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PubMed1986

Modulation of apomorphine-induced climbing behavior by estradiol.

The acute and chronic effects of estradiol benzoate were studied on apomorphine-induced climbing behavior in intact female mice. Climbing behavior was measured by determining the maximum climbing time and climbing index. Mice pretreated with estradiol benzoate (0.1 or 0.3 mg/kg, SC) for 3.5 or 24 hours prior to apomorphine administration showed no significant difference in climbing behavior when compared to corn oil-treated controls. However, mice pretreated with estradiol benzoate (0.1 mg/kg, SC) for 3 consecutive days showed an attenuation in apomorphine-induced climbing at 24 or 72 hours after the last steroid injection. This study shows that the mouse climbing behavioral model provides a simple and quantitative procedure for studying the antidopaminergic effects of estrogen.

Animals↗
PubMed1986

Anticonflict effects of low doses of the dopamine agonist apomorphine in the rat.

The effects of low, "autoreceptor" doses (3.13-100 micrograms/kg, SC) of the dopamine (DA) agonist apomorphine were investigated in a modified Vogel's conflict paradigm. The compound was found to exert a marked, dose-dependent increase in the number of shocks taken in the conflict situation (maximum: approximately 230% of control responding, obtained at 12.5 micrograms/kg), thus indicating an anxiolytic action. However, the dose-response curve was biphasic, inversely U-shaped, with the highest dose tried actually suppressing the punished response rate to below control levels. Neither low- nor high-dose apomorphine modified the rats' drinking "motivation" (glucose intake after 48 hr of water deprivation). On the other hand, while unaltered by 12.5 micrograms/kg, the pain threshold tended to be lowered by 100 micrograms/kg. It is suggested that the anxiolytic-like action of apomorphine might be due to central DA autoreceptor stimulation, possibly in limbic/cortical forebrain regions. The conflict-promoting effect seen at 100 micrograms/kg is likely related to the concomitantly elicited hyperalgesia. The possibility of developing novel DA-modulating agents for the treatment of anxiety is raised.

Animals↗
PubMed1986

Different behavioural patterns induced by the dopamine agonist apomorphine analysed by multivariate statistics.

Exploratory behaviour was recorded in an automatic holeboard apparatus measuring activity, locomotion, rearing, hole exploration and corner restricted behaviour. Multivariate statistical methods were used to analyse the results. Low doses of the dopamine agonist apomorphine (0.01-0.1 mg/kg SC) dose-dependently reduced most variables measured, although the pattern of behaviour resembled that of normal animals. High doses of apomorphine (0.2-1.0 mg/kg SC) induced a qualitative change in the pattern of behaviour with a stereotyped locomotion and a reduced mean time of exploration of holes. The described methods for detection and statistical analysis of behaviour differentiates between the behavioural patterns induced by high and low doses of apomorphine and may be useful in finding and analysing patterns of drug induced behaviour related to various mechanisms of action.

Animals↗
PubMed1986

Effect of 6-OHDA injected into the locus coeruleus on apomorphine-induced aggression.

Bilateral microinjections of 6-hydroxydopamine (6-OHDA) into the nuclei loci coerulei (LC) of male Wistar rats resulted in significant depletion of mesencephalic and striatal norepinephrine, accompanied by a small reduction in dopamine content only in the striatum. Apomorphine (2.5 mg/kg IP) induced marked aggression consisting of prolonged posturing, vocalization and attacks only in 6-OHDA lesioned animals. Biochemical analysis revealed that 6-OHDA antagonized the ability of apomorphine to raise the serotonin concentration in the striatum. It is concluded that the LC neurons play an inhibitory role in apomorphine-induced aggressiveness and the involvement of serotonergic neurons is suggested.

Aggression↗
PubMed1987

Effects of apomorphine and amphetamine on patterns of locomotor and investigatory behavior in rats.

Rats were tested in a Behavioral Pattern Monitor after various doses of either amphetamine or apomorphine in order to characterize their behavioral profiles, including patterns and sequences of holepokes, rearings and locomotor movements. To enable direct comparisons between the behavioral effects of the two stimulants, doses and times for each drug were selected with which locomotor hyperactivity was the predominant behavioral response. Although both drugs increased the total amount of locomotor activity, amphetamine induced a relatively varied behavioral profile while apomorphine induced repetitive behavior with a restricted range of responses. These contrasting effects of the stimulants were interpreted as reflective of their differing modes of action with regard to central dopaminergic systems. It is suggested that, in the dose range used, the release of dopamine by amphetamine is coupled to neuronal firing and therefore this release increases behavioral activity without altering the normal response repertoire of the animal. Conversely, the direct agonist action of apomorphine results in a restricted and perseverative behavioral pattern because its activation of forebrain dopamine receptors is independent of the normal physiological pattern of dopaminergic neuronal firing.

