in Goetz scores (both P < 0.01). Patients' self-assessment scores reflected these significant changes. Dyskinesia improvement correlated with reduction in oral medication and with the final apomorphine dose (P < 0.05). This prospective study confirms marked dyskinesia reduction on continuous subcutaneous apomorphine therapy, paralleled by reduced dyskinesias during dopaminergic challenge tests. Our findings support the concept that replacement of short-acting oral antiparkinsonian medication with continuous dopamine receptor stimulation may reverse, at least partially, the sensitization process believed to mediate the development of drug-induced dyskinesias in PD.

Aged↗
PubMed1996

A new sublingual formulation of apomorphine in the treatment of patients with Parkinson's disease.

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.

Administration, Sublingual↗
PubMed1993

External and implanted pumps for apomorphine infusion in parkinsonism.

Continuous delivery of dopaminergic agents to the striatum is a major challenge to improve the treatment of Parkinson's disease. Apomorphine is one of the best candidates because of its solubility and its D1 and D2 receptor agonist properties. Seventeen Parkinsonian patients suffering from severe L-dopa-induced on-off effects were treated by continuous subcutaneous (SC) infusion with a portable minipump. Administration of intracerebroventricular (ICV) apomorphine was carried out in 7 macaca fascicularis monkeys using implanted programmable pumps. Four of the monkeys were made Parkinsonian by MPTP injections. In patients receiving apomorphine, the mean duration of daily off periods was reduced by 61%. Psychiatric side effects were rare but SC nodules occurred in all patients and the external infusion method was therefore difficult to implement. In monkeys, the implanted system was well tolerated. ICV apomorphine infusion led to CSF apomorphine concentrations higher than the same apomorphine dose infused i.m. Motor function was considerably improved in two MPTP monkeys during the time of ICV infusion and 30 min after its arrest. Long-term ICV administration could not be carried out because of catheter blockage and/or apomorphine toxicity. SC and ICV apomorphine infusions are efficient for controlling motor activity in Parkinsonism but long-term toxicity remains to be studied further.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Involvement of different dopamine receptors in rat diphasic motility response to apomorphine.

A critical dose of apomorphine (300 micrograms/kg SC) given immediately before placing rats into a novel environment produced a diphasic motility response (initial sedation followed by enhanced locomotion). Various neuroleptics having different clinical and/or pharmacological profiles were studied by using such a model. (-)-Sulpiride and sultopride preferentially antagonized apomorphine inhibition; haloperidol and tiapride antagonized both phases of apomorphine response at similar doses; chlorpromazine, fluphenazine, thioridazine, metoclopramide and SCH 23390 preferentially antagonized apomorphine stimulation. The results are discussed in terms of the dopamine receptor subtypes involved in the two phases of apomorphine effect. Apomorphine stimulation can be antagonized by D-1 as well as D-2 receptor blockade. A higher affinity for D-2 receptors seems a necessary requisite for the antagonism of apomorphine inhibition; moreover, the ability of neuroleptics to antagonize apomorphine inhibition seems to depend on the ratio of their presynaptic versus postsynaptic D-2 activity.

Animals↗
PubMed1986

Apomorphine anorexia: the role of dopamine cell body autoreceptors.

Anorectic effects of apomorphine were studied in a microstructural analysis paradigm. Systemic apomorphine reduced food intake by reducing both the rate of eating and the time spent eating. Peripheral administration of sulpiride reversed the apomorphine effect on both eating rate and eating time but central administration of this neuroleptic into the ventral tegmental area (VTA) selectively reversed the apomorphine effect on eating time, sparing eating rate. Administration of apomorphine directly into the VTA reduced eating time but not eating rate; the effect on eating time was blocked by peripheral sulpiride. The results imply that the two components of apomorphine anorexia result from actions at different sites. Effects of apomorphine on eating time appear to result from an action on DA cell body autoreceptors. The apomorphine effect on eating rate appears to be mediated elsewhere.

Animals↗
PubMed1975

Influence of response topography on the effect of apomorphine and amphetamine on operant behavior of pigeons.

