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PubMed1991

Pavlovian conditioning between co-administered drugs: elicitation of an apomorphine-induced antiparkinsonian response by scopolamine.

Sprague-Dawley rats with unilateral 6-OHDA substantia nigra lesions were given combined scopolamine (0.5 mg/kg IP) and apomorphine (0.05 mg/kg SC) treatments. In this animal model, scopolamine, when administered separately, induces ipsilateral rotation and apomorphine, contralateral rotation. When these drugs are co-administered at 0.5 mg/kg and 0.05 mg/kg dose levels, respectively, animals rotate in the contralateral direction, creating the opportunity for the stimulus effect of scopolamine to become associated with the response effect of apomorphine. In tests with scopolamine (0.5 mg/kg), animals that previously had scopolamine and apomorphine co-administered rotated contralaterally in the test chamber, thereby behaving as if they had received apomorphine. Thus, scopolamine exhibited a functionally acquired conditioned stimulus (CS) property by eliciting the apomorphine response of contralateral rotation as a conditioned response. This acquired CS property was extinguished with separate scopolamine trials and reacquired following one scopolamine-apomorphine co-administration trial.

Animals↗
PubMed2002

Time courses of pCREB expression after dopaminergic stimulation by apomorphine in mouse brain.

Administration of dopamine agonist, apomorphine (2 mg/kg, s.c.), produces cage climbing behavior in mice that exhibit typical dopaminergic stimulation. The present study investigated the pCREB expression level in several brain regions following apomorphine treatment in order to determine whether the increased the dopaminergic activation produced by apomorphine accompanies the changes in pCREB immunoreactivity. A mouse brain was removed at 0 min, 10 min, 30 min, 1 h, 2 h, 7 h, and 24 h after apomorphine treatment. The brain tissue was fixed by an intracardiac perfusion with ice-cold 4% paraformaldehyde in PBS. Immunohistochemical study was conducted using the ABC-DAB method. The data showed that the immunoreactivity of pCREB increased in the striatum, nucleus-accumbens, piriform cortex and the dentate gyrus of the hippocampus of a mouse brain 30 min after the apomorphine treatment. Increased immunoreactivity began to diminish 2 h after the apomorphine treatment in all the brain regions measured. The time course for the pCREB immunoreactivity was similar to the behavioral response induced by the apomorphine treatment. These results suggest that activation of the dopamine receptor is accompanied by an increase in pCREB expression in the mouse brain.

Animals↗
PubMed1997

Prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning: involvement of nitric oxide.

The possible involvement of nitric oxide in the prevention by morphine of apomorphine- and oxytocin-induced penile erection and yawning was investigated by measuring the concentration of NO2- and NO3- in the dialysate obtained with a vertical microdialysis probe implanted in the paraventricular nucleus of the hypothalamus of male rats. Either apomorphine (80 micrograms/kg s.c.) or oxytocin (30 ng i.c.v.) increased significantly basal NO2- and NO3- concentration in the paraventricular dialysate, penile erection and yawning. Morphine (1.5 and 10 mg/kg i.p.) prevented dose-dependently either apomorphine or oxytocin responses when given 15 min before apomorphine or oxytocin. Prevention by morphine of apomorphine and oxytocin responses was abolished by naloxone (3 mg/kg i.p.) given 15 min before morphine. Morphine prevented apomorphine and oxytocin responses also when given in the lateral ventricles or directly in the paraventricular nucleus. In contrast, the selective agonist of the kappa opioid receptor subtype U-69,593 was found to be ineffective. The present results confirm previous findings showing that morphine acts through mu receptors in the paraventricular nucleus to prevent apomorphine and oxytocin-induced penile erection and yawning and suggest that this morphine effect is mediated by a decreased activity of nitric oxide in the paraventricular nucleus of the hypothalamus.

Analgesics, Opioid↗
PubMed1999

Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus.

