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PubMed1993

Vacuous jaw movements in rats induced by acute reserpine administration: interactions with different doses of apomorphine.

Two experiments were conducted to study the vacuous jaw movements induced in rats by acute administration of the monoamine-depleting agent reserpine. In the first experiment, different doses of reserpine (1.25, 2.5, and 5.0 mg/kg) were assessed for their ability to induce vacuous jaw movements. Acute administration of reserpine induced a dose-related increase in vacuous jaw movements, with the two highest doses being significantly different from the vehicle control. In the second experiment, interactions between 5.0 mg/kg reserpine and the dopamine agonist apomorphine were investigated. Coadministration of reserpine with the lowest dose of apomorphine (0.1 mg/kg) significantly increased vacuous jaw movements relative to reserpine alone. The two higher doses of apomorphine (0.5 and 1.0 mg/kg) significantly decreased vacuous jaw movements in reserpine-treated rats. These results demonstrate that vacuous jaw movements are induced by acute reserpine treatment in a dose-related manner. In addition, the interactions with apomorphine suggest that vacuous jaw movements are stimulated by decreases in dopamine release produced by low doses of apomorphine that are thought to have mainly presynaptic actions, but that these movements are decreased by higher doses of apomorphine that are known to act postsynaptically.

Animals↗
PubMed1993

Receptor-selective opioid peptides fail to affect behavioral responses induced by a low dose of apomorphine in the mouse.

The effects of intracerebroventricular injections of the mu-selective opioid agonist DAMGO ([D-Ala2,NMePhe4,Gly-ol]enkephalin), the kappa-selective opioid agonist dynorphin A-(1-13), and the delta-selective opioid agonist DPLPE ([D-Pen2,L-Pen5]enkephalin) on the decrease in different behavioral responses induced by a low dose of apomorphine (0.03 mg/kg) were investigated in the mouse. A low dose (0.03 mg/kg) of apomorphine produced a marked decrease in behavioral responses such as circling and rearing. Although the dopamine D1 antagonist SCH 23390 (0.01 and 0.03 mg/kg) did not influence behavior induced by apomorphine (0.03 mg/kg), the dopamine D2 antagonist sulpiride (3.0 mg/kg) reversed the decrease in circling and rearing behavior induced by apomorphine, suggesting that the effects of apomorphine on circling and rearing are mediated through dopamine D2 autoreceptors. DAMGO (0.003 or 0.01 microgram), dynorphin A-(1-13) (3.0 or 10.0 micrograms), or DPLPE (0.3 and 1.0 microgram) had no significant effects on the apomorphine-induced decrease in circling and rearing behavior. These in vivo results suggest that opioid peptides selective for receptor types fail to influence drug effects mediated by dopamine D2 autoreceptors.

Analgesics↗
PubMed1996

Pharmacological characterization of the enhancement of apomorphine-induced gnawing in mice by cocaine.

The present study was designed to provide additional information on the behavioral and pharmacological mechanisms associated with the augmentation of apomorphine-induced gnawing in C57BL/6J mice. (-)-Cocaine enhanced apomorphine-induced gnawing at doses devoid of effects on gnawing when given alone. The effect was stereoselective, with (+)-cocaine devoid of activity in this test. Peripheral synapses may also not be critical to the cocaine enhancement, as cocaine methiodide, a charged species, was also without effect. The local anesthetic actions of cocaine were evaluated with lidocaine, a local anesthetic without prominent dopaminergic actions. Like (-)-cocaine, lidocaine augmented the gnawing response to apomorphine without increasing climbing or gnawing when given alone. (+)-Amphetamine enhanced apomorphine-induced gnawing but only at a high dose that increased gnawing by itself. The selective dopamine uptake blocker. GBR 12909, augmented apomorphine-induced gnawing without increasing gnawing when given alone; however, unlike cocaine or lidocaine, GBR 12909 increased climbing at doses that augmented the gnawing response. These data indicate that the cocaine-augmented gnawing response to apomorphine does not appear to be the result of psychomotor stimulation per se. Rather, this effect may be due to blockade of dopamine uptake and/or the local anesthetic actions of cocaine.