Key-pecking and treadle-pressing behavior were maintained in five pigeons by a mult. FI5 key FI5 treadle schedule of food presentation. Dose-effect curves for apomorphine and amphetamine on overall rates of responding in both F1 componenets of the multiple schedule were determined. Effective doses of apomorphine caused dose-dependent decreases on treadle-pressing rates in all animals. Similarly, key pecking rates were decreased by increasing doses of apomorphine in two of the five pigeons. However, dose-dependent increases in key-pecking rates were caused by apomorphine in the other three birds. In this group of pigeons, the mean key-pecking rate was increased to over 500% of the control rate by the dose of 1 mg/kg of apomorphine. Observation of the animals under the effect of apomorphine showed continuous pecking at the operative key in these three animals while the other two pecked at different places of the floor and walls of the experimental chamber. Appropriate doses of amphetamine caused rate-increasing effects on key-pecking as well as treadle-pressing rates of all pigeons. These results suggest that the increases in key-pecking rate caused by apomorphine in some pigeons in a conventional operant situation due to the orientation of the drug-induced stereotyped pecking toward the response keypecking, as a consequence of the topographic compatibility between this behavioral effect of apomorphine and the operant selected for study.

Amphetamine↗
PubMed1987

Conditioning of pre- and post-synaptic behavioural responses to the dopamine receptor agonist apomorphine in rats.

We investigated whether pharmacological effects of the dopamine agonist apomorphine can be conditioned by establishing an association of apomorphine administration with exteroceptive cues. Apomorphine was repeatedly administered and subsequently, the rat was put into a test cage and exposed to an acoustic and an olfactory stimulus ("conditioned rats"). Control animals ("pseudoconditioned" rats) were treated with the same pharmacological schedule of apomorphine not temporally associated with the stimuli. On the test day, both groups were injected with saline and exposed to the stimuli described. The stereotyped behaviour produced by large doses of apomorphine (0.5 or 2.0 mg/kg SC), namely sniffing, licking and gnawing, could be conditioned in a pronounced way. During the conditioning period, a change in the stereotypies was observed with regard to the time-course (earlier occurrence) and to the character of the stereotypies (from sniffing to licking and gnawing), when 0.5 mg/kg apomorphine was used, but not with the dose of 2.0 mg/kg. The conditioned responses showed a relatively uniform distribution during the observation period with some increase towards the end of the observation period. Some signs produced by a low dose of apomorphine (0.07 mg/kg SC), namely hypomotility and ptosis, but not yawning, could also be conditioned, although in a less pronounced way. An intermediate dose of apomorphine (0.18 mg/kg SC) produced both signs observed after large doses and those observed after a small dose, occurring alternatingly. Both types of signs could be conditioned using this dosage. Conditioning did not alter striatal or mesolimbic dopamine turnover.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1981

Effects of apomorphine on behavioural activity and brain catecholamine synthesis in normal and L-triiodothyronine-treated rats.

The effect of chronic apomorphine treatment on behavioural activity as well as brain dopamine metabolism was studied in normal and neonatally L-triiodothyronine-treated rats. Neonatal hyperthyroidism was accompanied by an increase in spontaneous locomotor activity as well as by enhanced synthesis and release of dopamine as evidenced by increased catecholamine synthesis in crude synaptosomal preparation (P2 pellet), elevated tyrosine hydroxylase activity and higher concentrations of homovanillic acid and 3, 4-dihydroxyphenylacetic acid in striatum of rats. Repeated apomorphine treatment (1 mg/kg/day s.c) for 15 days, beginning from the 15th day of age, produced hypermobility and stereotyped behavior (consisting of sniffing, gnawing, rearing) which appeared to be more pronounced in neonatally hyperthyroid rats than in normal controls. In addition, apomorphine-treated hyperthyroid animals marched in a row with straub tail, and displayed increased aggressiveness and bizarre social behavior consisting of "mock fighting" when left in pairs. In contrast to normal rats, apomorphine-treated hyperthyroid animals displayed marked hyperactivity which was evident even at 24 hours after the last injection of apomorphine. Administration of apomorphine resulted in significant decreases in striatal tyrosine hydroxylase, catecholamine synthesis in crude synaptosomal preparation (P2 pellet) as well as dopamine metabolite levels in brains of both normal and hyperthyroid animals. Our present data showing that apomorphine potentiates behavioural activity in hyperthyroid rats suggest that L-triiodothyronine and apomorphine probably share certain features common to activating dopaminergic neurons in the brain.

