Apomorphine In Rats Research Articles

Modulation of dopamine-mediated behavioural responses by antidepressants: Effects of single and repeated treatment

The study concerned the effects of maprotiline, imipramine, clomipramine and amitriptyline on the stereotype and turning behaviour induced by apomorphine in rats. At either single or repeated doses of 25 mg/kg i.p. neither maprotiline nor imipramine changed the stereotyped responses induced by apomorphine. Clomipramine showed in contrast an inhibitory effect which increased after 7 daily injections of the drug. Moderate suppression of stereotypies was also observed after repeated administration of amitriptyline. In rats with unilateral 6-OHDA lesions of the s.nigra apomorphine-induced contralateral turning was markedly (70%) after a single 25 mg/kg i.p. injection of maprotiline. A tolerance to this effect developed after 7 daily injections of the drug. Clomipramine and amitriptyline caused an inhibition of turning which was markedly increased after repeated treatment. These results suggest that antidepressants do not uniformly affect the behavioural responses mediated by dopamine. Clomipramine and amitriptyline appear to possess dopamine receptor blocking properties which may become more pronounced after chronic treatment. In contrast, the dopamine receptor blockade by maprotiline diminished and disappeared under such conditions. Among the drugs investigated imipramine was the one which seemed to have the weakest influence on dopaminergic receptors.

Role of pars compacta of the substantia nigra in circling behavior

The significance of pars compacta of the substantia nigra in the mediation of ci circling behavior was assessed by placing unilateral radio-frequency lesions in that neural region, in adjoining tegmental areas, or in the median raphe and adjacent reticular formation; additional ablations were made by infusing 8 μg/4 μl 6-hydroxydopamine (6-OHDA) into the ventral mesencephalon. Rotational behavior was recorded in a photocell apparatus during 15 min sessions. Precise and virtually complete lesions of pars compacta, as evidenced by histological and histochemical analyses, resulted in spontaneous contralateral circling for a postoperative period of 5 days. More vigorous and sustained contralateral rotations were observed in animals with lesions in the region of the median raphe. Other thermal or 6-OHDA mesencephalic lesions did not produce spontaneous circling. On postoperative days 9–23, the animals were administered in random sequence d-amphetamine (1.5 and 5.0 mg/kg) and apomorphine (1.0 mg/kg). At least 48 hr separated each drug test. Amphetamine (1) facilitated contralateral turning in animals with damage to the median raphe and adjacent regions but induced ipsilateral circling in animals sustaining variable degrees of pars compacta damage as a result of midbrain 6-OHDA injections, (2) produced ipsilateral turning in rats with lesions involving portions of pars compacta in addition to the medial lemniscus (at 1.5 but not 5.0 mg/kg drug), pars reticulata (at 5.0 but not 1.5 mg/kg drug), or the ventromedial tegmentum and, in some cases, subthalamic regions (at 5.0 but not 1.5 mg/kg drug), and (3) had no effect upon circling in animals with discrete pars compacta lesions in a dose of 1.5 mg/kg but produced ipsiversive circling after 5.0 mg/kg. Apomorphine did not elicit turning in animals with relatively precise lesions of pars compacta but did produce turning in experimental groups that sustained simultaneous damage to pars compacta and additional systems including portions of the ventromedial tegmentum, pars reticulata of the substantia nigra, or medial lemniscus. The contralateral turning induced by apomorphine in rats with 6-OHDA or radio-frequency lesions of the ventral mesencephalon suggests that mechanisms mediating this drug-induced behavior, although previously attributed almost exclusively to dysfunctions in nigral function, probably include systems involving extra-nigral regions as well. Coupling this consideration with the finding that lesions in the median raphe and contiguous areas elicited more intense circling than nigral ablations suggests that the role of pars compacta in rotational behavior may be less significant than previously believed.

