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PubMed1980

Apomorphine: selective inhibition of the aversive component of lateral hypothalamic self-stimulation.

The effects of dopamine agonists on self-stimulation are a matter of considerable dispute. Apomorphine has variously been reported to inhibit, have no effect on, or to facilitate lever-press self-stimulation. To investigate the possibility that these discrepancies may reflect peculiarities of the lever-press test situation, the present study investigated the effects of apomorphine on locomotor initiation of and escape from lateral hypothalamic stimulation in a shuttle-box. Apomorphine had relatively little effect on the initiation behavior, but it produced a large and dose-dependent inhibition of escape. These data suggest that apomorphine acts to inhibit the aversive component of lateral hypothalamic stimulation. The implications of these findings for the usefulness of the shuttle-box in investigating the pharmacology of self-stimulation are discussed.

Animals↗
PubMed1981

Phencyclidine-induced stereotype in rats: effects of methadone, apomorphine, and naloxone.

Phencyclidine (PCP) given to male Wistar rats produced hyperactivity and various stereotypic motor behaviors. Methadone, apomorphine, and naloxone were tested for their effects on PCP-induced stereotypy. Methadone (0.5 mg/kg) had no effect on the hyperactivity produced by PCP, but significantly attenuated PCP-induced stereotypy when given both before and after PCP. Low doses of apomorphine were equally effective as methadone in attenuating PCP-induced stereotypy. However, when naloxone was given after methadone or apomorphine to PCP-treated rats, the full PCP-induced stereotypy was again observed. Naloxone pretreatment on doses up to 20 mg/kg was not effective in antagonizing PCP-induced behavioral effects. Methadone and apomorphine antagonism of PCP-induced stereotypy may be mediated by opiate receptors. The results of this study and observations from human studies collectively suggest the possible effectiveness of opiates in treating PCP-induced and functional psychoses.

Animals↗
PubMed1978

Subsensitivity of striatal and mesolimbic dopamine target cells after repeated treatment with apomorphine dipivaloyl ester.

The effects of acute and repeated treatments with the dipivaloyl ester of apomorphine on behaviour and brain dopamine metabolism were compared in rats. A single injection of the ester (50 mg/kg i.p.) indued a stereotyped behaviour lasting for at least 6 h and a concomitant decrease in striatal HVA levels. After repeated treatment (twice daily for 7 days) with the drug, both the stereotyped behaviour and the decreases in striatal HVA levels were attenuated as compared to acute treatment; the minimal dose tested which induced this tolerance was found to be 25 mg/kg i.p. The minimal length of treatment with 50 mg/kg of the ester after which tolerance was observed was 3-4 days. The ED50 for haloperidol-induced catalepsy was about 4 times lower in rats treated with apomorphine dipivaloyl ester (50 mg/kg) for 7 days than in naive rats. Similarly, a shift to the left of the haloperidol dose-response curve for the increase in striatal dopamine metabolite levels was observed in rats treated subacutely with the ester as compared to control rats. Repeated treatment (7 days) with the dipivaloyl ester of apomorphine also attenuated the decrease in NVA levels seen with acute treatment in nucleus accumbens and tuberculum olfactorium; however, the threshold dose inducing tolerance in limbic regions was higher than in striatum. No difference in the brain concentrations of apomorphine was found after acute and repeated treatments with the ester. Thus, the present study provides evidence for the development of subsensitivity of dopamine receptors after repeated administration of aopomorphine dipivaloyl ester.

Animals↗
PubMed1983

Apomorphine-induced biphasic circling behaviour in 6-hydroxydopamine-lesioned rats. A pharmacological kindling phenomenon.

Factors governing the development of apomorphine-induced biphasic circling behaviour in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra were investigated. It was found that a post-lesion time of at least 2--3 weeks and the repeated exposure to apomorphine were essential for its development. Optimal results were obtained when animals received weekly apomorphine, 0.05 mg/kg sc, in post-lesion weeks 6, 7 and 8. Pretreatment with haloperidol, 1.0 and 2.0 mg/kg ip 1 h beforehand in post-lesion week 9, converted the biphasic response into an enhanced, uniphasic one. The findings suggest that the development of the biphasic response to apomorphine is a multi-factorial process representing a pharmacological kindling phenomenon.

Animals↗
PubMed1985

Inhibitory effects of apomorphine and pergolide on neurogenic vasoconstriction in the hindquarters of the rat.

