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PubMed1984

Cytidine(5')diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striatum of the rat and to diminish stereotyped behavior induced by apomorphine.

Experiments were performed to determine whether exogenous cytidine(5')diphosphocholine (CDP-choline) could modify release of dopamine in the striatum and behavior dependent on dopamine, perhaps by providing supplemental choline for synthesis of acetylcholine. Rats received water (control) or CDP-choline orally (100 mg/kg per day, for 5 days), either alone or before injection with haloperidol (1 mg/kg, i.p.), apomorphine (0.15 mg/kg, s.c.), or both. Stereotyped behavior was measured during the hour after administration of apomorphine; levels of the dopamine metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum were assessed at the end of this period (2 hr after administration of haloperidol). In rats receiving the CDP-choline, the stereotyped behavior observed after injection of apomorphine alone (P less than 0.01), or after haloperidol plus apomorphine (P less than 0.01), was attenuated. The pretreatment with CDP-choline also significantly increased levels of HVA (by 24%) and DOPAC (by 23%) in the striatum over appropriate controls in animals receiving haloperidol, or by 29 and 59% (averaging data for all time points), respectively, in animals receiving haloperidol plus apomorphine. One mechanism by which CDP-choline may affect behavior involves contributing choline to enhance synthesis of acetylcholine.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Modulation by enkephalin analogues and neuroleptics of apomorphine-induced stereotypy and turning behaviour in rats.

The aim of the present investigation was to examine which areas of the brain might mediate the anti-apomorphine action of some opioids, which were found previously to be active upon subcutaneous application. As the first step, the substances were injected intracerebroventricularly or into the nucleus accumbens, a mesolimbic region which is rich in dopamine, and the inhibition of stereotypy induced by apomorphine was quantified. In a separate group of animals (rats with unilateral lesion of the nigra) the antagonism of turning behaviour elicited by apomorphine was measured. Substances examined were morphine, a mu-selective opiate; D-Ala2,Nle5-enkephalin sulphonic acid (ES), a delta-selective opioid peptide; D-Met2,Pro5-enkephalinamide (EA), a highly potent but non-selective opioid; and two dopamine receptor blockers, haloperidol and chlorpromazine, for comparison. Examining the antagonism of turning behaviour induced by apomorphine, the order of potency was EA greater than haloperidol greater than morphine greater than ES approximately equal to chlorpromazine if injections of the substances were intracerebroventricular and EA greater than morphine much greater than haloperidol approximately equal to ES much greater than chlorpromazine when administered into the nucleus accumbens. The order of potency for the suppression of stereotypy induced by apomorphine was EA much greater than haloperidol greater than morphine greater than ES greater than chlorpromazine upon intracerebroventricular application and EA much greater than haloperidol greater than morphine ES greater than chlorpromazine if injected into the nucleus accumbens. The data indicate that endogenous opioids might inhibit the activity of dopamine in brain through the nucleus accumbens.

Animals↗

PubMed1987

Apomorphine-induced behaviour during the oestrous cycle of the rat.

The effect of various doses of apomorphine (APO) (25, 250, 400 and 750 micrograms/kg, s.c.) on open field behaviour, stereotyped behaviour, body temperature and concentrations of serum oestradiol was studied in cycling females and in ovariectomized rats. With the exception of grooming, the hormonal variations during the cycle, or the ovariectomy, did not have an effect on behaviour related to stimulation of presynaptic dopamine (DA) receptors. The endocrine status on proestrus (PE), characterized by an increase in serum oestradiol, did influence hyperlocomotion and hypothermia induced by apomorphine; the former being attenuated and the latter increased, as compared to the other phases of the cycle. Ovariectomy resulted in an increase in the stimulatory effect of apomorphine on locomotion. Stereotypy induced by apomorphine was unaltered by hormonal variations during the cycle and it was slightly attenuated by removal of the ovaries. During phases of low levels of oestrogen (oestrus, metestrus) apomorphine significantly increased the levels of serum oestradiol, determined 30 min after the administration of drug. It is concluded that the various DAergic mechanisms in brain are differentially affected by hormonal variations during the cycle and by ovariectomy.

Animals↗

PubMed1989

Relationship between rotational behaviour induced by apomorphine and caffeine in rats with unilateral lesion of the nigrostriatal pathway.

The contralateral rotational behaviour produced by apomorphine and caffeine has been studied in 100 rats with unilateral lesion of the nigrostriatal pathway induced with 6-OHDA. Rats with a two-peak rotational pattern induced by apomorphine, showed a greater number of contralateral turns, induced by apomorphine and caffeine, than rats which did not show this rotational pattern. A correlation was observed between the number of rotations induced by apomorphine and those induced by caffeine. A relationship between the two-peak rotational pattern induced by apomorphine and the initial-peak pattern induced by caffeine was also observed.

