High Dose Of Apomorphine Research Articles

Injection of low doses of apomorphine into the nucleus accumbens of rats reduces locomotor activity

Low doses of apomorphine (1–100 ng) injected into the nucleus accumbens of rats decreased locomotor activity and rearing when the animals were tested in a novel test cage. Higher doses of apomorphine appeared to be less effective in this respect. It is suggested that tje hypo-activity induced by intra-accumbens apomorphine injection is mediated by dopamine receptors located at presynaptic elements of the mesolimbic dopaminergic system.

Time-related effects of apomorphine on noradrenaline metabolism and their regional differences in rat brain.

In the whole brain of rats, apomorphine in doses of 5-10 mg/kg elevated noradrenaline (NA) level 10-20 min after s.c. injection, but reduced NA level 60-90 min after injection in doses of 2-10 mg/kg associated with increased level of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4). With 5 mg/kg of apomorphine, NA content in the pons+medulla oblongata and midbrain showed biphasic changes as seen in the whole brain, whereas NA content increased in the cerebral cortex and hippocampus after 10-20 min, and decreased in the hypothalamus and amygdala after 60 min. Apomorphine in 0.1-0.2 mg/kg did not cause marked changes in brain NA metabolism. These results show that high doses of apomorphine which stimulate postsynaptic dopamine receptors have variable effects on noradrenergic neurons depending upon the time after injection and the brain region under investigation.

Antidepressant action of lithium: Proposed mechanism based upon behavioral analysis in the mouse

1. 1. Mice receiving lithium carbonate (1.5 or 3 mg/ml) in their drinking water for a duration of 7 to 10 days were examined on a battery of psychopharmacological tests. 2. 2. The well-known learned aversion of rats for lithium was confirmed in mice and the increase in body weight was reduced by lithium. These two effects were concentration-dependent. 3. 3. Lithium partly antagonized the hypothermia induced by reserpine, oxotremorine, or a high dose of apomorphine. 4. 4. As this antagonistic effect is also shared by the tricyclic or MAOI antidepressants as well as by beta-adrenergic stimulants, it is suggested that lithium could act as an anti-depressant by increasing the release of noradrenaline.

Effects of the potential neuroleptic peptide des-tyrosine 1-γ-endorphin and haloperidol on apomorphine-induced behavioural syndromes in rats and mice

The effects of haloperidol and Des-Tyr 1-γ-endorphin (DTγE) were studied on climbing induced in mice by high doses of apomorphine and on the yawning syndrome induced in rats by low doses of apomorphine. Haloperidol in a dose of 0.0046 mg/kg s.c. potentiated climbing whereas at higher doses climbing was inhibited (ED 50=0.03 mg/kg). DTγE had no effect on climbing under normal conditions in doses up to 2 mg/kg s.c.. After three days of handling and saline pre-injections DTγE potentiated climbing in doses from 0.1 to 1 mg/kg. Haloperidol inhibited yawning induced by low doses of apomorphine (ED 50=0.01 mg/kg). DTγE, on the other hand, potentiated yawning induced by low apomorphine at doses of 0.02 and 0.04 mg/kg s.c.. From the point of view that low doses of apomorphine predominantly activate presynaptic dopamine autoreceptors while higher doses predominantly activate postsynaptic dopamine receptors the following tentative conclusions are drawn. 1) Haloperidol blocks presynaptic dopamine autoreceptors at low doses and postsynaptic dopamine receptors at higher doses. 2) DTγE sensitizes presynaptic dopamine autoreceptors at low doses, thereby strengthening the local feedback mechanism at the dopaminergic nerve ending, and sensitizes postsynaptic dopamine receptors at higher doses.

Evidence for the role of noradrenaline in some effects of quipazine.

In mice, quipazine has shown several behavioral effects: It antagonizes hypothermia induced by a high dose of apomorphine without altering climbing or stereotyped behavior; it antagonizes oxotremorine-induced hypothermia without altering tremors or peripheral signs; and it increases the toxicity of yohimbine. These three responses are considered to be predictive of an antidepressive action; in these three tests the effects of quipazine are inhibited by D,L-propranolol but not by D-propranolol or methysergide. Quipazine, in mice pretreated with pargyline, induced head twitches which were inhibited by methysergide but not by D,L-propranolol. Quipazine, in addition to its well-known serotonergic effects, seems to have beta-adrenergic properties which should be kept in mind when this drug is used as a pharmacological tool and which suggest that the beta-adrenergic system is implied in depression.

Imipramine antagonism of apomorphine-induced hypothermia: A non-dopaminergic interaction

Imipramine antagonized high dose apomorphine-induced hypothermia, and did not modify small dose apomorphine-induced hypothermia. It is suggested that apomorphine-induced hypothermia is the result of two effects. The first, induced by small doses of apomorphine, and antagonized by pimozide and sulpiride, is probably related to dopaminergic receptor stimulation. The second, induced by high doses of apomorphine, and antagonized by imipramine, is probably not related to dopaminergic receptor stimulation.

