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Sensitization to and conditioning with apomorphine in pigeons.

Pigeons that repeatedly experienced the effect of apomorphine in the same environment showed an augmented behavioural response to the same drug dose as compared with controls that experienced the effect of the drug dose in differing environments. Sensitization, an increase in the behavioural response that is observed in pigeons when the same dose of apomorphine is repeatedly administered, may thus be mainly due to a conditioning of the drug response to incidental environmental cues. Apomorphine injections also induced place preferences. Pigeons that had experienced a particular environment under the influence of apomorphine subsequently favoured that environment to one they had experienced while under saline. This suggests that apomorphine administration has reinforcing properties for birds, much as it has for mammals.

Animals↗

Systemic or intracranial apomorphine increases copulation in long-term castrated male rats.

Testosterone or its estrogenic metabolite is thought to be necessary to activate male rat sexual behavior. However, systemic injections of dopamine agonists, alone or in combination with exogenous testosterone, can partially restore copulatory behavior during the prolonged period of its postcastration decline. The present experiments tested the ability of the dopamine agonist apomorphine, injected systemically or into the medial preoptic area (MPOA), to restore copulation in long-term castrates that had failed to copulate on two successive weekly tests. In Experiment 1, systemic injections of apomorphine increased the number of mounts and intromissions in castrated males, compared to vehicle. In castrates given subthreshold testosterone propionate (TP), apomorphine increased the number of mounts. In Experiment 2, microinjections of apomorphine into the MPOA increased the number of mounts in animals without TP. Subthreshold TP had no significant effects in either experiment, either alone or interacting with apomorphine. These results suggest that stimulation of dopamine receptors can partially restore copulation, even after its virtual elimination. Furthermore, dopamine receptors in the MPOA may contribute to sexual arousal in long-term castrates.

Animals↗

Effects of apomorphine on novelty-induced place preference behavior in rats.

Adult male rats were exposed to one of two different stimulus compartments by being placed into the compartment for 30 min on each of eight consecutive days. Following this exposure, each rat was administered 0, 0.05, 0.1, 0.5 or 5.0 mg/kg apomorphine. Thirty min after injection, each animal was given free-choice access to the familiar (exposed) compartment and to the novel (nonexposed) compartment. As expected, saline-injected control animals displayed a preference for the novel compartment. This novelty preference was disrupted in animals given either 0.05 or 0.1 mg/kg apomorphine, but not in animals given either 0.5 or 5.0 mg/kg apomorphine. The disruption in novelty preference by the low doses of apomorphine did not reflect a disruption of locomotor activity, as there was no direct relationship between the preference for novelty and the rate of horizontal or vertical activity among the different treatment groups. Instead, the low doses of apomorphine may have inhibited dopamine function by blocking presynaptic autoreceptors selectively, and thus the reinforcing effect of the novel stimulation may have been attenuated.

Animals↗

Behavioral concomitants of regional changes in the brain's biogenic amines after apomorphine and amphetamine.

Behavioral and neurochemical changes were analyzed in rats after systemical injections of the dopamine receptor agonist apomorphine (0.5 mg/kg) or the indirect agonist amphetamine (1.0 mg/kg). As expected, amphetamine led to an increase in locomotion, whereas apomorphine resulted in decreases in locomotion, rearings, and grooming. The analysis of biogenic amines in tissue samples showed that amphetamine decreased 3,4-dihydroxy-phenylacetic acid (DOPAC) levels and DOPAC/dopamine ratios in the neostriatum, and resulted in a lower 5-hydroxyindole-3-acetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the ventral mesencephalon. Apomorphine decreased the dopamine metabolites [DOPAC, homovanillic acid (HVA), 3-methoxy-tyramine (3-MT)] and their respective metabolite/transmitter ratios and increased dopamine levels in the neostriatum. Similar decreases in dopamine metabolites or their ratios were found in the ventral mesencephalon, septum, and frontoparietal cortex but not the thalamus. In addition to its effects on dopamine, apomorphine decreased norepinephrine in the ventral neostriatum and 5-HT and 5-HIAA in the cortex. Correlations between behavioral activity and neurochemical metabolism (using the metabolite-transmitter ratios for the latter) revealed relationships between locomotion and serotonergic activity in the thalamus of animals treated with amphetamine. Evidence for a relationship between locomotion or rearings and dopaminergic activity was found in all six brain areas analyzed. Here, the pattern of correlation was dependent on the kind of treatment and the behavioral and neurochemical measures. These results support earlier findings on the neurochemical effects of apomorphine and amphetamine in the neostriatum and ventral mesencephalon, and add new evidence for an action on the septal area, thalamus, and frontoparietal cortex.

