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PubMed2000

The role of genetic and early environmental factors in determining apomorphine susceptibility.

RATIONALE: There is ample evidence that rats show large individual differences in their response to dopaminergic drugs, such as apomorphine. OBJECTIVE: The aim of the present study was to investigate the role of genetic and (early) environmental factors in determining the adult susceptibility to apomorphine. Four experiments were performed: In experiment 1, the original selective breeding of rats for apomorphine susceptibility (leading to APO-SUS and APO-UNSUS rats) was extended and replicated in an independent group of Wistar rats. In experiment 2, APO-SUS males were cross-bred with APO-UNSUS females and vice versa. In experiment 3 APO-SUS litters were cross-fostered to APO-UNSUS mothers or infostered to unknown APO-SUS mothers and vice versa. In experiment 4 APO-SUS and APO-UNSUS rats were maternally deprived on postnatal day 9, for a single 24-h period. METHODS: Adult rats were subcutaneously injected with 1.5 mg/kg apomorphine and their gnawing response was automatically recorded in a gnawing box for 45 min. RESULTS: In experiment 1, the original breeding was extended up to generation 24, leading to a strong and consistent difference in gnawing scores. The replication experiment also succeeded in differentiating APO-SUS and APO-UNSUS. The cross breeding experiments showed that the APO-SUS/UNSUS offspring showed gnawing scores in between the original selection lines. Cross-fostering APO-SUS with APO-UNSUS significantly reduced the gnawing response in the offspring, whereas it did not affect the gnawing score in the APO-UNSUS animals. Maternal deprivation had the opposite effect: increase in gnawing response in APO-UNSUS, with no effect in APO-SUS. CONCLUSION: The results show a clear-cut contribution of both genetic and early environmental factors to the susceptibility of apomorphine.

Animals↗

PubMed1997

Discriminative stimulus effects of apomorphine and 7-OH-DPAT: a potential role for dopamine D3 receptors.

Previous studies have reported that the non-selective dopamine agonist, apomorphine, can serve effectively as a discriminative stimulus in experimental animals, and evidence has been presented that this effect is mediated by dopamine D2 receptors. More recently, it has been found that another dopamine agonist, 7-OH-DPAT, which has some selectivity for D3 receptors, also produces a discriminative cue in rats. The present study set out to make a direct comparison of the discriminative stimulus effects of these two compounds. Rats were trained to discriminate either apomorphine (0.05 mg/kg, SC) or 7-OH-DPAT (0.1 mg/kg, IP) from saline. Both discriminations were acquired but extended training was necessary. Cross generalisation occurred between the two compounds and both cues generalised to the dopamine agonists, quinpirole, quinelorane, PD 128207, and bromocriptine. When the potencies of these compounds to produce the apomorphine or 7-OH-DPAT cues were correlated with their potencies to produce D2 or D3 functional responses in vitro (mitogenesis in transfected cells-results taken from the literature) stronger correlations with D3 than with D2 responses were observed. Both the cueing and the response rate-decreasing effects of apomorphine and 7-OH-DPAT were antagonised by the autoreceptor selective dopamine antagonist amisulpride, and sulpiride also antagonised the cues but without affecting response rates. In contrast, haloperidol blocked the cues but potentiated the response rate decreases. These results suggest that, at the doses used, apomorphine and 7-OH-DPAT produce similar discriminative stimuli, which may be mediated by presynaptically located dopamine D3 receptors.

Animals↗

PubMed1997

Dopaminergic modulation of visual responses in toads. II. Influences of apomorphine on retinal ganglion cells and tectal cells.