The effects of locally administered apomorphine and pergolide were studied in the isolated autoperfused hindquarters of the rat, in an attempt to assess the possible role of presynaptic dopamine receptors at that level in the hypotensive effect of these dopamine agonists. Local infusion of apomorphine (1 micrograms . kg-1 . min-1 for 5 min) or pergolide (1 micrograms . kg-1 . min-1 for 5 min) [into the hindquarters] did not alter perfusion pressure per se, but reduced the pressor response to electrical stimulation of the lumbar sympathetic chains for the whole frequency range used during a cumulative frequency-response curve (0.25-16 Hz, 1 ms, supramaximal voltage). Apomorphine and pergolide reduced the pressor response elicited by 4 Hz electrical stimulation (applied until maximum response was reached) to 54.8 +/- 7.1% and 53.9 +/- 1.7% respectively, but they did not modify similar increases of perfusion pressure produced by locally administered noradrenaline. The inhibition by apomorphine and pergolide of the 4 Hz stimulation-evoked pressor response was completely antagonized by local administration of the dopamine antagonist haloperidol (1 microgram . kg-1), but was not influenced by the alpha 2-antagonist rauwolscine (100 micrograms . kg-1). This dose of rauwolscine antagonized the inhibitory effect of the alpha 2-agonist UK-14,304, which was not influenced by haloperidol. Local administration of rauwolscine increased the pressor response to stimulation at 4 Hz by 37.4-46.2%. In contrast, local administration of haloperidol did not influence the 4 Hz stimulation-evoked pressor response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Dissociated effects of apomorphine on various nociceptive responses in mice.

The effects of increasing doses of apomorphine were studied in mice in six nociceptive tests: (1) withdrawal of the tail immersed in hot water, (2) vocalization induced by the electrical stimulation of the tail, (3) tail flick using a radiant beam, (4) withdrawal of a tail-clip, (5) writhing induced by the i.p. injection of phenylbenzoquinone, (6) forepaw licking and jump latencies on a hot plate. Only in the tests (5) and (6), an apparent analgesia was obtained. Differences were observed between tests (5) and (6), as to: (i) the apparent relative effectiveness of (-)sulpiride (more effective in test [5] than in test [6]), (ii) the naloxone-induced modifications of apomorphine effects (whereas naloxone antagonized apomorphine effects in test [6], it did not in test [5]), (iii) the decrease of apomorphine-induced responses by prevention of hypothermia (in test [6] but not in test [5]). These data suggest that APO-induced increased jump latencies are at least partly related with hypothermia and endogenous opioid systems, whereas APO effect on the writhing test depends on the stimulation of dopamine receptors particularly sensitive to sulpiride and is independent from body temperature and opioidergic transmissions.

Analgesics↗
PubMed1990

Changes in pituitary-adrenal activity affect the apomorphine- and cholecystokinin-8-induced changes in striatal dopamine release using microdialysis.

The effects of apomorphine (0.05 mg/kg, i.p.) and cholecystokinin-8 (sulphated; CCK-8) were analyzed on the levels of dopamine and its metabolites using intrastriatal microdialysis in the adrenalectomized rat with or without corticosterone replacement treatment (5 mg/kg, twice daily for 7 days, last dose given 2 h before killing). Adrenalectomy did not affect the basal release of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) or homovanillic acid (HVA). However, the apomorphine-induced decrease in dopamine release was attenuated following adrenalectomy. Furthermore, there was an enhancement of the apomorphine-induced decrease in DOPAC levels without any modulation of the apomorphine-induced effects on HVA levels. In contrast, the CCK-8-induced increase in dopamine levels was potentiated following adrenalectomy. This potentiation was fully counteracted by replacement treatment with corticosterone. These results indicate that corticosterone may be involved in the regulation of dopamine release, perhaps through glucocorticoid receptors in nigral dopamine cells controlling inter alia the synthesis of G-proteins involved in the regulation of dopamine autoreceptors and CCK-8 receptors located on dopamine nerve terminals or of the receptor proteins themselves.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Effect of beta-adrenoceptor agonists on apomorphine-induced turning in rats.

The beta-adrenoceptor agonists clenbuterol, salbutamol and formoterol were found to inhibit apomorphine-induced turning behavior in rats with unilateral nigrostriatal lesions. The inhibitory effect of clenbuterol was antagonized by (-)-propranolol, but unaffected by practolol (which does not cross the blood-brain barrier), indicating a central localization of the beta-adrenoceptors mediating the inhibitory effect. A dopamine-releasing activity of clenbuterol did not seem to be responsible for the effect, because known dopamine-releasing agents (amphetamine, methylphenidate) did not antagonize apomorphine-induced turning behavior. Furthermore alpha-methyl-p-tyrosine pretreatment did not prevent the inhibitory effect of clenbuterol. Since L-5-hydroxytryptophan did not mimic the inhibitory effect of clenbuterol, it was concluded that the inhibition of turning behavior is not mediated by the interaction of clenbuterol with the serotonin system. The finding that clenbuterol depressed locomotor activity in the same dose range as it inhibited apomorphine-induced turning tentatively suggests that clenbuterol inhibits apomorphine-induced turning behavior by its central beta-adrenoceptor mediated sedative action.

