Effect of destruction of midbrain raphe nuclei on the behavioral effects of dopaminergic substances and I-tryptophan

In experiments on male albino rats, after electrolytic lesions of dorsal and median mesencephalic raphe nuclei, l-DOPA and apomorphine did not exert their stimulating effect on aggressiveness and emotional reactivity, seen in control false-operated animals. The inhibitory effect of haloperidol on emotional reactivity increased after raphectomy. The stereotype behaviour elicited by dopaminergic agents and their effects on exploratory motor activity were not changed by raphectomy. It is assumed that the effects of dopamino-potentiating agents on emotional reactivity are partly mediated by their influence on serotonergic system.     

Role of serotonin2 receptors in regulating aggressive behavior

Quipazine and pirenperone , the drugs interacting with serotonin2 -receptors, more readily displaced 3H-spiroperidol from its binding sites in the frontal cortex than in the striatum. Pirenperone (0,07-0,3 mg/kg), antagonist of serotonin2 -receptors, selectively decreased the intensity of apomorphine aggressiveness. The antiaggressive action of haloperidol (0,01-0,2 mg/kg) was in correlation with its antistereotypic activity. Long-term administration of naloxone (0,5; 15,0 mg/kg), together with apomorphine (0,5 mg/kg) reduced the number of head-twitches caused by quipazine (2,5 mg/kg). The administration of quipazine 48 hours after the last injection of naloxone and apomorphine caused spontaneous aggressiveness that did not differ from apomorphine aggressiveness. Intracerebroventricular injection of cholecystokinin tetrapeptide (CCK-4) markedly enhanced the foot-shock aggression. The same dose of CCK-4 also decreased the intensity of quipazine (2,5 mg/kg) head-twitches. Compared to haloperidol, pirenperone was a more selective antagonist of CCK-4. After long-term apomorphine treatment (0,5 mg/kg during 10 days, twice daily), the effect of CCK-4 on aggressive behaviour was markedly enhanced. It is possible that two subtypes of serotonin2 -receptors exist in the brain and have opposite action on the aggressive behaviour. CCK-4 may play the role of an endogenous modulator of sensitivity of serotonin2 -receptors involved in the control of aggressiveness.     

The effect of adren- and serotoninergic substances on the behavior of amygdalectomized rats and on the aggressiveness evoked by intra-amygdaloid administration of acetylcholine]

The effect of serotoninergic (serotonin, 1-trytophane, imipramime, methysergide), catecholaminergic (noradrenaline, amphetamine, dopamine, 1-DOPA, iproniazid) and cholinergic drugs (physostigmine, atropine, benactyzine) on emotional reactions and orienting-motor activity, as well as the effect of these drugs on shock-elicited aggressiveness enhanced by intraamygdaloid microinjection of acetylcholine was investigated in experiments on amygdalectomized male albino rats. In amygdalectomized animals, as compared to control false-operated rats, the stimulating effect of amphetamine, imipramine, tryptophane and m-cholinoblockators was enhanced and their inhibitory effect was weakened. Bilateral microinjection of cholinergic drugs (acetylcholine, physostigmine and carbacholine) and noradrenaline into the amygdaloid body intensified emotional reactivity and aggressiveness. Microinjection of serotonin and dopamine inhibited aggressiveness and caused facilitaion of orienting-motor activity. It is suggested that the adrenergic system intensifies and serotoninergic system depresses the m-cholinergic trigger mechanism of aggressive behavior in limbico-diencephalic structures.     

The role of the dopamine and noradrenaline systems in regulating autogenic motor activity in rat pups

In experiments on 3-day rat puppies, studies have been made of the effect of a stimulator of noradrenaline receptors--clonidine, and a stimulator of dopamine receptors--apomorphine on autogenic motor activity. It was shown that clonidine injections result in a significant increase of this activity, whereas apomorphine slightly decreases the latter. The data obtained in the present work together with those described earlier for l-DOPA effects, suggest that double regulation of autogenic activity is realized at early stages of ontogenesis. This regulation includes excitatory noradrenergic mechanisms and inhibitory influences which are mediated presumably by dopaminergic systems of the brain.     

Central effects of the tetrapeptide tuftsin

Under systemic administration tuftsin produces a marked influence on behavior and emotional reactivity in rats: enhances motor (vertical) activity, perception of pain stimulation and related aggressiveness and residual excitation. Activating effect is accompanied by an aggravation of the acquisition of passive avoidance reaction during single reinforcement. In vitro experiments revealed a direct inhibitory effect of tuftsin on the reaction rate of brain tyrosine hydroxylase activity. In vivo there was shown an increase in hypothalamic and especially striatal tyrosine hydroxylase activity. The data obtained indicate direct relationships between tuftsin central effects and the changes in brain catecholaminergic processes participating in the regulation of emotional-motivational and motor reactions.     