Amphetamine↗

Autosomal and Y chromosomal effects on the stereotyped response to apomorphine in wild house mice.

The behavioral response to apomorphine, a dopamine agonist, was shown to be different between a selection line characterized by Short Attack Latencies (SAL) and a selection line having Long Attack Latencies (LAL) (4). Aggressive SAL mice were more sensitive to apomorphine than nonaggressive LAL males. The aim of this research was to determine whether the stereotyped response to apomorphine is affected by the Y chromosome in the same way as it influences attack latency. For this purpose, F1 reciprocal hybrids as well as congenic lines (SAL.LY and LAL.SY) were used. The major difference between the congenic and parental lines is the nonpairing part of the Y chromosome (non-PAR). Apomorphine was injected subcutaneously at a preselected dose level of 5.0 mg/kg to induce stereotyped behavior manifested in compulsive sniffing, gnawing, and licking. Both the autosomes and the non-PAR Y chromosome affected the response to apomorphine. The effect of the autosomes was in accordance with the aggression data, whereas the effect of the non-PAR Y chromosome was different, and suggests a specific relation between dopamine systems and the non-PAR Y chromosome.

Aggression↗

Measurement issues in curve-shift analysis of apomorphine effects on rewarding brain stimulation.

The direct dopamine agonist apomorphine has been reported to reduce the rewarding efficacy of lateral hypothalamic (LH) self-stimulation. This effect has been claimed to support the notion that dopamine mediates the rewarding effects of LH self-stimulation. Using a standard rate-frequency curve-shift paradigm with ascending order of frequency presentation, we also found that apomorphine (0.1-0.8 mg/kg, SC) appeared to decrease LH self-stimulation reward. These apparent rightward curve shifts were exacerbated by shortening the test duration, which also produced a number of sessions in which the subjects did not respond at all. When the presentation order of stimulation frequencies was reversed, apomorphine did not produce large reward decreases. These results suggest that the previously reported effects of apomorphine on LH self-stimulation were the result of artifact, perhaps related to apomorphine-induced stereotypical behavior combined with rapid pharmacological recovery.

Animals↗

Apomorphine test to predict dopaminergic responsiveness in parkinsonian syndromes.

To evaluate apomorphine as an indicator of dopaminergic responsiveness, responses to subcutaneous apomorphine, to a single levodopa challenge, and to prolonged levodopa therapy were studied in 100 patients with parkinsonian syndromes (65 with idiopathic Parkinson's disease, 35 with other parkinsonian syndromes). Excellent agreement was found between the initial challenges of apomorphine and levodopa. Apomorphine also accurately predicted the response to long-term levodopa in 90% of the patients. There were 8 false-negative results; 7 were in patients with mild deficits. The apomorphine test is a quick, safe, reliable indicator of dopaminergic responsiveness in parkinsonian syndromes. The test is especially helpful to reassess patients who seem to have become less responsive to levodopa and it also has some predictive value in the assessment of an untreated patient's likely response to dopaminergic therapy.

Administration, Oral↗

Dopaminergic sensitivity and cocaine abuse: response to apomorphine.

Ten male patients with chronic cocaine abuse received a single dose of the dopamine agonist apomorphine. Self-ratings of cocaine craving, depression, and anxiety decreased in response to apomorphine. Neuroendocrine response was consistent with central dopaminergic stimulation. Patients in the "craving" phase of the cocaine abuse cycle differed in behavioral but not neuroendocrine response to apomorphine from patients in the "crash" phase. Decrease in cocaine craving correlated with decrease in plasma homovanillic acid (pHVA). Total cocaine consumption correlated negatively with baseline prolactin and pHVA levels and inversely with peak change in prolactin following apomorphine. Patients had blunted neuroendocrine response to apomorphine in comparison to historical normal controls. Implications for the "dopamine" hypothesis of cocaine abuse are discussed.