The behavioral studies of Part I have shown in common toads that after systemic administration of the dopamine agonist apomorphine the prey-directed orienting turning movements are suppressed while prey snapping is facilitated. Part II focuses on retinal and tectal single cell responses to moving objects. (1) After systemic administration of apomorphine, the discharge rates of retinal class R2 and R3 ganglion cell fibres--recorded from the retino-tectal projection--speeded up in response to visual objects traversing their excitatory receptive fields. This enhancing effect was independent of the recording site in the retino-tectal map. (2) The diameters of the excitatory receptive fields of R2 and R3 neurons doubled their sizes. Probably, apomorphine enhances the center-dominated excitatory responses at the expense of the strength of the inhibitory surround. (3) The apomorphine-induced effects were fully developed 20-35 min after drug administration. (4) At the same time the discharge rates of T5.1 and T5.2 tectal neurons were reduced under apomorphine. The effect was independent of the recording site in the retino-tectal map. The diameters of the excitatory receptive fields of these tectal neurons were not influenced. (5) To changes in configurational stimulus features, the basic pattern of discrimination was maintained. (6) It is suggested that tectal output to the turn-generating motor network--mediated by T5.1 and T5.2 neurons--is modulated by a pretecto-tectal pathway which involves dopaminergic pretectal cells. (7) The enhanced snapping can be interpreted in terms of a modulation of reticular/hypoglossal structures by dopaminergic preoptic/hypothalamic/solitary systems.

Animals↗

PubMed2005

The substituted (S)-3-phenylpiperidine (-)-OSU6162 reduces apomorphine- and amphetamine-induced behaviour in Cebus apella monkeys.

Low affinity dopamine (DA) D2 antagonists such as the substituted (S)-3-phenylpiperidine (-)-OSU6162 have been proposed to be putative antipsychotic agents not endowed with extrapyramidal side effects (EPS). In the present study we investigated the effects of (-)-OSU6162 on (-)-apomorphine and d-amphetamine-induced behaviours in EPS sensitised Cebus apella monkeys. (-)-OSU6162 was administered subcutaneously in doses of 1, 3, 6 and 9 mg/kg alone and in combination with (-)-apomorphine (0.25 mg/kg) or d-amphetamine (0.5 mg/kg). (-)-OSU6162 inhibited (-)-apomorphine-(1-9 mg/kg) as well as d-amphetamine (3-9 mg/kg)-induced arousal and stereotypy. EPS did not occur when (-)-OSU6162 was administered in combination with (-)-apomorphine or d-amphetamine. However, when (-)-OSU6162 was administered alone, dystonia was observed at high doses (6 and 9 mg/kg) in two out of six monkeys. The present study shows that (-)-OSU6162 can inhibit (-)-apomorphine-induced behaviours in non-human primates at doses that do not cause EPS. When (-)-OSU6162 was tested against d-amphetamine-induced behaviours a separation between dose levels that inhibit d-amphetamine effects and cause EPS was not observed. The data further substantiate a role for low affinity DA D2 antagonists in the pharmacological treatment of psychosis.

Amphetamine↗

PubMed1993

Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats.

In the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease, controversy exists concerning the use of apomorphine- or D-amphetamine-induced rotations as reliable indicators of nigrostriatal dopamine depletion. Our objective was to evaluate which, if either, drug-induced behavior is more predictive of the extent of nigrostriatal dopamine depletion. Fischer 344 and Sprague-Dawley rats were unilaterally injected with 9 micrograms/4 microliters/4 min 6-hydroxydopamine into the medial forebrain bundle. The animals were behaviorally tested with apomorphine (0.05 mg/kg, s.c.) and D-amphetamine (5.0 mg/kg, s.c.). Following testing, the brains were removed and the right and left striata, substantia nigra and ventral tegmental area were dissected free and quickly frozen at -70 degrees C for analysis of catecholamine content by high performance liquid chromatography coupled with electrochemical detection. Our results indicate that an animal which has greater than a 90% depletion of dopamine in the striatum might not rotate substantially on apomorphine, without a concomitant depletion of > 50% of the DA content in the corresponding substantia nigra. No correlations were seen involving depletions of the ventral tegmental area and the extent of the lesions to the striatum. Submaximally lesioned (75-90% depleted) rats were found to rotate on D-amphetamine but not on apomorphine. In addition, control rats that did not receive lesions were often seen to rotate extensively on D-amphetamine. We therefore conclude that maximal lesions of the striatum and substantia nigra are required to generate rotations demonstrable with low dose apomorphine but not with D-amphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

PubMed1995

Sensitization to apomorphine-induced rotational behavior in 6-OHDA-lesioned rats: effects of NMDA antagonists on drug response.