Genetical aspects of hormonal modification of the stress reactivity. II. Modification in early ontogenesis of the stress reactivity of adult gray rats selected for behavior toward man

Inherited and modificational changes of the stress reactivity in two outbreed stocks of wild Norway rats trapped in nature and selected for behaviour were studied. During 18 generations the rats of one stock were selected for the lack of defensive behaviour in the glove test (tame), while in another stock the aggressiveness was maintained by the selection (aggressive). Interstock differences in the brain noradrenaline mechanisms were observed. The emotional stress reactivity of the tame animals was decreased, in comparison with the aggressive ones. Definitive stress reactivity of adult rats was modified by injections of hydrocortisone to their mothers on the 16 and 18 days of gestation. Hormonal treatment changed noradrenaline mechanisms and decreased the reaction to emotional stressor in aggressive rats. The modified level of the stress reactivity of aggressive rats was similar to the definitive level of the tame ones. Hormonal treatment did not modify stress reactivity in tame rats. Thus, the phenotype only emerging in aggressive rats, as a result of hormonal modification, is the inherited norm of the tame animals. However, due to rat selection for the lack of defensive behaviour towards the man, high corticosteroid level in the blood of pregnant females, an external developmental factor, in respect to the fetus, loses regulatory function during the development of the neuroendocrine mechanisms of the stress reaction.     

The influence of 1-DOPA on emotional responses and serotonin metabolism in the rat brain]

Experiments were conducted on male Wistar rats. Intraperitoneal injection of 1-DOPA (.100 - 200 mg/kg increased the brain concentration of dopamine and homovanilinic acid and lowered the level of brain serotonin, with simultaneous elevation of its metabolite 5-HIAA. A decrease in serotonin level was accompanied by increased emotional reactivity and agressiveness in rats. L-DOPA (100 mg/kg) decreased the binding of serotonin formed from tryptophane (100 mg/kg), accelerating its catabolism in the brain; at the same time 1-DOPA eliminated the depressive action of tryptophane on the emotional reactivity and aggressiveness. It is supposed that increased emotional excitation elicited by 1-DOPA was partially mediated through the block of the serotoninergic system.     

Effect of chronic administration of lithium chloride on the development of dopamine receptor sensitivity during morphine withdrawal in rats

The morphine withdrawal syndrome was studied in male Wistar rats. Spontaneous aggressiveness, enhanced apomorphine aggressiveness, lowered pain threshold and decreased dopamine turnover were observed after withdrawal of 10-day treatment with the increasing doses of morphine (30-300 mg/kg). These changes attested to the increased sensitivity of dopamine receptors. Administration of morphine in conjunction with lithium chloride in a dose of 2 mekv/kg prevented the development of dopamine receptor hypersensitivity. Also, this method did not produce the increased spontaneous and apomorphine aggressiveness or the decreased dopamine turnover. Meanwhile the pain threshold remained lowered.     

Differentiation in brain and liver DOPA/5HTP decarboxylase activity after L-DOPA administration with or without pyridoxine in cats.

Abstract— Pyridoxine (50mg/kg, per os) given for 7 consecutive days did not modify the content of dopamine, noradrenaline, and serotonin in the neostriatum of the brain 3, 6 and 18 h after the last dose, but significantly increased DOPA/5HTP decarboxylase activity in both the neostriatum and liver. The administration of l-DOPA and pyridoxine (100 and 50mg/kg, per os, respectively) together for 7 days increased DOPA/5HTP decarboxylase activity in the brain to the same extent as did l-DOPA and pyridoxine given individually. Liver DOPA/5HTP decarboxylase activity remained normal when both drugs were administered together. However it decreased significantly after l-DOPA administration for 7 days but not after pyridoxine treatment. In cats under treatment with l-DOPA for 7 days, actinomycin D given for the final 3 days prevented the increased DOPA/5HTP decarboxylase activity induced by l-DOPA in the neostriatum and mesencephalon but had no effect on the enzymatic activity in the liver. These findings indicate that differences exist between brain and liver DOPA/SHTP decarboxylase activity in uivo. In addition, denatured supernatant from livers of animals treated with l-DOPA contained a dialysable compound which inhibits DOPA/SHTP decarboxylase activity in the supernatant from livers of untreated cats. In animals who received pyridoxine along with l-DOPA, no such inhibitor was found. These results may explain the mechanism by which l-DOPA exerts its beneficial effects and why pyridoxine administered with l-DOPA reduces the therapeutic effectiveness of l-DOPA in Parkinson's disease. These findings are consistent with the possibility that a tetrahydro-isoquinoline derivative formed in vivo in the liver after l-DOPA therapy for 7 days might affect DOPA/5HTP decarboxylase activity in the liver but not in brain. A tetrahydroisoquinoline derivative did not appear to be formed when l-DOPA and pyridoxine were administrated together suggesting that pyridoxine protected the enzyme and favored a more rapid degradation of l-DOPA peripherally with less l-DOPA available for the CNS.     