Adrenergic beta-Agonists↗
PubMed1986

Differential effects of apomorphine on spinal reflex activity following 6-hydroxydopamine or long-term haloperidol pretreatment.

The thermal cutaneous evoked tail flick response was measured both before and after intrathecal injection of R-apomorphine in spinal rats and in rats with an intact neuraxis pretreated with either long-term haloperidol or intrathecal 6-hydroxydopamine. Intrathecal R-apomorphine produced a dose-dependent increase of tail flick latency in spinal rats but not in intact rats. Long-term haloperidol treatment increased the effect of R-apomorphine in spinal rats while 6-OHDA decreased it. The present findings provide further evidence for the modulatory role of spinal DA receptor populations on spinal reflex activity. Pretreatment with long-term haloperidol or 6-OHDA may alter the conformational status of spinal DA receptors in opposite directions and thereby change the responsiveness of receptors to R-apomorphine.

Animals↗
PubMed1994

Individual differences in behavior following amphetamine, GBR-12909, or apomorphine but not SKF-38393 or quinpirole.

Subjects that respond more to a novel environment show a greater locomotor response to drugs of abuse such as cocaine and amphetamine. The current study was performed to examine differences between high (HR) and low (LR) responding rats to a novel environment following administration of amphetamine, a selective dopamine uptake blocker (GBR-12909), a nonselective dopamine agonist (apomorphine), and selective dopamine D1 and D2/D3 agonists. A behavioral checklist and a rating scale were used to determine the behavioral arousal caused by administration of amphetamine (0, 0.5, 2.0, and 8.0 mg/kg), GBR-12909 (0, 1.25, 5.0, and 20.0 mg/kg), apomorphine (0, 0.1, 0.3, and 1 mg/kg), SKF 39393 (0, 2.5, 10, and 40 mg/kg), or quinpirole (0, 0.05, 0.5, and 5.0 mg/kg). The five drugs produced behavioral activation profiles distinct from each other. Following amphetamine administration, both HR and LR subjects showed dose dependent increases in behavioral arousal. The behaviors primarily affected were sniffing, locomotor activity, rearing, and oral activity. HR rats showed a greater overall behavioral response to amphetamine administration compared with LR rats and there were differences in specific behaviors between the two groups. Following GBR-12909 administration, all subjects showed dose dependent increases in sniffing, locomotor activity, and rearing. Differences between HR and LR were observed in sniffing, locomotor activity, and rearing behaviors. HR and LR both showed dose dependent increases in behavior following apomorphine administration. HR showed greater behavioral activation after apomorphine than LR.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats.

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.

Acoustic Stimulation↗
PubMed1995

Sensitization to apomorphine in pigeons: unaffected by latent inhibition but still due to classical conditioning.

When administered apomorphine, pigeons exhibit protracted bouts of pecking behavior. This response is subject to sensitization, as it initially increases with repeated drug injections. The hypothesis is examined that the sensitization is due to a Pavlovian conditioning of the drug-induced pecking to the environment in which it first takes effect. In a first experiment, we attempted to suppress this conditioning by extensively pre-exposing the birds to the test environment and saline injections (latent inhibition procedure). As the experiment yielded undiminished sensitization, it cast doubt on the conditioning hypothesis. However, while inhibitory pretraining also proved ineffective in a second experiment, a shortening of response latencies specific to the environment in which the animals had first experienced the apomorphine effect supported the conditioning hypothesis. It is suggested that the absence of latent inhibition may be due to the interference of a context-dependent conditioning effect. A third experiment that examined the hypothesis that the reinforcing properties of apomorphine might be attributable to its well known anorectic properties. The results provided some support for this notion. At the same time, they also confirmed that apomorphine-induced pecking conditions reliably to environmental cues. These cues are then by themselves capable of provoking conditioned pecking.

Animals↗
PubMed1996

Behavioural effects in the rat of the putative dopamine D3 receptor agonist 7-OH-DPAT: comparison with quinpirole and apomorphine.