Anesthetics, Local↗
PubMed1984

Timing of yawns induced by a small dose of apomorphine and its alteration by naloxone.

The report examines the temporal sequence of yawns induced by apomorphine and whether the opiate antagonist, naloxone, affects it. Before administering apomorphine (0.075 mg/kg) or saline, rats (n = 8) were pretreated with naloxone (1 mg/kg) or saline. Each subject received all 4 possible treatments (saline-saline, saline-apomorphine, naloxone-saline, and naloxone-apomorphine) in random order. Results indicate that yawning induced by apomorphine seems to come in fits; that is, there is a series of yawns spaced closely together and followed by a period of quiescence before the start of another cluster of yawns. Naloxone reduced the number of apomorphine-induced yawns, and the occurrence of very short inter-yawn intervals. It is suggested that the timing of yawns may provide useful information regarding some pathologies and that opiates may potentiate the action of dopaminergic systems.

Animals↗
PubMed1985

Lateralizing effects of apomorphine on taxis, postural support and rotation in rats.

Subcutaneous injections of apomorphine, a dopamine receptor agonist, induced a lateralization of taxis for edges in 16% of rats and a reliable lateralization of postural support in 82% of rats. The relation among these effects and the lateralizing effects of apomorphine on rotational behavior were examined. Lateralized rotation did not reliably correlate with lateralized taxis. However, it correlated with a relatively large asymmetry of postural support. The lateralizing effects of apomorphine on taxis and rotation may reflect attentional and directional asymmetries, respectively. It is proposed that apomorphine can induce different types of lateralizations, including attentional, postural and directional, and that the lateralizing effects of apomorphine on posture and locomotor direction are interrelated. Regional brain interhemispheric asymmetries in the responsiviness of dopamine receptors may underlie different types of apomorphine-induced lateralizations.

Animals↗
PubMed1985

Effects of apomorphine on blood levels of homovanillic acid, growth hormone and prolactin in medicated schizophrenics and healthy control subjects.

Two doses of apomorphine (0.005 mg/kg as a subcutaneous injection and 0.015 mg/kg as a 90 min i.v. infusion), and corresponding placebo treatments, were administered to 11 chronic medicated schizophrenic patients and to 8 healthy control subjects. The purpose of the study was to asses the usefulness of drug-induced alterations in the concentration of homovanillic acid (HVA) in plasma as indicators of dopamine autoreceptor sensitivity in the central nervous system. Growth hormone and prolactin in serum were also measured and used as indicators of postsynaptic dopaminergic drug effects. In the control subjects, i.v. apomorphine increased growth hormone in serum from 1.8 +/- 0.2 to 28.3 +/- 4.6 ng/ml and reduced prolactin by 57 +/- 7%. In the patients, apomorphine caused only weak neuroendocrine effects. HVA in plasma was not affected by apomorphine in either group of subjects. The results for growth hormone and prolactin indicate that postsynaptic dopamine receptors in the tubero-infundibular system are antagonized to a considerable degree also during chronic treatment with neuroleptics. The lack of effect of apomorphine on HVA levels suggests that HVA in plasma is not a sensitive indicator of the inhibition of dopamine release caused by small doses of apomorphine and mediated through dopamine auto-receptors. Supersensitivity of this class of receptors could not be demonstrated in our patients, which contrasts with some earlier results.

Adult↗
PubMed1990

Apomorphine-like effect evoked by exposure to environmental cues associated with drug administration.

1. Over 12 days, two groups of mice were given one daily injection of apomorphine 2 mg/kg in a distinctive environment. One group received the drug in the experimental room where the apomorphine-induced climbing was evaluated. The second group was given apomorphine in the colony room. 2. On the placebo test day, all mice were injected with saline in the experimental room and climbing behaviour was scored. 3. Results showed that mice previously receiving apomorphine in the experimental room displayed under placebo an enhancement in climbing qualitatively similar to that observed following apomorphine administration. 4. This placebo effect is attributed to classical conditioning of apomorphine-induced climbing (unconditioned effect) to the environmental cues present at the time of drug exposure (conditioned stimulus).