Amphetamine↗
PubMed1987

D1 and D2 dopamine binding site up-regulation and apomorphine-induced stereotypy.

Treatments with drugs to up-regulate specific receptors is a strategy often employed in mechanism of action studies. In this type of experiment, changes in the numbers of receptors and concomitant changes in an animal's sensitivity to the drug have been used as evidence for the participation of the binding site in the behavior. In these studies, to test for the role of D1 and D2 receptors in apomorphine-induced stereotypy (AIS), dopamine binding sites were up-regulated by appropriate pre-treatments and the ability of these pre-treatments to alter AIS was subsequently investigated. In the first experiment, 19 days of pre-treatment with SCH 23390 or haloperidol selectively increased by 35 and 40% the numbers of striatal D1 and D2 binding sites, respectively, without affecting their affinities. However, when challenged with apomorphine, only the animals pre-treated with the D2 antagonist showed behavioral supersensitivity. In the second experiment, reserpine pre-treatment (30 mg/kg IP, 24-hr pre-test) increased the numbers of D1 binding sites by 18%, but did not significantly alter the numbers of striatal D2 binding sites. Behaviorally, these rats were supersensitive to apomorphine's stereotypy-inducing effects; however, they also showed an increased sensitivity to the ability of either haloperidol or SCH 23390 to block AIS. Moreover, this blockade was only attenuated by a D2 (but not a D1) agonist. Collectively, these data suggest that AIS is mediated by both D1 and D2 binding sites, but that D2 binding sites have a more important role.

Animals↗
PubMed1988

Haloperidol, but not apomorphine, differentially affects low response rates of male and female Wistar rats.

Amphetamine-induced behavioral differences between male and female rats have been observed in tests for stereotyped behavior, locomotor activity and rotational behavior. It has also been shown that amphetamine differentially affects schedule-controlled behavior of male and female rats. The present experiments were designed to further investigate sex differences in sensitivity to agents which act upon the dopaminergic system. In the first experiment, male and female rats responding on a schedule which maintained low response rates were challenged with different low (less than 0.5 mg/kg) doses of apomorphine. Low doses of apomorphine act on the dopamine receptors on the dopaminergic terminals themselves to inhibit the release of endogenous dopamine. In the second experiment, the same subjects were given different doses of haloperidol, which selectively blocks the post-synaptic dopamine receptors. The results of the present experiments showed that haloperidol, but not apomorphine, differentially affected the behavior of male and female subjects. A behavioral difference between the sexes was thus observed when post-synaptic dopamine receptors were blocked by a dopamine antagonist, but not when dopaminergic stimulation of post-synaptic dopamine receptors was reduced by pre-synaptic inhibition of dopamine release. These results suggest a role for post-synaptic receptor mechanisms in mediating sex differences in sensitivity to dopaminergic agents, although other possible mechanisms remain to be investigated.

Animals↗
PubMed1988

Effects of D1 and D2 antagonists on basal and apomorphine decreased body temperature in mice and rats.

In these experiments representative selective antagonists at D1 (SCH 23390) and D2 (haloperidol) receptors were studied for their effects on basal and apomorphine decreased body temperature in mice and rats. In mice, SCH 23390 (up to 3 mg/kg SC) neither affected basal body temperature nor blocked apomorphine-induced hypothermia (AIH). On the other hand, haloperidol alone was hypothermic and paradoxically also blocked AIH in mice. In rats, SCH 23390 alone produced hyperthermia; the mechanism by which this occurred is not known. SCH 23390 also blocked AIH in rats. However, the inhibition of AIH only occurred at doses of SCH 23390 that were themselves hyperthermic. Haloperidol did not alter basal body temperature but did block AIH in rats. These data suggest that apomorphine-induced body temperature changes are D2 mediated.

Animals↗
PubMed1988

Effects of apomorphine on punished and unpunished responding in the rat.

Apomorphine has been reported to increase shock-suppressed drinking, which suggests that it might have antianxiety activity. Because some drugs that increase shock-suppressed drinking are not active in other punishment procedures, the effects of apomorphine on punished and unpunished responding maintained by a multiple fixed-interval, fixed-interval schedule of food presentation were studied in rats. At doses from 3.125 to 100 micrograms/kg, apomorphine failed to increase punished or unpunished responding. In contrast, pentobarbital produced large increases in punished responding maintained by a fixed-interval schedule of food presentation.

Acoustic Stimulation↗
PubMed1988

Stimulant effects of apomorphine and (+)-amphetamine in rats with varied habituation to test environment.