Effects of apomorphine and haloperidol on exploratory behavior and latent learning in mice

In order to characterize the behavioral effects produced by drug-induced changes in central dopamine neurotransmission, the behavior of mice was studied in a maze. The animals were given haloperidol (0.2 mg/kg, IP), apomorphine (0.1–3.2 mg/kg, IP), or solvent vehicle, during a 30- and 10-min time of preexposure to the maze, respectively, and their exploratory activity was recorded. The ability of these animals to find food in the same maze was later (+24 h) compared with the performance of a group not previously exposed to the maze (naive). In comparison with naive animals, untreated mice preexposed to the maze displayed a more efficient performance (latent learning) when trained to find food in the maze. It was found that haloperidol (0.2 mg/kg) or apomorphine (0.1–0.8 mg/kg) significantly suppressed the exploratory behavior of the animals during the time of preexposure. However, animals thus treated learned the maze 24 h later as rapidly as animals treated with solvent vehicle. Higher doses of apomorphine (1.6–3.2 mg/kg) also produced a suppression of exploratory behavior similar to that seen after its administration at lower doses, or after treatment with haloperidol; however, these animals did not display latent learning 24 h later.

Evidence for increased apomorphine-sensitive dopaminergic effects after acute treatment with morphine

Apomorphine in a very small non-stimulant dose 0.05 mg/kg s.c. antagonized the locomotor stimulant effect of morphine (50 mg/kg) in mice. Apomorphine (0.05 mg/kg) antagonized also the locomotor stimulant effect of a single low dose of morphine (2 mg/kg) in the rat as well as “the late stimulatory effect” seen after a higher dose of morphine (10 or 20 mg/kg). The pretreatment with morphine in increasing doses induced an increasing degree of potentiation of stereotyped behavior induced by high doses of apomorphine (0.5 and 2 mg/kg s.c.) in the rat. The apomorphine stereotyped biting/gnawing activity was found strongly increased by morphine (10–50 mg/kg) during the time interval where morphine given alone induced catalepsy. Our results indicate that the acute treatment with morphine may induce an increase of apomorphine sensitive dopaminergic mechanisms. The inhibitory effect by a very small dose of apomorphine (0.05 mg/kg) of morphine stimulation may be due to a presynaptic dopamine receptor stimulant effect of apomorphine. The antagonism by the serotonin antagonist methergoline of morphine catalepsy and the increase by this drug of “the late morphine excitation” indicate in addition a role of a serotonergic mechanism.

The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain

The importance of extrapyramidal and mesolimbic function for circling behaviour was investigated by placing 6-hydroxydopamine (6-OHDA) and electrolesions in the cell bodies, axons and terminals of each system. Circling behaviour was weak when 6-OHDA was placed at the centre of the substantia nigra (SN), but the characteristic contralateral/ipsilateral turning to apomorphine/amphetamine were recorded. Circling was more marked when 6-OHDA was placed anterior to the SN but was generally absent following injections posterior to the SN. However, 6-OHDA placed in the medial forebrain bundle in the lateral hypothalamus resulted in intense contralateral/ipsilateral turning to apomorphine/amphetamine. Generally, the intensity of circling responses was related to the degree of striatal dopamine (DA) depletion but the more effective lesions also caused reductions in mesolimbic DA content. However, circling was not observed following any 6-OHDA injection into the mesolimbic DA system and it is concluded that mesolimbic DA function is not essential for the initiation of circling. In contrast to the 6-OHDA lesions, rats circled ipsilateral to both apomorphine and amphetamine when the SN was damaged by electrocoagulation to cause marked depletion of striatal dopamine. Lesser depletions of striatal dopamine after electrocoagulation in different regions of the medial forebrain bundle were associated with a lower intensity of ipsilateral circling to both drugs. In general, the differences between 6-OHDA and electrolesions could not be explained by additional damage to ascending noradrenaline or 5-hydroxytryptamine pathways. Lower doses of apomorphine were effective in the 6-OHDA circling rats, and the ipsilateral striatum of such rats was more sensitive to directly applied DA. Higher doses of apomorphine were required to produce circling after chronic electrolesions which rendered the ipsilateral striatum insensitive to DA. The contralateral circling to apomorphine after 6-OHDA lesions was abolished by chronic but not by acute electrolesion of the SN. It is suggested that electrolesions of the SN cause different effects to 6-OHDA because they destroy neuronal pathways in addition to the dopaminergic nigrostriatal tract. These appear to be required for the expression of circling behaviour caused by stimulation of the denervated striatum. Whereas 6-OHDA lesions result in supersensitivity of the denervated striatal DA receptors, electrolesions may cause a hyposensitivity of the same receptor sites.