The value of the apomorphine test as a predictor of the clinical outcome of deep brain stimulation of the subthalamic nucleus (STN) was evaluated in patients with advanced idiopathic Parkinson's disease (IPD) or multiple system atrophy (MSA). Thirteen IPD patients with severe diurnal fluctuations and one MSA patient not responding to dopaminergic drugs were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) and the timed finger tapping test (FTT), measured preoperatively on and off apomorphine and postoperatively on and off STN stimulation. UPDRS motor items 20-25 were assessed intraoperatively on and off STN stimulation when the clinically effective target was approached. The motor response to immediate intraoperative and long-term STN stimulation was correlated with results of the apomorphine test. The response to immediate intraoperative STN stimulation was accurately predicted by apomorphine challenge in all 13 IPD patients. Clinical outcome following long-term STN stimulation was correlated significantly with preoperative changes due to apomorphine measured with the UPDRS motor scores (r = 0.7125, P < 0.01) and FTT (r = 0.9276, P < 0.001). Moreover, comparison of long-term STN stimulation to preoperative drug treatment displayed a significant reduction in the duration of off-phases and a significant increase in the duration of on-phases. However, in the single patient with MSA no beneficial response was obtained either to apomorphine or to STN stimulation intraoperatively and during the postoperative externalized test period. Our results indicate that the apomorphine test can predict the outcome of immediate and long-term STN stimulation and may help in the selection of candidates for surgery.

Aged↗
PubMed1998

Transient increase of pancreatic enzymes evoked by apomorphine in Parkinson's disease.

In one of our first patients with severely disabling and fluctuating Parkinson's disease (PD) we observed a transient pancreatic enzymes increase 6 months after continuous apomorphine therapy. Since this adverse effect had not been previously reported, we systematically investigated the course of pancreas and liver functions in response to apomorphine: laboratory and neurological assessments were conducted before initiation of apomorphine therapy, during the increment phase up to the optimal motor effective level and at all follow-up visits. We found in five out of 29PD patients a transient increase of pancreatic enzymes during the initial phase of continuous subcutaneous apomorphine application. Peaks of pathological plasma levels were apparent from the first day up to the fifth day after apomorphine initiation, and returned to normal levels within 10 days in all 5 patients. Otherwise, this pancreatic enzymes increase was not accompanied by any raising in plasma levels of corresponding liver enzymes. No pathological signs in the endoscopic-retrograde cholangiopancreatography, the abdominal ultrasonography and the computed tomography of the abdomen were found in any of the affected PD patients. Furthermore, there was no evidence of pancreato-hepatal risk factors in the previous history in any of the PD patients studied. With respect to the course of PD, no differences were obtained upon comparison of affected and non-affected PD patients. Considering the patients' history, clinical course and current knowledge about the effect of apomorphine on pancreato-hepatal function, we conclude that a possible cumulative pathomechanism between transient pancreato-hepatal enzymes and continuous applied apomorpine, especially in the titrating phase, might cause this adverse event in about 20% of PD patients treated with apomorphine continuously.

Adult↗
PubMed1977

Apomorphine-stimulated growth hormone release.

Apomorphine, a dopaminergic receptor stimulant, was tested and compared in subemetic doses (0.76 mg subcutaneously) to levodopa (500 mg orally) as a stimulant of growth hormone release in 10 normal volunteer subjects (five male, five female). The administration of levodopa failed to cause a normal increment in serum growth hormone levels (greater than 5 ng/ml from base line) in four patients, produced a borderline normal response in two patients with a normal response in four patients. Apomorphine stimulation produced a borderline normal response in one patient and a normal response in the remaining nine patients. The peak response to apomorphine administration was 26.94 +/- 6.60 ng/ml and to levodopa 9.76 +/- 2.67 ng/ml (p less than 0.025). There was no statistical difference between men and women in whom apomorphine testing was utilized. Side effects (nausea, vomiting) were seen in three patients tested with levodopa and in four patients tested with apomorphine. Such symptoms began within 20 minutes of apomorphine administration, persisted from 30 to 40 minutes and disappeared abruptly. All patients treated with apomorphine noted transient drowsiness.