The stimulants (+)-amphetamine and apomorphine are known to increase motility and induce stereotypy in rats. The present study examined the effects of an habituation period immediately prior to injection on these stimulant effects. Male Wistar rats received doses of either drug including 0, 0.01, 0.1, 0.25, 1.0, 2.0 and 4.0 mg/kg in a random order. Activity was assessed in 6 automated chambers where horizontal and vertical activity were tabulated hourly for 4 hours. Initially all rats had equal exposure to the chambers over 5 days. In the subsequent drug phase, habituated rats were placed in the chambers for the 1-hr period prior to each injection whereas non-habituated rats were in their home cages at the corresponding time. (+)-Amphetamine stimulated horizontal activity, although under either condition the effect was not seen until the second hour post-injection, but lasted until the fourth hour. Vertical activity was similarly enhanced, but with habituation there was a significant stimulant effect in the first hour as well. With apomorphine the habituation period resulted in an absence of a significant stimulant effect. Non-habituated rats showed a significant stimulant effect with the highest dose only on vertical activity in the first hour and a stimulant effect with horizontal activity in the second hour. It is suggested that the relative novelty of the environment affected the behavioral response to apomorphine but not to (+)-amphetamine. Furthermore, the activating effects accompanying drug administration should be taken into account as a factor affecting responses to drugs. Such environmental factors may be of particular importance when considering drugs with a short duration of action.

Animals↗
PubMed1989

The effect of pre- and postoperative procedures on physostigmine- and apomorphine-induced yawning in rats.

Previous experiments have shown that the potentiation of physostigmine-induced yawning by nifedipine is abolished by sham-lesioning procedures in rats, whereas the nifedipine potentiation of apomorphine-induced yawning is unaffected. The present results demonstrate that either the presurgical drug treatment (desmethylimipramine and pentobarbital) or 7 days isolation was alone sufficient to reduce the yawning response to physostigmine and abolish its potentiation by nifedipine. The sham-lesioned rats responded normally to a combination of apomorphine and nifedipine. These results suggest that the stress associated with standard operative procedures can differentially affect drug interactions with yawning induced by either apomorphine or physostigmine and that caution should be exercised when interpreting results from animals that have been similarly stressed.

Animals↗
PubMed1990

Scopolamine produces locomotor stereotypy in an open field but apomorphine does not.

Both dopaminergic and nondopaminergic drugs produce hyperlocomotion in rats. Dopaminergic drugs also produce focused stereotypy (absence of locomotion and intense sniffing or licking/biting of a restricted area of the environment). Some drugs produce repetitive routes of locomotion; this phenomenon might represent a combination of hyperlocomotion and stereotypy. Scopolamine (an acetylcholine antagonist) and apomorphine (a dopamine agonist) both produce hyperlocomotion in rats; apomorphine also produces focused stereotypy but scopolamine does not. This research determines whether these drugs also produce locomotor stereotypy as measured by gamma. Scopolamine (0.5 and 2.0 mg/kg) produced locomotor stereotypy at both doses. Apomorphine (1.0, 2.0, and 3.0 mg/kg) failed to reliably produce locomotor stereotypy. Thus, there is not necessarily a relationship between the ability of a drug to produce focused stereotypy and the ability of the drug to produce locomotor stereotypy.

Animals↗
PubMed1990

Pretreatment with an irreversible muscarinic agonist affects responses to apomorphine.

The main aim of the present study was to investigate if responses to the direct dopamine agonist, apomorphine, could be modified by changes in the activity of cholinergic neurones. A novel approach was adopted in which these responses were assessed following reduction of muscarinic receptor concentration (mAChR) in the brain (assessed from [3H] QNB binding) by the alkylating derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)]-2-pyrrolidone (BM 123). Stereotyped responses elicited by apomorphine were significantly reduced when QNB binding was 12% and 50% of control values. No changes in [3H] spiperone binding were found. There was significant hypothermia in the group with 12% QNB binding sites which was significantly increased by apomorphine. Body temperature returned to normal when QNB binding was 50% of control values. There was a significant decrease in activity when QNB sites were reduced to 12% of normal and vertical activity was still significantly reduced at 50% QNB binding, though horizontal activity was not then different from controls. These data are consistent with the hypothesis that changes in the function of mAChR modify responses elicited by dopamine receptor stimulation in both the striatum and other brain regions.

Animals↗
PubMed1990

Effects of hemivibrissotomy in the rat: time-dependent asymmetries in turning and biogenic amines induced by apomorphine.