Brain dopamine receptors and sleep in the rat: Effects of stimulation and blockade

A high dose of apomorphine, a stimulator of brain dopamine receptors, caused a reduction in total sleep, intermediate sleep and a delayed appearance of paradoxical sleep. With a lower dose, a small and not significant trend toward an increase of paradoxical sleep was observed. Spiroperidol, considered as a specific blocker of dopamine receptors, produced a dose-dependent increase of total sleep and a decrease of paradoxical sleep. Chlorpromazine induced a different effect, that is clear enhancement of paradoxical sleep. Taken together, these results indicate that an activation of dopamine systems in the brain is partly involved not only in behavioral activation, but also in corticl activation of waking and paradoxical sleep. The effect of chlorpromazine on paradoxical sleep cannot be attributed to the antidopaminergic properties of this drug.

Catecholamine receptor agonists

Motor activity during the first 5 min in a motility meter was measured in mice given 0.025-3.2 mg/kg of the dopamine and noradrenaline receptor agonists apomorphine and clonidine, respectively. The accumulation of Dopa, as induced by the inhibitor of aromatic amino acid decarboxylase, NSD 1015, was measured in parallel in two dopamine-rich regions, i.e. the limbic system and the corpus striatum, and in two noradrenaline-rich regions, i.e. the neocortex and the lower brain stem. Low doses (0.025-0.2 mg/kg) of apomorphine reduced locomotion in a dose-dependent manner, while the reduction after higher doses was less pronounced, indicating a biphasic dose-response relationship. Clonidine caused a dose-dependent locomotor depression. When low doses of the two drugs were combined, the inhibitory effect observed was at least additive. When clonidine was combined with a high dose of apomorphine (0.8 mg/kg), it caused a significant inhibition of locomotion in a dose of 0.1-0.2 mg/kg, but not after 0.8 mg/kg, indicating a biphasic dose-response relationship. Either drug given alone reduced Dopa accumulation after inhibition of its decarboxylation, in all regions, but smaller doses of apomorphine had a clearcut effect only in the dopamine-rich regions, whereas the lowest dose of clonidine investigated (0.05 mg/kg) had an inhibitory effect on Dopa formation only in the neocortex. The relationship between the dose of apomorphine and Dopa formation in the neocortex appeared biphasic, the highest dose (3.2 mg/kg) having no significant effect. Further, apomorphine in this dose accelerated the disappearance of noradrenaline after inhibition of synthesis by alpha-methyltyrosine. Reversal of reserpine-induced suppression of motor activity was taken to indicate postsynaptic receptor activation. The threshold dose of apomorphine causing reversal was 0.2 mg/kg. The inhibitory effect of e.g. 0.05 mg/kg on locomotion and on Dopa formation suggests a preferential activation of inhibitory autoregulatory dopamine receptors by low doses of this drug. A similar trend was observed for clonidine. The basal importance of dopamine neurones for the locomotor function studied in the present paper is illustrated by the marked inhibition by low doses of apomorphine. On the other hand, the observations with clonidine suggest a somewhat less striking and perhaps less direct influence of noradrenaline neurones on motor activity. Mice with a low motor activity, as induced e.g. by reserpine or, in another experiment, mice adapted to the motility meter, displayed an increased motor activity after higher doses of apomorphine (from 0.2 and 2 mg/kg, respectively), whereas all doses depressed the initial high motor activity. Probably, high motor activity requires active dopamine neurones, making this behaviour more susceptible to interference with autoregulatory mechanisms, whereas a low basal activity may be more affected by activation of postsynaptic dopamine receptors.

Activity of the nigro-striatal dopaminergic system during precipitated morphine withdrawal investigated in rats with acute unilateral inactivation of the striatum

The activity of the striatal dopamine system during precipitated morphine withdrawl was studied in rats using a model in which the striatum was unilaterally inactivated by the local injection of KCl. In naive rats dopamine agonists administered just prior to KCL induced ipsilateral turning or circling, while dopamine antagonists in the same situation caused contralateral turning. Withdrawal precipitated by morphine antagonists in rats made dependent by repeated implantation of morphine pellets induced contralateral circling during unilateral inactivation of the striatum. This contralateral circling was only slightly enhanced by haloperidol, but strongly enhanced by a low dosage of apomorphine as well as by some weak dopamine agonists such as CB 154 or By 101. However, high doses of apomorphine completely reversed the withdrawal-induced contralateral circling into ipsilateral circling. Other dopamine agonists, such as d-amphetamine, L-Dopa and piribedil, did not abolish the withdrawal-induced contralateral circling, however, they caused the appearance of an additional ipsilateral circling. Other types of drugs which are known to intensify withdrawal-induced jumping (desipramine, atropine, caffeine) enhanced contralateral circling. There are also other parallels jumping and contralateral circling induced by withdrawal. The direction of naloxone-induced asymmetric behaviour during acute unilateral inactivation of the striatum suggests that striatal dopaminergic activity is reduced during precipitated withdrawal; the other results reported point to the possiblity that extrastriatal dopaminergic mechanisms or different dopamine receptor types within the striatum are involved.