Animals↗

PubMed1990

Dopamine D1 and D2 receptors mediate opposite effects of apomorphine on the body temperature of reserpinized mice.

In mice, rendered poikilothermic by a prior (18 hr) subcutaneous administration of reserpine (3 mg/kg), the subcutaneous administration of apomorphine increased dose-dependently the body temperature. This effect was potentiated by the specific D2 dopamine antagonist sulpiride. On the contrary, it was reduced by the specific D1 dopamine antagonist SCH 23390. A desensitization of D2 receptors was produced by the repeated administration of the specific D2 agonist RU 24926. This pretreatment led to an increased efficacy of apomorphine in antagonizing reserpine-induced hypothermia. Similarly, a desensitization of D1 receptors was created by the repeated administration of the specific D1 agonist CY 208-243. This pretreatment significantly diminished the efficacy of apomorphine in antagonizing reserpine-induced hypothermia. The repeated administration of the D1 agonist CY 208-243, in non-reserpinized mice, significantly increased the hypothermic effect of apomorphine (1 mg/kg). Thus, it appears that, in normal mice, but especially in reserpinized mice, the stimulation of D1 receptors by apomorphine induces an increase in body temperature that is masked, especially in normal mice, by the hypothermic effect, resulting from the simultaneous stimulation of D2 receptors.

Animals↗

PubMed1991

Apomorphine effect on single and paired rat open-field behavior.

The present study aims to investigate the effect of apomorphine, dopamine agonist, on single and paired rat open-field behavior by using a video analysis system. Experimental rats were injected with saline or apomorphine (0.01, 0.05, 0.1, 0.5, 1.0, 5.0 mg/kg, SC) and put into an open field for 30 min singly or paired with another rat. The rats' movements were plotted on XY coordinates by a video analysis system every 0.5 s and analyzed by distance and time factors. Although when paired, the experimental rat moved more than when single, the total distance moved decreased according to dose of apomorphine. While two rats in the open field often stand in contact with each other, apomorphine in doses of over 0.5 mg/kg tends to keep the two rats separate. These phenomena show that apomorphine induces indifference toward others.

Animals↗

PubMedDate not supplied

Inhibition by bromoestrogens of the effects of estradiol on apomorphine-induced climbing behavior.

The chronic administration of estrogens to mice or rats will result in antidopaminergic effects. Apomorphine-induced climbing behavior in mice, the result of direct stimulation of dopamine receptors in the striatal and mesolimbic regions, is a simple animal model for examining these antidopaminergic effects of estrogens. Bromoestrogens, inhibitors of catechol estrogen formation, have been utilized in order to examine the role of estrogen metabolism in dopaminergic antagonism. Mice were pretreated for 3 days with 2-bromoestradiol, 4-bromoestradiol, or 2,4-dibromoestradiol dibenzoates alone or in combination with estradiol benzoate prior to apomorphine administration. The haloestrogens did not alter the climbing-induced responses elicited by apomorphine, whereas estradiol benzoate clearly attentuated the actions of apomorphine. Furthermore, the bromoestradiol dibenzoates were effective in reversing the effects of estradiol benzoate when the two steroids (estradiol benzoate and a bromoestrogen dibenzoate) were administered simultaneously during pretreatment. Thus, the bromoestrogens are able to inhibit the antidopaminergic effects of estradiol exhibited in the apomorphine-induced mouse climbing model.

Animals↗

PubMed1976

Effect of harmine and brain lesions on apomorphine induced motor activity.

Application of harmine (10 mg/kg IP) 30 min before apomorphine decreased the motoric effects of the latter. Following harmine an increase in 5-HT and a decrease in 5-HIAA in different brain regions have been found. Injection of 5,6-DHT into nucleus medianus raphe 7 days before the experiment caused a significant increase of the apomorphine effect. Harmine pretreatment reduced this escessive motility as well as additional lesion of the substantia nigra with 6-OH-DA. Lesion induced by 6-OH-DA alone was without significant effect on the hypermotility following apomorphine. Application of PCPA 3 days before testing elicited an increase of apomorphine-induced hypermotolity which could be abolished by preceding harmine application. The experiments demonstrate the inhibitory effect of the central serotoninergic system on the apomorphine syndrome as well as the serotoninergic-dopaminergic interaction in hypermotility.

5,6-Dihydroxytryptamine↗

PubMed1980

Reversal of stress-induced analgesia by apomorphine, but not by amphetamine.