Behavioral and neurochemical changes accompanying unilateral removal of vibrissae were investigated in the rat. Rats were tested either 4 hours or 10 days after hemivibrissotomy. A systemic injection of apomorphine (0.5 mg/kg) induced turning behavior towards the intact vibrissae side in rats tested 4 hours after hemivibrissotomy. Compared to these animals, apomorphine induced more turning towards the side of vibrissae removal and less turning towards the intact side in animals tested 10 days after vibrissae removal. This reversal is suggestive of time-dependent changes in dopamine receptor sensitivity. Analysis of biogenic amines (dopamine, norepinephrine, serotonin) in the hemispheres ipsi- and contralateral to the side of vibrissae removal revealed evidence for neurochemical changes in apomorphine- and amphetamine-treated rats. Lateralized and bilateral differences were found in the neostriatum, septum and ventral mesencephalon, which were dependent on the side and duration of hemivibrissotomy. These results are discussed with respect to the behavioral and neural analogy between hemivibrissotomy and unilateral 6-hydroxydopamine lesions of the nigrostrial system.

Amphetamine↗
PubMed1991

Metoclopramide decreases apomorphine-induced yawning and penile erection.

Acute administration of metoclopramide, a dopamine (D2) antagonist, reduced both apomorphine-induced yawning and penile erections. Metoclopramide, prominent in clinical use as an effective antiemetic, has been shown to be associated with decreased erectile function in humans. Experimentally naive rats were given a standardized dose of apomorphine and one of a range of doses of metoclopramide. The study shows that metoclopramide decreases the erectile response to apomorphine and suggests that the erectile difficulties experienced in humans after metoclopramide treatment may be a result of interference with a central dopaminergic mechanism(s).

Animals↗
PubMed1995

Differential effects of low versus high doses of apomorphine on retinal dopamine metabolism in light- and dark-adapted rabbits.

Previous electrophysiologic results from this laboratory indicate that apomorphine exerts a differential dose-related effect on rabbit electroretinograms, with low doses increasing the b-wave and higher doses decreasing this parameter. Results were interpreted as reflecting apomorphine's agonistic properties at two different receptors: 1.0 mg/kg acting at the postsynaptic site, and the lower dose, 0.01 mg/kg, preferentially stimulating inhibitory autoreceptors. The purpose of this experiment was to investigate further this hypothesis by determining retinal levels of dopamine, dihydroxyphenylacetic acid, and homovanillic acid in retinas of light- or dark-adapted rabbits treated with saline, 1.0, 0.1, or 0.01 mg/kg apomorphine intravenously. Results indicate that in dark-adapted rabbits only the highest dose tested, 1.0 mg/kg, decreased dopamine concentrations. In animals exposed to light, the lowest dose tested, 0.01 mg/kg, significantly reduced dopamine and metabolite levels, whereas the highest dose unexpectedly increased retinal dopamine turnover. Results are discussed in terms of receptor sites and the influence of lighting conditions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Prevention by NG-nitro-L-arginine methyl ester of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain.

The effect of NG-nitro-L-arginine methyl ester (NAME), a potent inhibitor of nitric oxide (NO) synthase, injected into different brain areas on penile erection and yawning induced by apomorphine or oxytocin was studied in male rats. The compound was found to be able to prevent the above behavioral responses dose dependently when injected into the paraventricular nucleus of the hypothalamus (PVN), but not in the caudate nucleus, medial septum, preoptic area, and the CA1 field of the hippocampus. When injected in the PVN, 5 micrograms of NAME induced a 30% reduction of apomorphine and oxytocin responses, while 20 micrograms induced an almost complete reduction. The effect of NAME seems to be related to the inhibition of guanylate cyclase secondary to the prevention of NO formation, because a dose-dependent reduction of apomorphine and oxytocin responses was obtained also with the inhibitor of guanylate cyclase methylene blue injected intracerebroventricularly (100-400 micrograms ICV), but not into the PVN. The results provide further support for a neurotransmitter role of central NO in the control of penile erection and yawning.

Animals↗
PubMed1996

Low-dose apomorphine attenuates morphine-induced enhancement of brain stimulation reward.

Thresholds for brain stimulation reward (BSR) delivered to the medial forebrain bundle-lateral hypothalamus were determined by means of a rate free psychophysical method. Lower doses of apomorphine (0.5 to 0.2 mg/kg) produced modest elevations in BSR thresholds. A 0.4 mg/kg dose of apomorphine resulted in emergence of stereotypic behaviors and the loss of stimulus control. Morphine's BSR threshold lowering effects were significantly blocked by the concurrent administration of a 0.1 mg/kg dose of apomorphine. These results support the hypothesis that presynaptic dopamine neurons are involved in the mediation of morphine's reinforcing effects and that dopamine autoreceptor agonists may be of some use in the pharmacotherapy of opiate abuse.

Animals↗