Adolescent↗
PubMed1984

Effects of an intrathecal dopamine agonist, apomorphine, on thermal and chemical evoked noxious responses in rats.

The thermal cutaneous evoked tail flick and hot plate nociceptive responses as well as the chemical visceral elicited acetic acid writhing response were determined in rats following lumbar intrathecal administration of the dopamine (DA) agonist apomorphine. Apomorphine failed to influence tail flick latency even at high doses (660 nmol). In contrast, intrathecal apomorphine (33-330 nmol) produced a dose-dependent increase of the hot plate and acetic acid writhing responses, which was antagonized by the prior intrathecal administration of cis-flupenthixol (a DA receptor antagonist). Intrathecal pretreatment with either trans-flupenthixol (the inactive stereoisomer of cis-flupenthixol), methysergide, phentolamine or naloxone did not antagonize the apomorphine-induced increase of hot plate response latency. Intrathecal apomorphine did produce an increase of tail flick latency following pretreatment with methysergide and phentolamine, however. Intraventricular administration of apomorphine (82.5-165 nmol) had no influence on either tail flick or hot plate response latencies. The present data provide evidence for the modulatory role of apomorphine on spinal afferent sensory functions. It is suggested that a spinal DA receptor population has an inhibitory effect on noxious input to the spinal cord.

Afferent Pathways↗
PubMed1984

Electrolytic lesions of the substantia innominata and lateral preoptic area attenuate the 'supersensitive' locomotor response to apomorphine resulting from denervation of the nucleus accumbens.

Apomorphine-stimulated locomotion in the rat is greatly enhanced following destruction of dopamine terminals in the nucleus accumbens (NA) with 6-hydroxydopamine (6-OHDA). While this augmented response is ascribed to the action of the dopamine stimulant apomorphine on supersensitive receptors within the NA, little is known regarding the mechanisms by which increased receptor stimulation within the NA influences lower motor circuitry to produce changes in locomotion. In this study, we examined apomorphine-stimulated locomotion in 6-OHDA-infused rats following electrolytic damage to the terminal region of first-order NA efferent fibers within the substantia innominata and lateral preoptic area. This damage greatly diminished the locomotor response to apomorphine in 6-OHDA-infused animals, but did not diminish locomotion in vehicle-infused animals. Destruction of dopamine terminals within the NA has also been reported to enhance the place-preference response to apomorphine in rats. Damage to the substantia innominata and lateral preoptic area significantly decreased the place-preference for apomorphine-paired environments in 6-OHDA-infused animals, but did not alter place-preference responses in vehicle-infused animals. Our results indicate that the efferent pathway from the NA to the substantia innominata and lateral preoptic area serves as an important output of mesolimbic activity into motor circuitry involved in the expression of apomorphine-stimulated locomotion and place-preference.

Animals↗
PubMed1984

Genetic control of apomorphine-induced climbing behavior in two inbred mouse strains.

Over a wide dose range (1-32 mg/kg), apomorphine-induced climbing behavior was significantly greater in the AKR/J than in the DBA/2J inbred mouse strain. A similar difference was found when apomorphine-induced stereotypy was examined. A cross-fostering study demonstrated that the strain difference in apomorphine-induced climbing behavior did not result from differences in post-natal rearing environment. After apomorphine administration, brain levels of the drug were similar in the two strains indicating that the difference in behavioral response to apomorphine in the two strains was not due to differences in metabolism or distribution of the drug. The climbing response to apomorphine was examined in the F1 cross of the two strains (AKD2F1/J) and in 10 AKXD recombinant inbred strains. Results suggested that the trait was partially dominant and not X-linked; furthermore, a few and possibly one locus was responsible for the differences in apomorphine-induced climbing behavior observed in the AKR/J and DBA/2J mice.

Animals↗
PubMed1989

Dynorphin A(1-13) modulates apomorphine-induced behaviors using multidimensional behavioral analyses in the mouse.