The development of drug-induced behavioral sensitization is thought to underlie many of the motor complications that accompany chronic L-DOPA treatment of patients with Parkinson's disease. As the development of sensitization to some dopaminergic behaviors has been linked to alterations in NMDA neurotransmission in animal models, we sought to determine whether or not NMDA antagonists can block the development of sensitization to rotational effects of dopamine agonists in rodents with unilateral nigrostriatal lesions. Rats with unilateral 6-hydroxydopamine lesions received either a single dose or eight daily doses of apomorphine, each dose preceded by the NMDA antagonists MK-801 or CPP. Three days after the last apomorphine dose, the circling behavior produced by the D1 agonist SKF 38393 was measured. A single dose of MK-801 (0.1 mg/kg) prevented the subsequent response to SKF 38393 but neither repeated treatment with MK-801 (0.1 or 0.3 mg/kg) nor CPP (0.1 mg/kg) preceding apomorphine prevented the subsequent response to SKF 38393 or attenuated the response in comparison to a control group. Each of the chronic treatment groups exhibited an increase in rotational effects of apomorphine despite MK-801 or CPP pretreatment. These data suggest behavioral sensitization in unilateral nigrostriatally lesioned rats chronically treated with apomorphine is not dependent upon stimulation of NMDA receptors.

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

PubMed1979

Sleep induced by low doses of apomorphine in rats.

The effect of apomorphine on the EEG of freely moving rats was studied. Apomorphine at the dose of 1 mg/kg caused stereotypy and a marked reduction of total sleep. On the contrary, acute subcutaneous administration of apomorphine at the dose of 100 microgram/kg, or less, markedly increased the amount of total sleep (corresponding mostly to synchronized sleep). Moreover, the infusion of apomorphine (80 microgram/kg/h) for 4 h doubled the duration of slow and REM sleep. The hypnotic effect of apomorphine was prevented by neuroleptics, such as pimozide, benzperidol and L-sulpiride, at doses which, per se, did not modify the EEG of the animals. These results suggest the existence in the CNS of DA receptors mediating sleep.

Animals↗

PubMed1978

Imipramine antagonism of apomorphine-induced hypothermia: a non-dopaminergic interaction.

Imipramine antagonized high dose apomorphine-induced hypothermia, and did not modify small dose apomorphine-induced hypothermia. It is suggested that apomorphine-induced hypothermia is the result of two effects. The first, induced by small doses of apomorphine, and antagonized by pimozide and sulpiride, is probably related to dopaminergic receptor stimulation. The second, induced by high doses of apomorphine, and antagonized by imipramine, is probably not related to dopaminergic receptor stimulation.

Animals↗

PubMed1981

Detailed analysis of the effects of apomorphine and d-amphetamine on spontaneous locomotor behaviour of rats as measured in a TV-based, automated open-field system.

Rat open field behaviour was measured in a TV-based, automated system. Habituation was evident in saline-treated rats. Most variables measured declined over a 10 min period. Apomorphine affected rat open-field behaviour bimodally, i.e. low doses of apomorphine (0.02-0.08 mg/kg, s.c.) decreased most aspects of rat open-field behaviour, whereas at higher doses (0.2 and 0.5 mg/kg, s.c.) various aspects of open-field behaviour were stimulated. Rearing and average speed, however, were monotonically depressed. Amphetamine (1 and 2 mg/kg) stimulated most aspects of rats open-field behaviour, including rearing. Speed was not affected by amphetamine. Habituation was more pronounced after low doses of apomorphine than after saline treatment and was absent after high doses of apomorphine and after amphetamine. The results represent a detailed analysis of apomorphine and amphetamine effects on rat open-field behaviour and show that the distinct components of this behaviour are affected differentially.

Animals↗

PubMed1983

Systemic apomorphine reverses intrastriatal dopamine-induced contralateral deviation.

Contralateral deviation induced by unilateral injection of 25 micrograms or 100 micrograms dopamine into the dorsal CPU was reversed to ipsilateral deviation by apomorphine administered systemically (1 mg/kg s.c.) before, at the same time, or after the dopamine. Contralateral deviation to a unilateral intrastriatal injection of 6.25 micrograms apomorphine was also reversed to ipsilateral deviation by systemically administered apomorphine. No significant effects on postural deviation were found when a control solution was injected unilaterally into the striatum, followed by systemic apomorphine. Contralateral deviation to the unilateral intrastriatal dopamine injection continued following a further bilateral intrastriatal injection of either dopamine or apomorphine. These results suggest that intrastriatal dopamine indirectly affects sites receptive to dopamine outside the striatum.