Adult↗

Chemical lesions of the nucleus accumbens septi in rats: effects on muricide and apomorphine-induced aggression.

To assess the influence of monoaminergic neurones in the nucleus accumbens septi (NAS) on muricidal and apomorphine-induced aggression, bilateral intraaccumbens injections of relevant neurotoxins were performed. Neurochemical effects in the mesolimbic area (NAS and tuberculi olfactorii) and striatal tissue were investigated using high performance liquid chromatography. 6-Hydroxydopamine (6-OHDA) with desipramine pretreatment significantly decreased mesolimbic dopamine (DA) metabolism, 5,7-dihydroxytryptamine (5,7-DHT) plus desipramine diminished serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), while DSP-4 depleted noradrenaline (NA), 5-HT, 5-HIAA and tryptophan in the mesolimbic area. No significant biochemical changes were observed in the striatum. Behaviourally, 6-OHDA-treated rats were markedly more aggressive in the apomorphine-induced fighting test. Similarly, DSP-4 injections into the NAS (10 micrograms/1 microliter) enhanced this type of aggression. The 5,7-DHT lesion did not alter apomorphine-induced fighting. None of the neurotoxins induced muricidal behaviour. It is concluded that dopaminergic postsynaptic receptors in the NAS may be involved in the pro-aggressive effect of apomorphine. The results support the hypothesis that NA-containing neurones play an inhibitory role in apomorphine-induced aggression and suggest that such a DA-NA interaction might occur in the NAS.

5,7-Dihydroxytryptamine↗

Behavioural correlates of a progressive dysfunctioning of the caudate nucleus: effects of apomorphine.

During the ontogeny of many mammalian species there exists a remarkable resemblance with respect to the strict order in the appearance of distinct motor patterns during development. Moreover, along a cephalocaudal gradient more and more body parts become involved in these motor patterns. The same sequence in motor behaviour can be observed when adult animals start to explore a novel environment. On the other hand, s.c. injections of apomorphine result in a reversed 'ontogenetic' sequence of motor patterns: a 'breakdown' of motor behaviour. The present study investigated whether striatal injections of apomorphine produced a reversed 'breakdown' of a motor pattern sequence. Therefore, cats were tested in a paradigm in which they executed sequences of distinct motor patterns in order to collect food pellets when walking on the belt of a treadmill. As only one of the motor patterns in the sequence is caudate-specific, disturbances at the level of the caudate nucleus as well as disturbances at the level of other brain structures can be distinguished. In contrast to 0.6 and 2.5 micrograms, doses of 5.0 and 10.0 micrograms of apomorphine resulted in the successive breakdown of motor pattern sequences, whereby not only caudate-specific motor patterns were reduced, but also non-caudate-specific motor patterns. Moreover, this regression appeared in the reversed order compared to the order in which distinct patterns are executed during eating behaviour. The regression in motor behaviour following 5.0 micrograms apomorphine was induced via caudate dopamine receptors since it could be prevented by pretreatment with haloperidol. Because of the fact that 5.0 and 10.0 micrograms of apomorphine also affected motor patterns which are not caudate- and dopamine-specific, it is concluded that also brain structures receiving (in)directly caudate output signals are involved in the regression of the motor pattern sequence as observed in the present study. The clinical relevance of the presented data is discussed.

Animals↗

Somatosensory evoked potentials at rest and during movement in Parkinson's disease: evidence for a specific apomorphine effect on the frontal N30 wave.