The effects of intracerebroventricular injection of dynorphin A(1-13) on apomorphine-induced behavioral changes were investigated in the mouse using multidimensional behavioral analyses based upon a capacitance system. Although lower doses (0.1 or 0.3 mg/kg) of apomorphine were without marked effects on behaviors, a 0.56 mg/kg dose of the drug evoked a significant increase in rearing behaviors. Furthermore 1.0 and 3.0 mg/kg doses of apomorphine produced a marked increment in linear locomotion, circling and rearing. Dynorphin A(1-13) (3.0 or 10.0 microgram) itself had no effects on behaviors. The apomorphine (0.56 and 1.0 mg/kg)-induced increase in rearing behaviors was clearly inhibited by treatment with dynorphin A(1-13) (3.0 and 10.0 microgram). Simultaneously, the marked increases in linear locomotion and circling were displayed by apomorphine (1.0 mg/kg) plus dynorphin A(1-13) (10.0 microgram). The effects of dynorphin A(1-13) (10.0 microgram) on the apomorphine (1.0 mg/kg)-induced increase in rearing were entirely reversed by the opioid antagonist Mr2266. These results suggest that the antagonistic effects of dynorphin A(1-13) on the apomorphine (1.0 mg/kg)-induced increase in rearing are mediated via opioid receptors, possibly K-sites.

Animals↗
PubMed1990

Behavioral sensitization following subchronic apomorphine treatment--possible neurochemical basis.

Subchronic treatment with the dopamine agonist apomorphine produces a sensitization to the stereotypic effects of subsequent apomorphine challenge. The present study investigated the effects of this subchronic treatment on apomorphine induced stereotypic behavior and striatal dopamine synthesis, release, metabolism, and D2 receptor binding. The pretreatment, which enhanced the behavioral response to apomorphine challenge, also elevated basal dopamine synthesis and metabolism, but left the ability of a challenge dose of apomorphine to inhibit dopamine synthesis and metabolism unaltered. Thus, ongoing dopamine synthesis and extracellular levels of metabolites would be higher following apomorphine challenge in animals treated subchronically with the agonist. In contrast, neither synaptosomal dopamine release in response to depolarizing stimuli nor the density of D2 dopamine receptors was altered by the treatment. Overall, the results suggest that, while we did not find evidence of autoreceptor desensitization per se, apomorphine treatment may result in enhanced extracellular dopamine levels following dopamine agonist challenge to provide a greater stimulation of an intact dopamine receptor system.

Animals↗
PubMed1975

Effects of penfluridol and other drugs on apomorphine-induced stereotyped behavior in monkeys.

The effects of some drugs on apomorphine-induced stereotyped behavior were studied in male cynomolgus monkeys. Apomorphine produced the dose-dependent stereotyped behavior characterized mainly by continuous licking and biting, and repetitive movements of the hands, head and body in the monkeys. Penfluridol as well as haloperidol showed a clear antagonistic effect on the apomorphine-induced stereotyped behavior, while chlorpromazine was less antagonistic than haloperidol. The antagonistic effect of penfluridol lasted longer than that of haloperidol. Reserpine did not inhibit the apomorphine-induced stereotyped behavior though the drug elicited markedly the behavioral depression and alpha-methyl-p-tyrosine also did not block the stereotyped behavior. Nialamide did not depress the apomorphine-induced stereotyped behavior. In provoking the stereotyped behavior in monkeys, apomorphine probably acts directly on dopamine receptors in the extrapyramidal system, and penfluridol is suggested to act as a dopamine receptor blocker with a long action. The results indicate that protection against apomorphine-induced stereotyped behavior in monkeys may be a useful method for evaluating neuroleptic drugs.

Animals↗
PubMed1975

Differences between the effects of dopamine and apomorphine on rat aortic strips.