Animals↗
PubMed1992

Effects of disulfiram, phenoxybenzamine and propranolol on the behaviors evoked by apomorphine and amphetamine in adult cats.

The aim of this work was to study the role that the noradrenergic system could play in the mechanism of production of the behaviors evoked by parenteral injection of apomorphine and amphetamine in adult cats. Ten cats were injected s.c. with 2 mg/kg of apomorphine and 2.5 mg/kg of amphetamine in separate sessions. The behaviors were recorded, until control conditions were again attained. In a second stage, disulfiram was administered ip., followed by apomorphine and amphetamine in the same doses as cited above. The effects on behaviors produced by disulfiram and those of apomorphine and amphetamine were recorded by three independent observers. Comparisons of the pre- and post-disulfiram behavioral results were analyzed with the help of the non-parametric Wilcoxon signed rank test. In another group of ten cats a similar procedure was carried on employing the alpha and beta noradrenergic blocking agents, phenoxybenzamine and propranolol. The noradrenergic blocking drugs, especially disulfiram and phenoxybenzamine produced by themselves a decrease in motility, in alertness and an increase in indifference and inappetence. Apomorphine and amphetamine administered after the blocking drugs showed slight behavioural modifications, reflection most of them the changes produced by the three blocking drugs. It is concluded that probably the nor-adrenergic system could be involved in the hypomotility elicited by amphetamine. NA is not involved in the induction of the other behaviors evoked by apomorphine and amphetamine.

Amphetamine↗
PubMed1993

Effects of SCH 23390 and sulpiride on the behaviors evoked by amphetamine and apomorphine in adult cats.

1. The aim of the present study was to analyze whether the dopaminergic D1 and D2 receptors are involved in the production of the behaviors evoked by parenteral administration of amphetamine and apomorphine in adult cats. 2. Fifteen mongrel cats of both sexes were injected, in separate sessions, with 2.5 mg/kg of amphetamine and 2.0 mg/kg of apomorphine. The D1 receptor blocker, SCH 23390 was administered (0.3 mg/kg i.p.) and after 60 min, amphetamine and apomorphine were again injected on different days. The same procedure was carried on with sulpiride in two doses (20 and 30 mg/kg i.p.). The behaviors induced by the two dopaminergic drugs, before and after the receptor blocker administration were respectively compared. The Wilcoxon signed rank test was employed for statistical analysis. Three independent observers recorded the behaviors. 3. SCH 23390 and sulpiride produced per se hypomotility and sedation, effects that were considered when analysing the results. Some of the behaviors produced by amphetamine (pupillary dilation, head movements) were slightly modified by both receptor blockers. SCH 23390 only modified the licking behavior produced by apomorphine. In contrast, sulpiride blocked almost all the behaviors elicited by apomorphine, especially when the 30 mg/kg dose was administered. It is concluded that the behaviors produced by the 2 mg/kg dose of apomorphine are evoked by its binding to the post-synaptic dopaminergic D2 receptors and blocked by sulpiride.

Amphetamine↗
PubMed1988

Diltiazem suppresses apomorphine-induced fighting and pro-aggressive effect of withdrawal from chronic ethanol or haloperidol in rats.

Dopaminergic receptor stimulation with apomorphine (5 mg/kg, i.p.) induced irritable aggression consisting of defensive upright postures, vocalization and biting attacks in pairs of responsive rats. Aggression was considerably decreased when the animals were pretreated with diltiazem, a Ca2+ channel inhibitor (5 or 10 mg/kg, i.p.). Originally non-responsive rats exhibited apomorphine-induced fighting upon withdrawal from prolonged ethanol (21 days, 3 g/kg, twice daily, intragastrically, i.g.) or haloperidol (14 days, 0.5 mg/kg, twice daily i.g.). If the animals were co-administered diltiazem i.g. 30 min prior to each dose of ethanol or haloperidol the aggressive response to apomorphine was significantly decreased; reduction in attack score being the most prominent. Chronic (14 or 21 days) diltiazem by itself did not facilitate the appearance of apomorphine-induced fighting in non-responsive rats. These results suggest that diltiazem can inhibit apomorphine-induced fighting and prevent the development of ethanol and haloperidol-induced behavioural supersensitivity to apomorphine.