Animals↗

PubMed1983

Neuroleptic-like effects of ceruletide and cholecystokinin octapeptide: interactions with apomorphine, methylphenidate and picrotoxin.

Haloperidol in low doses antagonized the apomorphine-induced cage-climbing behaviour of mice, whereas ceruletide (CER) and its analogue, Nle8-CER-(4-10) had very weak anticlimbing efficacy; Nle8-CER and diazepam were inactive. The ptosis caused by CER and cholecystokinin octapeptide (CCK-8) was antagonized by apomorphine in doses 27 times smaller than those effective against the haloperidol-induced ptosis. No such differences occurred when either methylphenidate or picrotoxin replaced apomorphine. Low-dose haloperidol was an antagonist to the antiptotic effect of apomorphine versus both CER and CCK-8. The rearing inhibiting effect of CER and haloperidol, in contrast to that of clonazepam, was very resistant to apomorphine. Methylphenidate was weakly effective against clonazepam and haloperidol but inactive versus CER. Picrotoxin was no antagonist to either rearing inhibiting agent. The results taken together suggest presynaptic sites of the dopaminergic system as important for the production of ptosis by CCK-like peptides.

Animals↗

PubMed1987

Alterations in regional energy metabolism in rat brain produced by small and by large doses of apomorphine: possible relations to autoreceptors.

Dose-dependent changes in behavioural patterns and in local cerebral glucose utilization (LCGU) following subcutaneous application of apomorphine were measured in conscious, unrestrained rats by means of a scoring system and of the autoradiographic [C14]2-deoxyglucose technique, respectively. The behavioural patterns of akinesia, ptosis, yawning and penile erections were scored. Akinesia and ptosis were most prominent after 0.02 and 0.07 mg/kg apomorphine but not after 0.18 mg/kg. Maximal scores for yawning and penile erections were obtained after 0.07 mg/kg. LCGU was not significantly changed after 0.07 mg/kg except for decreases in the cingulate cortex and hypothalamus. Apomorphine 0.5 mg/kg decreased LCGU in the cingulate, parietal and occipital cortex, anteromedial and lateral thalamus and lateral habenula but increased it in laminae IV and VI of the sensorimotor cortex, in the parafascicular nucleus of the thalamus, and in some parts of the basal ganglia and related nuclei. Similar changes in LCGU occurred after 2.0 mg/kg apomorphine, which also increased LCGU in the ventral tegmental area. The lower dose did not produce changes in LCGU opposite to those occurring after larger doses. The data obtained with LCGU do not support the idea that behavioural effects after low doses of apomorphine are elicited by activation of dopamine autoreceptors.

Animals↗

PubMed1991

Cholecystokinin octapeptide and caerulein injection into the dorsomedial nucleus accumbens potentiate apomorphine-induced jaw movements in rats.

The effects of bilateral intra-accumbal and intrastriatal injections of CCK-8 sulphate and its analogue, caerulein, on apomorphine-induced jaw movements were studied in ketamine-anaesthetized rats after C1 spinal transection. Jaw movements were detected by a photo-transducer attached to the mandible. CCK-8 (5, 10 and 20 ng) and its analogue, caerulein (1 and 5 ng), injected into the dorsomedial nucleus accumbens increased the frequency of apomorphine (0.2 mg/kg i.v.)-induced jaw movements. The potentiation was prevented by administration of a CCK-A receptor antagonist, lorglumide (5 ng), together with CCK-8 (20 ng) or caerulein (5 ng). Injection of lorglumide alone into the dorsomedial nucleus accumbens did not alter apomorphine (0.5 mg/kg i.v.)-induced jaw movements. Injections of CCK-8 (20 ng) and caerulein (5 ng) into adjacent sites (the ventrolateral nucleus accumbens, dorsal striatum and ventral striatum) did not affect the responses elicited by apomorphine (0.2 mg/kg i.v.). These results demonstrate that CCK-8 modulates responses elicited by a dopamine receptor agonist, apomorphine, in a region of the brain where CCK-8 is known to co-exist with dopamine.

Animals↗

PubMed1995

Apomorphine produced more yawning in Sprague-Dawley rats than in F344 rats: a pharmacological study.