Studies attempting to relate the abnormalities of the frontal N30 components of the somatosensory evoked potentials (SEPs) to motor symptoms in Parkinson's disease (PD) have shown contradictory results. We recorded the frontal and parietal SEPs to median nerve stimulation in 2 groups of PD patients: a group of 17 patients presenting the wearing-off phenomenon, and a group of 10 untreated PD patients. The results were compared with a group of 13 healthy volunteers of the same age and with a group of 10 non-parkinsonian patients. All parkinsonian and non-parkinsonian patients were studied before ("off" condition) and after a subcutaneous injection of apomorphine ("on" condition). The gating effects of a voluntary movement (clenching of the hand) on the SEPs were also studied for the wearing-off group of PD patients (in states off and on) in comparison with the healthy subjects. At rest and in the off condition the amplitude of the frontal N30 was significantly reduced in the 2 groups of PD patients. We demonstrate that the movement gating ability of the PD patient is preserved in spite of the reduced amplitude of the frontal N30. This result suggests that the specific change in the frontal N30 in PD is not the consequence of a continuous gating of the sensory inflow by a motor corollary discharge. Clinical motor improvement induced by apomorphine was associated with a significant enhancement of the frontal N30 wave. In contrast, the subcortical P14 and N18 waves and the cortical N20, P22, P27 and N45 were not statistically modified by the drug. Apomorphine infusion did not change the absolute reduced voltage of the N30 reached during the movement gating. While the frontal N30 component of the non-parkinsonian patients was significantly lower in comparison to healthy subjects, this wave did not change after the apomorphine administration. In the wearing-off PD patient group the frontal N30 increment was positively correlated with the number of off hours per day. This specific apomorphine sensitivity of the frontal N30 was interpreted as a physiological index of the dopaminergic modulatory control exerted on the neuronal structures implicated in the generation of the frontal N30.

Aged↗

Age-related changes in apomorphine-induced erections.

Advancing age produces a noticeable and well-documented decline in erectile function in humans. The effects of aging on the ability of apomorphine to stimulate erection and yawning behavior in rats was studied in our bioassay for potency. At the age of seven months, rats failed to respond to the same dose of apomorphine which, just one month earlier, produced erections. Erectile function was then tested in thirty-two seven-month-old rats naive to apomorphine injections, and these rats also failed to respond. Experimentally naive rats of six months of age were then tested and apomorphine produced reliable erections. It is felt that an alteration in dopamine autoreceptor function may be occurring in the central nervous system of rats at approximately seven months of age rendering them incapable of responding to apomorphine with penile erections.

Aging↗

Apomorphine response and subtyping of schizophrenia.

(1) We conducted a double-blind study of acute effects of low-dose apomorphine (0.01 mg/kg) in 12 chronic schizophrenic patients. (2) Overall, there was no significant difference in therapeutic response to apomorphine versus placebo. (3) Of the individual subscales of the Brief Psychiatric Rating Scale, anxiety and depression syndromes showed significant improvement with apomorphine. (4) On dividing the schizophrenic patients into two groups on the basis of computed tomography (CT) scans, it was found that there was a significant difference in their responsiveness to apomorphine. (5) Patients with abnormal CT scans (primarily, large ventricles) tended to have improvement or no change with apomorphine, whereas those with normal CT scans tended to have worsening of symptoms. (6) Possible implications of our findings are discussed.

Adult↗

Effects of p-chloro-phenylalanine on the behaviors induced by apomorphine and amphetamine in adult cats.

1. The effects of serotonin depletion on the behaviors evoked by apomorphine or amphetamine are analyzed. Amphetamine (5 mg/kg, s.c.) or apomorphine (2 mg/kg, s.c.) were administered to fourteen adult mongrel cats. Inhibition of tryptophan hydroxylase was achieved by intraperitoneal injection of p-chlorophenylalanine (100 mg/kg daily for three consecutive days). Serotonin depleted animals were tested with either apomorphine or amphetamine (same doses as above). 2. Behaviors evoked by both drugs were recorded and quantified. The following behaviors were rated: motility (locomotion), alertness, fear, indifference, olfaction and lateral head movements. 3. Biochemical analysis of the raphe dorsalis and caudate nuclei of p-CPA treated animals showed an average drop in serotonin concentration of 77%. Serotonin depletion induced statistically significant changes in the following behaviors in amphetamine-treated cats: locomotion, fear, lateral head movements and alertness. Serotonin depleted cats tested with apomorphine showed significant changes only in olfaction and indifference behaviors. 4. Serotonin appears to play a significant modulatory role in some of the behaviors evoked by amphetamine, specially locomotion. Such role is less evident for the behaviors evoked by apomorphine.

Amphetamine↗

Cholinergic blockade with scopolamine in adult cats. Effects on the behaviors evoked by apomorphine and amphetamine.