Aggression↗
PubMed1983

The effect of melanotropin release inhibiting factor, its metabolites and analogs on [3H]spiroperidol and [3H]apomorphine binding sites.

The effects of melanotrophin release inhibiting factor (Pro-Leu-Gly-NH2, MIF), its possible metabolites, Pro-Leu-OH, Leu-Gly-NH2, Leu-Gly-OH and an analogue, cyclo(Leu-Gly), on [3H]spiroperidol binding sites in the striatum and on [3H]apomorphine binding sites in the striatum and hypothalamus of male Sprague-Dawley rats were determined. [3H]Spiroperidol binding to dopamine receptors in striatal membranes was unaffected by any of the above peptides in concentration up to 0.1 mM. The binding of [3H]apomorphine was enhanced by MIF, Pro-Leu-OH and cyclo(Leu-Gly) in both striatal and hypothalamic membranes in submicromolar concentrations. Leu-Gly-NH2 and Leu-Gly-OH did not affect [3H]apomorphine binding to dopamine receptors in striatum of hypothalamus. The enhancement in binding of [3H]apomorphine by MIF and cyclo(Leu-Gly) was not related to the changes in the number of binding sites but to an increase in the affinity to the receptors. The results indicate that MIF and some of its related peptides do not affect dopamine receptor binding sites labeled by the neuroleptic [3H]spiroperidol but facilitate the transmission in those sites labeled by [3H]apomorphine. Since [3H]apomorphine and [3H]spiroperidol predominantly label pre- and post-synaptic dopamine receptors, it is concluded that MIF and its active analogs interact with presynaptic dopamine receptors.

Animals↗
PubMed1988

Correlation between the discharge rate of non-dopamine neurons in substantia nigra and ventral tegmental area and the motor activity induced by apomorphine.

The effects of systemic apomorphine on the discharge rates of non-dopamine neurons of the ventral tegmental area and the substantia nigra were investigated in the behaving rat to determine the relationship between the neural responses and the motor activity induced by the dopamine agonist. Apomorphine, 3.0 mg/kg, induced large increases in motor activity and in the rate of firing of non-dopamine neurons in both ventral tegmental area and substantia nigra. The effects were similar in both structures, but only a portion of the non-dopamine neurons sampled were sensitive to the dopamine agonist. The motor and unit responses were correlated for latencies, magnitude and duration. These effects were dose-responsive, 0.75 mg/kg and 1.5 mg/kg inducing smaller behavioral and neural responses than 3.0 mg/kg. Apomorphine, 3.0 mg/kg, given to rats pretreated with haloperidol, 1.5 mg/kg, 60 min before the recording session, induced smaller behavioral and neural responses than in controls. The dopamine agonist given to rats in which gross motor activity was prevented through light anesthesia with urethan, 600 mg/kg, led to a decrease in the magnitude of the unit response in ventral tegmental area, and to a potentiation of the response in substantia nigra. In rats with bilateral electrolytic lesions of nucleus accumbens given one week earlier, apomorphine induced a smaller behavioral response than in controls, and differential effects on the neural responses. In ventral tegmental area the response was the same as in controls, but in substantia nigra it was blocked. These results indicate the presence in substantia nigra and ventral tegmental area of subpopulations of non-dopamine neurons responding with excitation to experimental manipulations that activate dopamine receptors. The dissociation between the motor effects of apomorphine and the neural effects in the subjects prevented from expressing gross motor activity, and in the lesioned animals, indicates that the neural responses were not the result of behavioral feedback. And the differential effects of apomorphine in ventral tegmental area and substantia nigra in these two groups of subjects suggest that the dopamine motor influence, at this brain level, may be fractionated, different groups of non-dopamine neurons conveying different aspects of the dopamine influence on motor activity to premotor neurons. The results, taken together, support the notion that non-dopamine efferent neurons in ventral tegmental area and substantia nigra function as dopamine output neurons, their output being critical for the behavioral effects of dopamine agonists.

Action Potentials↗
PubMed1993

Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines.