Animals↗
PubMed1994

Effects of GABA-ergic drugs on penile erection induced by apomorphine in rats.

The effects of GABA agonists and antagonists on penile erection (PE) induced by apomorphine were investigated in rats. Subcutaneous (SC) administration of apomorphine (0.01-0.1 mg/kg) induces a dose-dependent PE in rats. The maximum effect was obtained with 0.1 mg/kg of the drug. The response was decreased with increasing doses of apomorphine from 0.1 to 0.5 mg/kg. The response induced by apomorphine (0.1-0.5 mg/kg) was decreased in animals pretreated with either the GABA-A agonist muscimol or the GABA-B agonist baclofen. Combination of muscimol with baclofen caused a stronger inhibitory effect on apomorphine-induced PE. Bicuculline or picrotoxin but not phaclofen reduced the inhibitory effect of muscimol on PE induced by apomorphine, whereas phaclofen but not GABA-A antagonists decreased the inhibitory action of baclofen on apomorphine-induced PE. Pretreatment of animals with higher doses of the GABA-A antagonists bicuculline and picrotoxin or the GABA-B antagonist phaclofen elicited inhibition of apomorphine-induced PE. However, the inhibitory effects of GABA-A and GABA-B antagonists are lost on combination. Administration of GABA-A and GABA-B receptor stimulation inhibit PE induced by dopaminergic mechanism(s).

Animals↗
PubMed1999

Behavioral interactions produced by co-administration of 7-OH-DPAT with cocaine or apomorphine in the rat.

Previous research from our laboratory suggests that low doses (<0.1 mg/kg) of the dopamine (DA) D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) attenuate conditioned place preference (CPP) produced by the indirect DA agonist d-amphetamine, but enhance d-amphetamine-induced stereotypic behaviors. This study further examined the effects of 7-OH-DPAT on behaviors produced by the indirect DA agonist, cocaine, and the non-selective direct DA agonist, apomorphine. To examine whether 7-OH-DPAT would alter cocaine and apomorphine dose-response curves for motor behaviors and CPP, 0.1 mg/kg 7-OH-DPAT was co-administered with 0-30 mg/kg cocaine and 0-3 mg/kg apomorphine. To establish place conditioning, drug injections were paired with one of two distinctly different compartments, whereas saline injections were paired with the other compartment. Locomotion, sniffing, oral stereotypy, and headbobbing were measured following acute and repeated drug administration during conditioning, and place conditioning was assessed 24 h following the last conditioning day. 7-OH-DPAT enhanced cocaine- and apomorphine-induced stereotypies following repeated administration. 7-OH-DPAT also attenuated cocaine-CPP, but potentiated apomorphine-CPP. Furthermore, 7-OH-DPAT attenuated locomotion produced by high doses of apomorphine. The attenuation of cocaine-CPP by 7-OH-DPAT likely involves stimulation of D2/D3 autoreceptors in the mesolimbic pathway, whereas the potentiation of apomorphine-CPP likely involves stimulation of D2/D3 postsynaptic receptors. Furthermore, it is suggested that attenuation of apomorphine-induced locomotion by 7-OH-DPAT likely involves stimulation of postsynaptic D3 receptors in the mesolimbic pathway. Thus, if postsynaptic D3 receptors are involved in mediating CPP and locomotion, then stimulation of D3 receptors may facilitate CPP but inhibit locomotion.

Animals↗
PubMed1994

Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine.

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of [3H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere. The concentrations of dopamine and its metabolites (DOPAC, HVA and 3-MT) were quantified by gas chromatography-mass spectrometry in the right and left striata at 5 and 15 min after unilateral intracarotid infusion of 1 microgram apomorphine. At both time intervals and regardless of the side infused, the metabolites of dopamine increased ipsilateral to the side of infusion. Moreover, 3-MT levels were significantly decreased in the contralateral striatum. After direct intrastriatal injection of either 0.1 or 1.0 microgram apomorphine into the right striatum, the levels of dopamine metabolites were again increased in the ipsilateral striatum. 3-MT levels were also decreased significantly in the left striatum. In contrast to the effects observed after systemic administration of apomorphine, these results demonstrate that dopamine release in the striatum is increased by selectively delivering higher concentrations of apomorphine to the nerve terminals of the nigrostriatal neurons. The effects of unilateral apomorphine on dopamine metabolism in the contralateral striatum are most likely the effect of interhemispheric communication.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Effect of the dopamine D-1 antagonist SCH 23390 on rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats.