Dopamine and apomorphine have been compared with regard to contraction and relaxation of aortic strips prepared from rats of different ages. Both dopamine and apomorphine contracted aortic strips from older (9-12 weeks) rats to greater maximal tension than preparations from younger (3--5 weeks) animals. Contraction in response to both agonists could be blocked by the alpha-blocker, Dibenamine. In contrast to dopamine contraction by apomorphine was associated with the development of tachyphylaxis. Both apomorphine and dopamine relaxed the aorta after alpha blockade, however, the relaxation produced by these drugs differed in two major aspects. First, dopamine-induced relaxation was greatest in aortic strips from young rats compared to older rats whereas relaxation with apomorphine was not age dependent. Second, dopamine-induced relaxation was abolished by propranolol but not haloperidol whereas apomorphine relaxation was only blocked by haloperidol. These data establish that the aortic relaxation caused by dopamine is most likely a beta-adrenergically mediated response whereas that produced by apomorphine is not. Moreover, only dopamine was able to increase the concentration of rat aortic cyclic AMP. Should these data be applicable to other vascular beds or species, it is possible that the vascular effects of dopamine will be influenced by age and drugs which impinge on cyclic nucleotide disposition.

Age Factors↗
PubMed1985

Mechanism of action of apomorphine on rat gastric secretion.

The effects of apomorphine on the volume of gastric secretion and its content of H+, K+, Na+ and Cl- were determined in conscious rats having gastric cannulas. Apomorphine dose-dependently (0.25-0.5 mg/kg s.c.) decreased the volume of gastric secretion, its acid concentration and, at the highest dose, Cl- concentration. However, Na+ and K+ concentrations were unchanged. The alpha 1- and alpha 2-adrenoceptor antagonists prazosin (0.25-0.5 mg/kg i.p.) and yohimbine (5-10 mg/kg i.p.), the beta 1- and beta 2-adrenoceptor antagonist propranolol (5 mg/kg i.p.), the beta 2-adrenoceptor antagonist ICI 118551 (1 mg/kg i.p.) and the dopamine receptor antagonists haloperidol (0.25-2.5 mg/kg i.p.), metoclopramide (2.5-10 mg/kg i.p.) or domperidone (2.5 mg/kg i.p.), administered alone, had little or no effect on the volume, H+, Na+ or Cl- concentrations of gastric secretion. Propranolol prevented the action of apomorphine to reduce the volume of gastric secretion but failed to modify the reductions in H+ and Cl- concentrations. The action of propranolol was mimicked by ICI 118551 but not by the beta 1-adrenoceptor antagonist atenolol. Yohimbine, prazosin or domperidone had little or no effect on the actions of apomorphine. Haloperidol (0.5 mg/kg i.p.) and metoclopramide (10 mg/kg i.p.) antagonised apomorphine's action to reduce H+ and Cl- concentrations but significantly enhanced the action of apomorphine to reduce the volume of gastric secretion. The results suggest that the ability of apomorphine to reduce the volume of gastric secretion is mediated via beta 2-adrenoceptors whilst acid concentration is reduced via an action on neuroleptic sensitive receptors.

Adrenergic beta-Antagonists↗
PubMed1985

Clonidine sensitizes mice for apomorphine-induced stereotypic gnawing: antagonism by neuroleptics and cholecystokinin-like peptides.

In mice sensitized for apomorphine by either scopolamine or teflutixol, clonidine antagonized the antistereotypic effect of ceruletide and haloperidol. The same effect of clonidine occurred in normal mice with methylphenidate-induced gnawing. In naive mice, clonidine alone had a sensitizing effect for the action of apomorphine leading to wire-gnawing. Yohimbine and rauwolscine (but not corynanthine) antagonized this effect of clonidine. The gnawing-inducing effect of methylphenidate was also enhanced by clonidine but not to the same extent as that of apomorphine. The stereotypic effect of apomorphine (in mice sensitized by either scopolamine or clonidine) was antagonized by yohimbine and rauwolscine but not by corynanthine. Apomorphine-induced wire gnawing was used as test of the antistereotypic effect of haloperidol, trifluoperazine, teflutixol, CCK-8, ceruletide and 8 related peptides. Ceruletide and 2 of its analogues were more potent than the neuroleptics; CCK-8 was 7 times less active than ceruletide. In conclusion, clonidine sensitized mice for the stereotypic effect (wire-gnawing) of apomorphine and methylphenidate. The clonidine-apomorphine effect permits the estimation of antistereotypic effects.