The scavenging and iron-reducing properties of a series of benzylisoquinolines of natural and synthetic origin have been studied. Bulbocapnine, boldine, glaucine, and stepholidine acted as scavengers of hydroxyl radical in the deoxyribose degradation by Fe(3+)-EDTA + H2O2. On the contrary, laudanosoline, apomorphine, protopapaverine, anonaine, and tetrahydroberberine increased deoxyribose degradation by a mechanism related to generation of superoxide anion. Only apomorphine had a stimulating effect in the system using citrate instead of ethylenediaminetetraacetic acid (EDTA) as well as in the absence of chelator. Apomorphine also stimulated DNA damage by Cu2+. The iron-ion reducing ability of apomorphine and laudanosoline was confirmed using cytochrome c. Both compounds scavenged peroxyl radicals in an aqueous medium, while in Fe(3+)-induced microsomal lipid peroxidation apomorphine acted as an inhibitor and laudanosoline stimulated the process. It is suggested that in microsomes the chain-breaking antioxidant properties of apomorphine overcome its possible influence on redox cycling of iron, or prooxidant properties.

Animals↗
PubMed1995

The behavioral effects of habituation and challenge with apomorphine after 6-OHDA lesioning of the nucleus accumbens in rats.

In rats the function of the dopamine system in the nucleus accumbens was tested after 6-OHDA lesioning of this brain area and after ORG 2766 induced facilitation of recovery in 6-OHDA lesioned animals. A low dose of systemically administered apomorphine (50 micrograms/kg) decreased motility when sham operated rats were placed in a novel environment. A similar decrease was found in saline treated rats tested for the second time 1 day later. In thus habituated animals, the low dose of apomorphine did not induce hypomotility. Thus habituation and hypomotility after a low dose of apomorphine may be due to a similar mechanism, viz. diminished dopamine release. A higher dose of apomorphine (125 micrograms/kg) increased motility, but only when the rats were habituated to the test environment. Animals with a bilateral 6-OHDA lesion of the nucleus accumbens showed hypomotility when tested for the first time 1 week after the lesion. The low and the higher dose of apomorphine elicited hypermotility in both nonhabituated and habituated lesioned rats. Their activity was higher than in sham operated animals, suggesting supersensitivity of postsynaptically located dopamine receptor systems in lesioned rats. Treatment with the ACTH(4-9) analog ORG 2766 during the first week after induction of the lesion counteracted the hypomotility of the lesioned rats. Furthermore ORG 2766 enhanced the supersensitivity as revealed by challenge with the low dose of apomorphine.

Adrenocorticotropic Hormone↗
PubMed2004

Genetic background, nature of event, and time of exposure to event direct the phenotypic expression of a particular genotype. A study with apomorphine-(un)susceptible Wistar rats.

The aim of this study was to investigate the differential long-term after-effects on the apomorphine-susceptibility in the apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) rats of either a saline injection (a mild stressor) or a clonidine-injection (a moderate stressor) applied around the onset of the stress-hypo-responsive-period (SHRP) on postnatal day (PND) 2, 4, 6 or 9. The present study shows that an injection of saline on PND 2 decreases the apomorphine-induced gnawing score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; clonidine given on this day has no effect. An injection of saline on PND 4 decreases the apomorphine score in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. An injection of clonidine on PND 4 counteracts the long-term after-effects of a saline injection on this PND in adult APO-SUS rats, but has no effect in adult APO-UNSUS rats. Finally, an injection of clonidine on PND 9 has no effect on the apomorphine score in adult APO-SUS rats, but increases this score in adult APO-UNSUS rats; saline given on this day has no effect. It is concluded that the long-term after-effects of early postnatal stressors depend on the interrelationship between, rather than the separate impact of, the genetic background of the rat, the nature of the event, and time of exposure to the event, thereby implying that these factors direct the phenotypic expression of a particular genotype at adult age.

Adrenergic alpha-Agonists↗
PubMed2006

Influence of morphine- or apomorphine-induced sensitization on histamine state-dependent learning in the step-down passive avoidance test.