The experiments concerned the effects of the D-1 dopamine antagonist SCH 23390 on the rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats. SCH 23390 dose dependently inhibited the rotational behaviour induced by apomorphine. A significant inhibitory effect was obtained after 0.05 mg/kg s.c. of SCH 23390, which involved a change of the typical two-peak pattern of rotation induced by apomorphine. While the first peak of rotation was not significantly modified, the last peak of rotation induced by apomorphine was inhibited in a dose-dependent manner. No significant inhibition of the total rotation induced by pergolide was observed after SCH 23390 pretreatment. SCH 23390 seemed to enhance the duration of the rotation induced by pergolide, resulting in an increase in the total number of turns. However, the intensity of the maximal peak of rotation induced by pergolide was significantly inhibited after 5.0 mg/kg s.c. of SCH 23390. Comparison of the potency with which SCH 23390 inhibited the apomorphine- and pergolide-induced maximal peaks of rotation reveals that SCH 23390 was approximately 100 times more potent in inhibiting the apomorphine than the pergolide response. The results, compared with those in our previous report, show that the D-2 dopamine antagonist sulpiride was 1000 times more potent in inhibiting the pergolide than the apomorphine rotation. The present results support the hypothesis that apomorphine and pergolide induce rotation in 6-hydroxy-dopamine denervated rats by differential actions on D-1 and D-2 receptor sites.

Animals↗
PubMed1986

Desenkephalin-gamma-endorphin restores the impaired sensitivity of hypophysectomized rats to small doses of apomorphine.

Hypophysectomized male rats, tested 7 days after removal of the pituitary, showed a reduced sensitivity to small doses of apomorphine. In these rats, subcutaneous (s.c.) treatment with apomorphine (25, 100 or 250 micrograms/kg) did not elicit any reduction in locomotor activity measured 5 min after injection in contrast to that observed in sham-operated control rats. The enhancement of locomotor activity and stereotyped behavior, 20 min after the s.c. administration of apomorphine, was similar in hypophysectomized rats and in control animals. Prolactin does not seem to be implicated in this altered sensitivity, since hyperprolactinaemia induced by pituitary homografts under the kidney capsule did not change the response to apomorphine in hypophysectomized rats. Chronic treatment with desenkephalin-gamma-endorphin (DE gamma E), a beta-endorphin fragment with neuroleptic-like properties, administered s.c. twice a day for 7 days at the dose of 10 micrograms/rat, restored the sensitivity to small doses of apomorphine in the hypophysectomized rats. The data suggest that removal of the pituitary leads to impaired sensitivity of presumably presynaptically located dopamine receptors mediating the effects of small doses of apomorphine without altering the sensitivity of postsynaptically located dopamine receptors that mediate the hypermotility and stereotypy induced by apomorphine. This impaired sensitivity to low doses of apomorphine could be restored by DE gamma E but not by prolactin, supporting the conclusions from previous experiments that DE gamma E and prolactin may selectively interfere with pre- and postsynaptic dopamine receptors respectively.

Animals↗
PubMed1994

Clozapine injected into the nucleus accumbens potentiates apomorphine-induced jaw movements.