Apomorphine induced yawning in both Sprague-Dawley and F344 rats in the same dose range, but F344 rats emitted only about 1/4 as many yawns as did Sprague-Dawley rats. At higher doses, rats of both strains exhibited stereotypic behavior with a comparable intensity. Pretreatment with either SCH 23390 [R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o l] or pindolol increased apomorphine-induced yawning further in Sprague-Dawley rats, but had little effect on the low yawning score produced by apomorphine in F344 rats. The low yawning response to apomorphine in F344 rats is, therefore, not due to a high baseline dopaminergic or adrenergic activity. Apomorphine-induced yawning in F344 rats was increased after an acute injection of physostigmine, or 24 h after an injection of reserpine. It is postulated that a low baseline cholinergic activity in F344 rats may be responsible, in part, for their lower yawning response to dopaminergic receptor stimulation.

Adrenergic alpha-Antagonists↗

PubMed1982

Low-dose apomorphine reduces serum homovanillic acid concentrations in schizophrenic patients.

This study was carried out to evaluate the postulated dopaminergic auto-receptor regulatory effect in man of low-dose apomorphine. Behavior and serum homovanillic acid concentrations following low-dose apomorphine were investigated. Five medicated chronic schizophrenic patients had serum homovanillic acid concentrations measured by mass fragmentography before and after 0.005 mg/kg of apomorphine or saline placebo. Results demonstrate significant reductions in serum homovanillic acid concentrations in all five subjects following apomorphine as compared with placebo. These findings present direct evidence of a specific dopamine autoreceptor effect of low-dose apomorphine in schizophrenic patients.

Adult↗

PubMed1985

Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain.

The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (DA) receptors in extrapyramidal and limbic preparations of rat brain tissue. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulating adenylate cyclase (D-1 sites) and in competing for high affinity binding of 3H-spiroperidol (D-2 sites) and of 3H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity or higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical and functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

Adenylyl Cyclases↗

PubMed1986

The emetic effect of B-HT 920 and apomorphine in the dog: antagonism by haloperidol.

Recent investigations have suggested that the alpha 2-adrenoreceptor agonist B-HT 920 is also a dopamine (DA) agonist with a selectivity for presynaptic receptors. In the present study, the emetic effect of B-HT 920 was investigated. Intravenous injections of B-HT 920 (0.32-10.0 micrograms/kg) and a DA2-agonist apomorphine (3.2-100.0 micrograms/kg) caused dose-dependent emesis. The ED50 of B-HT 920 and apomorphine were 3.2 and 12.3 micrograms/kg, respectively. When haloperidol (10.0-24.5 micrograms/kg i.v.), a DA2-antagonist, was given 5 minutes before B-HT 920 (10 micrograms/kg) or apomorphine (32 micrograms/kg), it caused a dose-dependent prevention of B-HT 920- and apomorphine-induced emesis. The ED50 of haloperidol in preventing the emetic effect of both drugs was identical (13.5 micrograms/kg). In contrast, haloperidol (32 micrograms/kg i.v.) did not prevent the emetic effect of ouabain (40 micrograms/kg i.v.). Neither did yohimbine (0.1 mg/kg i.v.), an alpha 2-adrenoreceptor antagonist, prevent the emetic effect of B-HT 920 (10 micrograms/kg). These results suggest that B-HT 920, acting like apomorphine, induces emesis by activating DA2-receptors probably in the chemoreceptor trigger zone of the area postrema.

Adrenergic alpha-Agonists↗

PubMed1982

Antagonism of the apomorphine-induced yawning by "atypical" neuroleptics.

In relatively small doses, the four "atypical" neuroleptics, sulpiride, clozapine, thoiridazine and mezilamine were effective antagonists of apomorphine-induced yawning in rats. Of the four drugs, used in doses which inhibited apomorphine-induced yawning almost completely, only clozapine also antagonized yawning induced by physostigmine. Therefore it appears that the antagonism of this effect of apomorphine, already reported for classical neuroleptic agents, is also shown by "atypical" ones. By combining apomorphine- and physostigmine-induced yawning, it is possible to assess the anticholinergic component in the antagonism of this effect of apomorphine and this may be of value for the understanding of the mechanisms underlying the "atypical" character.

Animals↗