1. The aim of this work is to analyse the role that the cholinergic system could play in the production of the behaviors evoked by apomorphine and amphetamine in adult cats. These two drugs were injected s.c. in separate sessions, before and after a s.c. administration of scopolamine which blocked the muscarinic receptors. The pre and post-scopolamine results of the behaviors produced by the two catecholaminergic drugs were compared using the non-parametric Wilcoxon signed rank test. 2. In a previous step a dose-response study of the behavioral effects of scopolamine, in doses of 0.05, 0.1, 0.4 and 0.8 mg/kg was carried out in ten cats. The Kruskal-Wallis and the non-parametric multiple comparison tests were employed. A dose-dependent decrease in motility (locomotion) and a dose-dependent increase in inappetence and pupillary dilation were found. 3. In thirteen cats which were injected with 2 mg/kg of apomorphine and 2.5 mg/kg of amphetamine the findings were: 1--apomorphine after scopolamine produced a decrease in the hypermotility, compared with the results observed with the former drug previous to scopolamine; 2--with amphetamine an increase in immobility and a decrease in indifference were observed. 4. The authors conclude that the decrease in motility recorded with apomorphine and amphetamine after scopolamine, could be attributed to the proper effect of scopolamine. No explanation could be found for the decrease in indifference found by injecting amphetamine after scopolamine. 5. Considering the antagonistic effect between the dopaminergic and the cholinergic systems and that the latter one has an arousal effect, we postulate that the behavioral indifference produced by apomorphine and amphetamine could be the result of a kind of blockade of the cholinergic system when the catecholaminergic system is activated through the administration of the two cited drugs.

Amphetamine↗

Accumulation of apomorphine in caudate nucleus and hippocampus of the rabbit.

Apomorphine concentration was assayed in the caudate nucleus, hippocampus and cerebellum of rabbits injected with various doses of the drug 30 min earlier. Apomorphine accumulation was dose-dependent but uneven in the structures tested: the accumulation in the caudate nucleus being approx. 5 times higher than in cerebellum. Pretreatment with haloperidol significantly depressed the accumulation of apomorphine in the caudate nucleus and hippocampus, but not in the cerebellum. The amount of apomorphine displaceable by haloperidol was approx. 10 times higher in the caudate nucleus than in the hippocampus. The results suggest the existence of small number of apomorphine binding sites in the hippocampus.

Animals↗

Effects of apomorphine administration on rearing activity of control and experimental rats withdrawn from long-term haloperidol treatment.

Rats were administered increasing doses of haloperidol or control solution for 25 days. 72 hr after drug withdrawal they were observed for rearing activity in an open field with or without apomorphine treatment. Rearing frequency was higher in haloperidol withdrawn rats. In control rats rearing frequency decreased 15 min after apomorphine administration in a dose-dependent way. In haloperidol withdrawn animals the apomorphine effects were dual, first an increase in rearing frequency induced by the smaller apomorphine doses (0.025-0.1 mg/kg) was observed and secondly a progressive and dose-dependent decrease was scored. Apomorphine also induced different motor effects not necessarily similar in control and experimental rats. Supersensitivity of dopaminergic receptors induced by the long-term neuroleptic administration was considered to be involved with the difference observed.

Animals↗

Characterization of dopamine receptors involved in apomorphine-induced pecking in pigeons.

1. The possible involvement of subtypes of dopamine-receptors in apomorphine induced pecking was studied in pigeons. Different doses of apomorphine induced pecking in pigeons which was dose-dependent. 2. The response was decreased by SCH 23390 (D-1 antagonist) or high doses of sulpiride (D-2 antagonist) pretreatment, but increased by lower doses of sulpiride. 3. Combination of SCH 23390 with sulpiride completely antagonized the apomorphine effect. 4. Single dose administration of SKF 38393 (D-1 agonist) or bromocriptine (D-2 agonist) and combination of these drugs did not induce pecking, although either SK 23390 or bromocriptine increased the apomorphine-induced pecking which was decreased by SCH 23390 or sulpiride pretreatment. 5. It may be concluded that pecking, induced by apomorphine in pigeons, is elicited through activation of both D-1 and D-2 dopamine-receptors.

Animals↗