Acute exposure to severe stressors induce profound analgesia as well as depleting catecholamine levels. The present study examined whether d-amphetamine and apomorphine, agents which increase catecholamine availability, would alter the analgesic effectiveness of cold-water swims (CWS) and 2-deoxy-D-glucose (2-DG) as measured by an operant liminal escape procedure. Two groups of 10 rats each were tested to determine alterations in liminal escape threshold functions following amphetamine at doses of 0.25, 0.5, 1, 2 mg/kg and following apomorphine at doses of 0.025, 0.05, 0.1, 0.2 mg/kg. Half of the amphetamine and half of the apomorphine groups were tested across their respective dose ranges for the drug effects upon CWS analgesia. The remaining animals in each group received 2-DG (600 mg/kg IP) alone followed by 2-DG paired with each stimulant dose. No dose of amphetamine or apomorphine alone altered escape thresholds. While amphetamine produced slight potentiations of 2-DG analgesia at the two low doses, apomorphine at the 0.05 and 0.1 mg/kg doses returned CWS and 2-DG analgesia to within normal placebo values. These results provide indirect evidence for a role for brain norepinephrine and dopamine in stress-induced analgesia, and these data are discussed with respect to catecholamine involvement in pain-inhibitory processes.

Animals↗

PubMed1980

Caffeine potentiation of apomorphine discrimination.

Rats were trained to discriminate between the stimulus properties of intraperitoneal 0.16 mg/kg apomorphine and saline in a two-lever, food-motivated operant task. Apomorphine, at doses different than the training dose, produced a dose-response relationship, whereas, caffeine (7.5-30 mg/kg) produced saline-like responding. However, co-administered of 15 mg/kg caffeine with 0.01, 0.02 or 0.04 mg/kg apomorphine potentiated the discriminative stimulus properties of these low apomorphine doses. This potentiation was antagonized by pretreatment with 0.25 mg/kg haloperidol. The results are consistent with the idea that caffeine, by virtue of being a phosphodiesterase inhibitor, may increase post-synaptic cyclic-AMP and this, in turn, may supersensitize the dopamine receptors and result in the potentiation of the apomorphine-induced dopaminergic responses.

Animals↗

PubMed1982

Analysis of the difference in the behavioral effects of apomorphine in C57BL/6 and DBA/2 mice.

The influence of pimozide on the effects of apomorphine on locomotor activity and stereotypy was studied in two inbred strains of mice. In C57BL/6 mice, in which apomorphine did not produce stereotypy of gnawing, the biphasic effect of apomorphine on locomotor activity (hypomotility followed by hypermotility) was unaffected by pimozide. In DBA/2 mice, in which high doses of apomorphine produce hypomotility and compulsive gnawing, both these effects (but not hypomotility produced by low doses of apomorphine) were counteracted by pimozide. The results are consistent with the assumption that both strains of mice have separate inhibitory and stimulatory dopamine receptors mediating locomotor activity. In addition, DBA/2 but not C57BL/6 mice have dopamine receptors which mediate stereotypy and are sensitive to pimozide.

Animals↗

PubMed1985

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline.

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.

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

PubMed1986

The effects of some atypical neuroleptics on apomorphine-induced behaviors as a measure of their relative potencies in blocking presynaptic versus postsynaptic dopamine receptors.

The effects of the atypical neuroleptics clozapine, thioridazine and sulpiride on behaviors induced by apomorphine were recorded, using a time-sampling observational paradigm. A low dose of apomorphine (0.1 mg/kg, SC) produced hypomotility. Of the neuroleptics tested, only sulpiride antagonized this hypomotility. Apomorphine in higher doses (0.2-1.0 mg/kg, SC) produced stereotyped behaviors (sniffing down and licking or gnawing). All three atypical neuroleptics antagonized stereotypy. The effects of sulpiride on apomorphine-induced hypomotility and stereotypy are consistent with the notion that this drug has strong presynaptic and weak postsynaptic blocking effects at dopamine receptors. The mechanisms of action of clozapine and thioridazine may be different from that of sulpiride. Perhaps the anticholinergic activities of these drugs mediate some of their behavioral effects. The effects of these atypical neuroleptics on apomorphine-induced stereotypy are opposite in direction to their effects on amphetamine-induced stereotypy, suggesting that these two behavioral patterns are not measures of the same neural process.

Amphetamine↗

PubMed1987

Electrophysiological correlates of stereotyped sniffing in rats injected with apomorphine.

Macroelectrodes were chronically implanted in the olfactory bulb, dorsal hippocampus, neocortex and under the mystacial pad in a group of rats. Recordings were taken during spontaneous behavior, during exploration of novel objects and odorous material, and during handling. Similar observations were made following injection of apomorphine (1.25-5 mg/kg, SC). The lower dose of apomorphine elicited a pattern of sniffing, olfactory bulb activity and vibrissal EMG which resembled closely the patterns observed in undrugged rats sniffing while in tactile contact with a novel object. However, unlike normal rats, the apomorphine-treated rats did not orient toward novel objects or odors. Apomorphine also elicited nearly continuous hippocampal rhythmical slow activity which occurred in correlation with head movements and locomotion. It is suggested that apomorphine elicits a motor pattern which resembles normal contact sniffing but which, unlike normal sniffing, is relatively impervious to control by visual and olfactory stimuli.