Effects of morphine- or apomorphine-induced sensitization on histamine state-dependent memory of passive avoidance task were examined in mice. Pre-training intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) decreased the learning of a one-trial passive avoidance task. Pre-test administration of histamine (10 and 20 microg/mouse) reversed amnesia induced by pre-training of histamine, with maximum response at 20 microg/mouse. Pre-training histamine-induced amnesia was also reversed in morphine- or apomorphine-sensitized mice that had previously received once daily injections of morphine (20 and 30 mg/kg) or apomorphine (0.5 and 1 mg/kg) for 3 days. The reversion of histamine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5 and 1 mg/kg), SCH 23390 (0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) prior to injection of morphine (30 mg/kg/day, 3 days). Furthermore, once daily administration of sulpiride (50 and 100 mg/kg) but not SCH 23390 (0.01, 0.05 and 0.1 mg/kg) prior to apomorphine (1 mg/kg, for 3 days) decreased the reversion of pre-training histamine-induced amnesia by apomorphine. The results suggest that apomorphine or morphine sensitization affects the impairment of memory induced by histamine and thus it is postulated that opioid and dopamine receptors may play an important role in this effect.

Animals↗
PubMed2006

Biphasic effect of apomorphine on rat nociception and effect of dopamine D2 receptor antagonists.

Studies on the effect of dopaminergic agonists in behavioral measures of nociception have gathered numerous but rather conflicting data. We studied the effects of the D(1)/D(2) receptor agonist apomorphine, as well as the modulatory effects of (S)-(-)-sulpiride (selective D(2) receptor antagonist) and domperidone (peripheral D(2) receptor antagonist), on thermal, mechanical and chemical nociception on rats. Apomorphine induced a biphasic dose-response relationship, low doses producing hyperalgesia and high doses inducing antinociception. Tonic (chemical) pain was more sensitive to apomorphine than phasic (thermal and mechanical thresholds) pain. (S)-(-)-sulpiride, but not domperidone, fully antagonized the antinociceptive effect of apomorphine in all three measures of nociception, pointing to a participation of D(2) dopaminergic receptors for the antinociceptive action of apomorphine. Although spinal sites for dopaminergic ligands mechanistically may account for the effects observed, involvement of dopaminergic receptors of the forebrain could probably explain better the antinociceptive effects of apomorphine, especially in chemical tonic pain.

Analgesics↗
PubMed2005

Apomorphine-induced alterations in striatal and substantia nigra pars reticulata glutamate following unilateral loss of striatal dopamine.

We have reported time-dependent changes in extracellular glutamate within the striatum at 1 and 3 months following a unilateral lesion of the nigrostriatal pathway using the neurotoxin, 6-hydroxydopamine (6-OHDA) (Meshul, C.K., Emre, N., Nakamura, C.M., Allen, C., Donohue, M.K., Buckman, J.F., 1999. Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion. Neurosci. 88, 1-16.). The aim of the present study was to determine the effects of such a lesion on glutamate within the substantia nigra pars reticulata (SN-PR) and the effect of subchronic administration of the dopamine D-1/D-2 agonist, apomorphine, on extracellular glutamate within both the striatum and the SN-PR using in vivo microdialysis. One month after the lesion, there is an increase in extracellular glutamate within the striatum and apomorphine treatment leads to a further increase. Within the SN-PR, a loss of striatal dopamine leads to a decrease in extracellular glutamate, while apomorphine treatment leads to a further decrease in nigral glutamate. Three months after a 6-OHDA lesion, there is a decrease in extracellular striatal glutamate, with apomorphine administration leading to essentially no further change in glutamate. The loss of striatal dopamine increased extracellular glutamate within the SN-PR while apomorphine administration resulted in a decrease in extracellular glutamate back to the value observed in the control group. The data suggests that the increase in striatal glutamate 1 month following a 6-OHDA lesion alone or following subchronic apomorphine is consistent with the hypothesis that a decrease in glutamate within the SN-PR leads to activation of the thalamo-cortico-striatal pathway. The decrease in striatal glutamate 3 months after a nigrostriatal lesion is also consistent with the observed increase in extracellular glutamate within the SN-PR, thus leading to a decrease in output of the thalamo-cortico-striatal pathway.

Animals↗