Animals↗
PubMed1986

Apomorphine anorexia: a further pharmacological characterization.

Low doses of apomorphine reduce food intake, primarily by decreasing the rate of eating and also by reducing eating time. We have previously reported that the effect on eating time is mediated by dopamine cell body autoreceptors in the ventral tegmental area. The present experiments were designed to elucidate the pharmacological basis of the effect of apomorphine on eating rate. In the first experiment dopamine was also found to reduce food intake, but mainly by an effect on eating time. The peripheral DA antagonist domperidone abolished the effects of DA, but enhanced the effects of apomorphine. In the second experiment phentolamine, yohimbine, propranolol, scopolamine, naloxone and methergoline all failed to reverse the effect of apomorphine on eating rate. However, in the third experiment, effects of apomorphine on total food intake, eating time and eating rate were all blocked by the neuroleptics, pimozide and sulpiride. It is concluded that the reduction of eating rate by apomorphine is also mediated by an interaction with central DA receptors, but that this receptor population is anatomically distinct from that responsible for the effect of apomorphine on eating time.

Animals↗
PubMed1987

Central mechanisms for apomorphine-induced emesis in the dog.

In order to investigate whether different receptor populations mediate emesis induced by intracerebroventricular (i.c.v.) and intravenous (i.v.) apomorphine, adult beagle dogs were tested with various doses of the drug with and without central and peripheral pretreatment with the dopamine antagonist sulpiride. The threshold dose of apomorphine to induce emesis by i.c.v. injections was 30-50 times lower than via the i.v. route, while the response latencies after i.c.v. administration were typically longer and the number of bouts of vomiting greater. I.v. pretreatment with sulpiride was more effective than i.c.v. pretreatment in blocking emesis induced by i.v. apomorphine, whereas both i.v. and i.c.v. sulpiride effectively blocked vomiting after i.c.v. apomorphine. Finally, in separate experiments, surgical interruption of blood flow in the region of the area postrema permanently abolished the emetic response to i.c.v. apomorphine, but only transiently disrupted emesis induced by i.v. apomorphine. These data suggest the possibility that i.v. and i.c.v. apomorphine-induced emesis may be mediated by separate dopamine receptors on the cerebrospinal fluid-side and blood-side of the area postrema.

Animals↗
PubMed1989

Reversal by apomorphine of the gabaculine-induced GABA accumulation in mouse cortex.

To test the assumption that in the mice cortex the rate of accumulation of gamma-aminobutyric acid (GABA) after irreversible inhibition of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) represents an index of GABA turnover, we examined whether the reversal of the gabaculine-induced accumulation of GABA elicited by apomorphine was due to a decrease in GABA turnover or to a modulation of the activity of the GABA-T inhibitor. Therefore, we simultaneously measured the action of apomorphine on gabaculine-induced accumulation of GABA and on GABA-T activity. In vitro, apomorphine (3 and 30 microM) did not alter the concentration-dependent inhibition of GABA-T by gabaculine. Ex vivo, apomorphine (2 x 0.5 mg/kg s.c.) markedly decreased (69%) gabaculine-induced (150 mg/kg i.p.) accumulation of GABA. This drug had no direct effect on GABA-T activity, but significantly reduced from 83 to 71% the inhibition of GABA-T by gabaculine. The linear correlation found between GABA levels and GABA-T activity allowed the quantification of the decrease in GABA turnover elicited by apomorphine. The results showed that apomorphine decreased significantly (P less than 0.001) the rate of GABA synthesis from 7.48 to 3.36 micromol GABA/g per h, if the partial reversal of gabaculine-induced inhibition of GABA-T is considered and 2.44 micromol/g per h if not. Apomorphine effect on GABA accumulation is mainly due to a decrease of the rate of GABA synthesis and to a lesser extent to a reversal of the inhibitory activity of gabaculine. Thus, inhibition of GABA-T by gabaculine is a sensitive and reliable method for the estimation of the rate of synthesis.

4-Aminobutyrate Transaminase↗