Animals↗

PubMed1988

Apomorphine and haloperidol, but not domperidone, affect penile reflexes in rats.

Previous studies have shown that systemic administration of the dopamine agonist apomorphine produced a biphasic effect on erection in the freely moving rat, with lower doses facilitating, and high doses inhibiting, erection. However, those studies did not distinguish between erection per se and seminal emission. The present results demonstrate that apomorphine produces a similar biphasic effect on penile reflexes in the restrained, supine rat, while facilitating seminal emission in a monophasic fashion. Haloperidol, a centrally-acting dopamine antagonist, either blocked the effects produced by apomorphine administration, or had actions opposite to those of apomorphine. Domperidone, a dopamine antagonist that does not readily penetrate the blood-brain barrier, did not antagonize apomorphine's effects, and did not affect penile responses when administered alone. These results suggest that dopamine receptors in the central nervous system regulate genital responses, and that effects on penile reflexes and seminal emission can be experimentally dissociated.

Animals↗

PubMed1988

Effects of pretreatment with luteinizing hormone releasing hormone (LHRH) on behaviors induced by apomorphine in rats.

The influence of LHRH on the behavioral effects induced by apomorphine (APO) was studied in male rats. Several doses of apomorphine (31.25, 62.5, 125, 250 and 500 micrograms/kg) were administered subcutaneously (SC) after LHRH 100 micrograms/kg or solvent. Low doses of apomorphine induced hypomotility and impaired acquisition of a conditioned avoidance response (CAR). High doses produced hypermotility, stereotyped sniffing and a short lasting increase, followed by a decrease in the acquisition of CARs. Pretreatment with LHRH potentiated the hypomotility induced by low doses of apomorphine (62.5 and 125 micrograms/kg) and the hypermotility, stereotyped sniffing and the enhancement in acquisition of CARs produced by higher doses of apomorphine (250 and 500 micrograms/kg). These findings suggest that LHRH could indirectly regulate dopamine activity through an increase in sensitivity of dopamine receptors (pre- and postsynaptic), which mediate the behavioral effects of APO. It is postulated that this hypersensitivity of DA receptors could be the consequence of an inhibition of presynaptic dopaminergic transmission, induced by LHRH.

Animals↗

PubMed1989

Independent effects of morphine and apomorphine on stereotyped gnawing in the hamster.

Eight experiments were conducted to investigate the effects of apomorphine, a dopaminergic agonist, and of morphine, an opiate, on stereotyped behavior in the hamster. Animals were observed at two minute intervals for one hour and incidents of stereotyped gnawing, licking and sniffing were recorded using a time-sampling method. Both morphine and apomorphine produced dose-related increases in stereotyped gnawing. A low dose of the opiate antagonist, naloxone (0.4 mg/kg), blocked morphine-induced gnawing but neither that dose nor higher doses of naloxone (1, 4 and 10 mg/kg) blocked apomorphine-induced gnawing. A low dose of the dopaminergic antagonist, haloperidol (0.05 mg/kg), blocked apomorphine-induced gnawing but did not block morphine-induced gnawing. Further experiments indicated that morphine administration did not sensitize, or influence in any way, subsequent apomorphine-induced stereotyped behavior.

Animals↗

PubMed1989

Breaking points on a progressive ratio schedule reinforced by intravenous apomorphine increase daily following 6-hydroxydopamine lesions of the nucleus accumbens.

It has been shown previously that 6-hydroxydopamine (6-OHDA)-induced lesions of the nucleus accumbens cause extinction of cocaine self-administration behavior, yet fail to affect the rate of apomorphine self-administration on a Fixed Ratio 1 schedule of reinforcement. Since the dopamine (DA) receptors in this nucleus should become supersensitive, and since these receptors are thought to mediate the reinforcing effects of apomorphine, then some change in apomorphine self-administration would be expected. We have therefore reinvestigated the effect of 6-OHDA lesions on apomorphine self-administration using a progressive ratio schedule of reinforcement. Rats were trained to self-administer apomorphine (0.033 mg/inj, IV) on a schedule in which the response requirements increased after each reinforcement. The breaking point was defined as the final ratio completed during each daily session. Sham lesions had no effect on the breaking points, and a steady increase in the breaking point was observed in the 6-OHDA-lesioned animals which may parallel the development of DA receptor supersensitivity.

Animals↗