This study assessed the effects of IP injections of (+/-) 7-hydroxy-2(N,N-di-n-propylamino)tetralin (7-OH-DPAT), a dopamine agonist that has been reported to have preferential affinity for the dopamine D3 sub-type of receptor, on four behavioural procedures in the rat: 1) spontaneous locomotion, 2) electrical self-stimulation of the ventral tegmental area (VTA), using the curve-shift procedure 3) operant responding for food under a progressive-ratio (PR) schedule and 4) induction of stereotypies. The effects of (+/-) 7-OH-DPAT were compared to the effects of apomorphine, a non-specific DA agonist, and quinpirole, a selective D2/D3 agonist. All three dopamine agonists decreased locomotor activity at low doses (0.01-0.3 mg/kg), and only apomorphine had clear locomotor stimulant effects at the highest dose tested (3 mg/kg). The three drugs dose-dependently depressed VTA self-stimulation in a similar way, with low doses inducing a fairly parallel rightward shift of the frequency/rate curves and higher doses flattening the curves. In contrast, responding for food under the PR schedule appeared to be differentially affected by the three agonists: 7-OH-DPAT induced a biphasic effect, with a maximal decrease in lever-pressing at 0.1 mg/kg, followed by a return to baseline levels with increasing doses (0.3-3 mg/kg); quinpirole showed a tendency to decrease responding over the whole dose-range tested with a maximal effect of about 50% of baseline between 0.25 and 1 mg/kg, and apomorphine dose-dependently decreased responding, with rats ceasing to respond at 0.3 mg/kg. All three DA agonists induced stereotypies, but there was a difference in the maximal stereotypy score induced by each of the ligands: 7-OH-DPAT produced a lower maximal effect than quinpirole or apomorphine. This indicates that each of the three dopamine agonists preferentially induced different types of stereotypies. Together, these data suggest that the putative dopamine D3 agonist 7-OH-DPAT, at low doses, has depressant effects similar to those induced by low doses of the other two DA agonists. Differences in the behavioural effects of higher doses were, however, mostly observed in two procedures, PR responding and induction of stereotypies.

Animals↗
PubMed1992

Control of turning behavior under apomorphine by sensory input from the face.

It has been shown that peripheral manipulation of sensory input by removal of vibrissae on one side of the rat's face induces turning behavior which is directed towards the contralateral vibrissae-intact side, under the influence of the dopamine receptor agonist apomorphine. In the present experiment, we examined whether rats under apomorphine turn towards the side with more sensory input, or simply away from the manipulated side. Thus, an experimental manipulation was designed to increase sensory input. Sensory stimulation was applied by attaching a clip into the fur on one side of the face. Rats injected with apomorphine in doses of 0.5-5.0 mg/kg (but not with 0.05 mg/kg or vehicle) exhibited turning behavior towards the side of the clip. This sensory stimulation was also found to influence spontaneous behavioral asymmetries. These results show that an imbalance in sensory input is sufficient to produce turning under apomorphine.

Animals↗
PubMed1993

Effects of daily SKF 38393, quinpirole, and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine.

In three experiments, male Wistar rats (250-350 g) were injected (SC) daily with the D1-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D2-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D1-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8-10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D1 receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D2 receptor stimulation also contributes to the effect.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1996

Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effects.

Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine-induced learning and post-training consolidation deficits. Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and apomorphine (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory.

Animals↗
PubMedDate not supplied

Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application.

Apomorphine was administered subcutaneously and intranasally to 7 patients suffering from Parkinsonism with 'on-off' problems. This comparative pharmacokinetic study showed that the two routes of administration are comparable with respect to absorption kinetics. Apomorphine is rapidly absorbed when administered intranasally or subcutaneously with an absorption half life of 8.6 min and 5.8 min, respectively. The high rate of absorption is also reflected by the time for the plasma concentration to peak (tmax) and the lag times. The tmax was 23 min for intranasal route and 18 min for the subcutaneous route while the lag times were 2.8 min and 3.9 min, respectively. The bioavailability of intranasal apomorphine compared to the subcutaneous route amounted to 45%. After intranasal and subcutaneous administrations, the elimination half life of apomorphine amounted to 31 min and 27 min, respectively.

Administration, Intranasal↗
PubMed2001

[Apomorphine therapy versus deep rain stimulation. Clinical and economic aspects in patients with advanced Parkinson disease].

Long-term dopaminergic treatment of Parkinson's disease is complicated by the occurrence of dyskinesia and motor fluctuations and is responsible for increasing the costs of treatment. In these patients, continuous subcutaneous therapy with the dopamine agonist apomorphine or deep-brain stimulation represents a promising strategy. While the costs for the treatment with apomorphine are covered by health insurance, separate reimbursement for deep-brain stimulation does not exist in Germany. The case reports (n = 3) presented here emphasize that deep-brain stimulation is less cost-intensive than subcutaneous treatment with apomorphine in selected patients. Even in the first postoperative year costs for medication and hospital stays were reduced by approximately 60%. Moreover, in all three patients, motor complications improved after deep-brain stimulation in comparison to previous subcutaneous application of apomorphine. Thus, to further ensure deep-brain stimulation in parkinsonian patients it is mandatory to find a mode of reimbursement for the institutions concerned.

Aged↗