Sleep induced by low doses of apomorphine in rats

The effect of apomorphine on the EEG of freely moving rats was studied. Apomorphine at the dose of 1 mg/kg caused stereotypy and a marked reduction of total sleep. On the contrary, acute subcutaneous administration of apomorphine at the dose of 100 μg/kg, or less, markedly increased the amount of total sleep (corresponding mostly to synchronized sleep). Moreover, the infusion of apomorphine (80 μg/kg/h) for 4 h doubled the duration of slow and REM sleep. The hypnotic effect of apomorphine was prevented by neuroleptics, such as pimozide, benzperidol and l-sulpiride, at doses which, per se, did not modify the EEG of the animals. These results suggest the existence in the CNS of DA receptors mediating sleep.

Rotometer for recording rotation in chemically or electrically stimulated rats

An improved rotometer is described which accurately records circling behavior (rotation) in rats with an imbalance of the nigrostriatal pathways. Results of circling induced by apomorphine in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra and circling elicited by electrical stimulation of the nigrostriatal pathway are presented.

Similarities and contrasts between the effects of amphetamine and apomorphine in rats chronically treated with haloperidol

1. 1. Following discontinuation of chronic haloperidol, rats exhibited an enhanced spontaneous locomotor activity and an enhancement in stereotypy and locomotor stimulation produced by amphetamine. 2. 2. Amphetamine stimulation in normal rats was blocked by the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine in a dose of 200 mg/kg, but this dose failed to block the amphetamine stimulation in haloperidol withdrawn rats. 3. 3. Locomotor stimulation or aggression caused by apomorphine was also enhanced during with-drawal from chronic haloperidol. In contrast to the effect of apomorphine, neither (+) nor (−) amphetamine was able to consistently produce aggression. 4. 4. These results support the previous evidence that supersensitivity of dopamine receptors develops following chronic blockade of those receptors by haloperidol, but also suggest that at specific brain areas, the haloperidol treatment may produce a long-lasting presynaptic change so that release of dopamine by amphetamine is inhibited.

Effects of 5-hydroxytryptophan, oxotermorine, and tetrahydroaminoacridine on apomorphine-induced stereotypy.

The stereotyped behavior induced by apomorphine in rats was inhibited by oxotremorine and tetrahydroaminoacridine (THA). 5-Hydroxytryptophan (5-HTP) did not change stereotypy scores. These data show influence of cholinergic mechanisms on such behavior. Possible clinical applications are discussed.

The effect of LSD and 2-bromo LSD on the striatal DOPA accumulation after decarboxylase inhibition in rats

LSD and BOL (0.125–0.5 mg/kg) were equipotent in increasing the in vivo tyrosine hydroxylation in the striatum as measured by the accumulation of DOPA after inhibition of neuronal decarboxylase. However, with 2–4 mg/kg doses, the maximum effect of BOL was larger than that of LSD. LSD and BOL antagonized the apomorphine-induced decrease of DOPA accumulation, without affecting the haloperidol-induced increase. LSD like apomorphine inhibited the increase of DOPA accumulation seen after reserpine, cerebral hemisection and after γ-butyrolactone (GBL). The effect of apomorphine in rats given GBL was blocked by haloperidol, but not by BOL and promethazine, whereas that of LSD was inhibited by haloperidol, BOL, and promethazine. These findings suggest that LSD and BOL directly affect nigro-neostriatal dopamine neurons. LSD therefore appears to be a partial agonist and BOL a pure autoreceptors. It is proposed in addition that LSD activates and BOL blocks 5-HT receptors that control DOPA formation.

Animal models for tardive dyskinesia: effects of thioridazine.

After repeated administration of classical neuroloptics to the rat, supersensitivity of striatal dopamine (DA) receptors towards DA-receptor agonists can be demonstrated. This effect can be quantified (a) by measuring the turning response to apomorphine in rats with unilateral striatal lesions or (b) by measuring the changes induced by neuroleptics in the DA metabolism in the striatum of intact rats. In these test systems, thioridazine induces an increase in DA-receptor sensitivity which is significantly less intense and of shorter duration than that induced by haloperidol. The tendency of a drug to increase DA-receptor sensitivity has been related to its propensity to induce tardive dyskinesia in man, and on this basis it may be expected that tardive dyskinesias following treatment with thioridazine will be rare and less intense than those seen after classical neuroleptics.

Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats.

Rats learned to press a lever for intravenous injections of amphetamine or apomorphine. They also learned to avoid the taste of saccharin which was associated with experimenter-administered amphetamine or with self-administered apomorphine. Thus these, and presumably other, self-administered drugs serve as compound pharmacological stimuli, having both positively reinforcing and aversive properties.

The interaction of neuroleptic and muscarinic agents with central dopaminergic systems.

1. The effect of muscarinic and neuroleptic agents on the turning behaviour induced by methamphetamine and apomorphine in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine has been examined. 2. Turning towards the side of the lesion induced by (+)-methamphetamine (5 mg/kg) was inhibited by alpha-flupenthixol (1 mg/kg) and alpha-clopenthixol (8 mg/kg) but not by high doses of their beta-isomers. 3. Turning was inhibited by chlorpromazine (4 mg/kg) and pimozide (0.2 mg/kg). Thioridazine and clozapine (16 mg/kg) were ineffective. Turning in the same direction produced by scopolamine (10 mg/kg) was also inhibited by alpha-flupenthixol (1 mg/kg) and pimozide (0.25 mg/kg). 4. Turning produced by methamphetamine (5 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) even in the presence of methylatropine (5 mg/kg). 5. Turning away from the side of the lesion induced by apomorphine (0.1 mg/kg) was inhibited by oxotremorine (0.75 mg/kg) but not by thioridazine or clozapine (16 mg/kg). 6. These results are discussed with regard to the mode of action of neuroleptic drugs in producing anti-psychotic effects and drug-induced Parkinsonism.

Biochemical and behavioral antagonism between fenfluramine and apomorphine in rats

Pretreatment witn apomorphine markedly antagonized the increase of striatal homovanillic acid induced by fenfluramine. In contrast, the effect of amphetamine on honovanillic acid was not affected by apomorphine pretreatment. Fenfluramine significantly reduced the apomorphine stereotypy in a dose-dependent manner. It is suggested that fenfluramine acts on striatal dopamine by a mechanisms similar to that of neuroleptics.

Influence of midbrain raphe lession on some pharmacological and biochemical effects of apomorphine in rats.

The influence of apomorphine on body temperature, motor activity and forebrain content of serotonin and 5-hydroxyindoleacetic acid in midbrain raphe lesioned rats was investigated. Apomorphine elevates the brain concentration of serotonin and its metabolite and promotes hypothermia in normal and in sham-lesioned rats but it does not produce these biochemical effects and attenuates hypothermia in rats with lesions of the midbrain raphe nuclei. In the lesioned subjects apomorphine stimulates the locomotor activity more strongly. The results confirm the previously expressed hypothesis concerning the role of serotonin in the locomotor stimulation and hypothermia induced by apomorphine in rats.

Effect of clonidine on the 5-hydroxytryptamine and 5-hydroxyindoleacetic acid brain levels

The effects of clonidine on the brain levels of 5-HT and 5-HIAA in rats and mice were studied. Clonidine did not change the levels of 5-HT and 5-HIAA in the whole brains of either animal species but the 5-HT concentrations were elevated in rat brain pons + medulla oblongata. Clonidine antagonized the increase in the brain 5-HIAA levels induced by apomorphine in rats and mice. The decrease in the 5-HT level and the increase in the 5-HIAA level observed in rats after L-dopa (given with peripheral decarboxylase inhibitor RO 4-4602) were counteracted by clonidine.

Biological Disposition of Apomorphine II: Urinary Excretion and Organ Distribution of Apomorphine

A method for estimation of free and “bound” apomorphine in biologic media is described. Apomorphine, after parenteral administration to different animal species, is biotransformed and excreted in urine largely in its “bound” form. Studies on the organ-distribution of injected apomorphine in rats revealed a localization of “bound” apomorphine in the liver.