The effects of clozapine injected into the nucleus accumbens on apomorphine-induced jaw movements were studied. Jaw movements induced by apomorphine (0.5 mg/kg i.v.) were potentiated by clozapine (10 micrograms/0.2 microliters) injected into the nucleus accumbens 10 min before apomorphine. Enhancement of the apomorphine-induced jaw movements was also found with the muscarinic acetylcholine receptor antagonist, methylscopolamine (2.5 micrograms), whereas the acetylcholine receptor agonist, carbachol (2.5 micrograms), inhibited the effects of apomorphine. Injection of a smaller dose of carbachol (0.1 microgram) alone into the nucleus accumbens 10 min before failed to alter the effects of apomorphine but prevented the potentiation induced by clozapine. Both the 5-hydroxytryptamine(5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.1 and 0.2 microgram), and the alpha 1-adrenoceptor antagonist, prazosin (0.05 and 0.2 microgram), failed to affect the effects of apomorphine(0.5 mg/kg i.v.). In contrast, clozapine (1, 5 and 10 micrograms), ICI 169,369 (0.1 and 0.2 microgram) or prazosin (0.05 and 0.2 microgram) given into the ventral striatum inhibited the effects of apomorphine (0.5 mg/kg i.v.). It is suggested that the clozapine-induced potentiation in the nucleus accumbens might be due to its antimuscarinic properties.

Analysis of Variance↗
PubMed1996

Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction.

Ergoline-derived dopamine receptor agonists, like pergolide or bromocryptine, have recently attracted attention as potential neuroprotective drugs. The classical mixed type dopamine D1 and D2 receptor agonist apomorphine, although used clinically in the therapy of Parkinson's disease, has never been examined for any properties related to neuroprotection. In this paper, we examine the effects of 0.1-100 microM apomorphine on ascorbate/iron-stimulated free radical processes in rat brain mitchondrial fraction. Lipid peroxidation as assayed by the thiobarbituric acid reaction can be completely inhibited by submicromolar concentrations of apomorphine (0.3 microM with 2.5 microM Fe2+ and 0.6 microM with 5.0 microM Fe2+), which proved to be more than twice as effective as desferrioxamine and twenty times as compared with dopamine. The inhibition of lipid peroxidation in mitochondria correlates with an increased rate of apomorphine oxidation. The formation of protein carbonyls, which is generally less sensitive to antioxidants, could be significantly reduced by apomorphine. In the model system we employed, apomorphine was more active than dopamine, desferrioxamine, or pergolide in preventing the formation of thiobarbituric reactive substances. The time course of the reaction suggests that apomorphine acts as a radical scavenger and that its iron chelating properties may not be of major importance. Since oxidative stress has been implicated in Parkinson's disease, the role of apomorphine as a neuroprotective is worthy of examination.

Animals↗
PubMed1983

Alterations in apomorphine concentration in spinal cord and brain follow the time course of catalepsies induced by different treatments.

Because evidence for the neurotransmitter role of dopamine in the gray matter of the spinal cord is accumulating, a question arises of whether or not spinal dopamine receptors are also involved in the effects of dopaminomimetics which are believed to induce beneficial effects in Parkinson's disease through an action thought to be mediated mainly by striatal dopamine receptors. To test this hypothesis muscimol and picrotoxin were injected unilaterally into the posterior part of the substantia nigra of rabbits permanently implanted with stainless-steel cannulae. Muscimol (a GABA-mimetic) enhanced locomotor activity, evoked a stereotyped behavior and contralateral rotations, and increased apomorphine-induced gnawing. Picrotoxin, a substance which inhibits GABA transmission, induced ipsilateral rotations, evoked catalepsy and muscle rigidity, and inhibited locomotor activity. Picrotoxin abolished apomorphine-induced gnawing, and increased haloperidol-mediated catalepsy. The catalepsy induced by an intranigral injection of picrotoxin, and the picrotoxin-evoked blockade of the apomorphine-induced gnawing disappeared within 16 h after the intranigral injection. Alterations in the apomorphine concentration in brain structures (n. caudatus and cerebral cortex) and in spinal cord after picrotoxin injection followed the same time course as the behavioral changes, and returned to the control values 16 h after injection of picrotoxin. Apomorphine was always injected 30 min before the rabbits were killed. Moreover, the substantial increase (to 300%) in apomorphine concentration in the spinal cord probably reflects the antagonism between behavioral changes induced by picrotoxin and the haloperidol catalepsy, rather than the decreased apomorphine concentrations observed in the brain structures. We suggest, therefore, that there exists a correlation between the behavioral effects, which are generally accepted as laboratory models of Parkinson's disease, and the enhanced apomorphine concentration in the spinal cord.

Animals↗
PubMed1991

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats.

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.

3,4-Dihydroxyphenylacetic Acid↗