Effect of endogenous oligopeptides and brain-specific proteins on aggressive behavior in the rat

In experiments on non-bred males of white rats, the effect was studied on their aggressive behaviour of intraventricular injections of brain-specific proteins of S-100 group, gamma-globuline fraction from the serum of rabbits immunized by proteines S-100 (gamma S-100) and non-immunized rabbits (gamma-SNK) as well as of angiotensin, bradikinin and saline. S-100 lowered intermales aggressivity and that connected with pain, and had phasic inhibitory effects on rats emotional reactivity. gamma S-100 increased the aggressivity connected with pain, did not affect the intermales aggressivity and phasically raised (as well as gamma-SNK) the emotional reactivity. gamma-SNK, angiotensin and bradikinin did not change these kinds of aggressivity. None of the administered agents influenced the level of rats predetary aggressivity.     

Microwave-induced stimulation of l-DOPA,phenolics and antioxidant activity in fava bean (Vicia faba) for Parkinson’s diet

Fava bean sprouts are rich in levo-dihydroxy phenylalanine (l-DOPA), the precursor of dopamine, and are being investigated for use in the management of Parkinson’s disease. The phytopharmaceutical value was improved during germination by a microwave treatment of the seeds, the phenolic content of the germinated sprouts increasing 700% and l-DOPA content by 59% compared to control. A higher antioxidant activity that was observed correlated with total phenolics and l-DOPA contents. The glucose-6-phosphate dehydrogenase activity peaked on the seventh day of germination with a concurrent increase in phenolics indicating enhanced mobilization of carbohydrates. A higher guaiacol peroxidase activity was observed indicating an increased polymerization of phenolics. The elevated superoxide dismutase activity was proportional to the stimulation of antioxidant activity. The major implication from this study is that microwave treatment can significantly stimulate the phenolic antioxidant activity and Parkinson’s relevant l-DOPA content of fava beans sprouts.     

INHIBITION OF CATALASE IN MESENCEPHALIC CULTURES BY l-DOPA AND DOPAMINE

Catalase activity in cell cultures of fetal rat mesencephalon was decreased by 42 and 50%, respectively, after exposure to l-3,4-dihydroxyphenylalanine (l-DOPA, 100 μM) or dopamine (100 μM) for 48 h. Catalase activity was also decreased 21% by 10 μM hydroquinone. Ascorbic acid (200 μM), an agent that suppresses the autoxidation of l-DOPA and dopamine, blocked the anti-catalase effect of l-DOPA, but not that of dopamine. Inhibitors of the A and B forms of monoamine oxidase (20 μM clorgyline plus 20 μM pargyline) had no effect on the anti-catalase action of either l-DOPA or dopamine. The latter results suggest that products of the oxidative deamination of dopamine by monoamine oxidase are not involved in the suppression of catalase activity. However, autoxidation reactions of l-DOPA may play a role since ascorbate suppressed the anti-catalase effect of l-DOPA. On the contrary, the basis for the failure of ascorbate to similarly block the anti-catalase effect of dopamine is uncertain. l-DOPA and dopamine (25 μM) also inhibited crystalline catalase in solution after incubation for 1 h at neutral pH (40–50% inhibition). Inhibition was blocked by 0.45 M ethanol, indicating a need for autoxidation and the formation of compound II, which is an enzymatically inactive form of catalase. The ability to model the enzyme inhibition in purely chemical experiments indicates a probable mechanism for loss of enzymatic activity in cell cultures. Inhibition of catalase may contribute to cell damage during incubation of cultures with l-DOPA, dopamine, or other autoxidizable compounds. Copyright © 1996 Elsevier Science Ltd     

L-pyroglutamyl-D-alanine amide normalizes the function of the developing brain damaged by antenatal alcoholization in rats

The effects of the synthetic dipeptide, L-pyroglutamyl-D-alaninamide (LPDA) were studied in the experiments on offspring of alcoholized during the pregnancy (5 g/kg/day) females. This dipeptide, which revealed the nootropic activity in previous experiments, was injected to the pups in dose of 1 mg/kg from 8 to 19 days of life. LPDA was shown to prevent the delayed disturbances of learning in passive avoidance test, of extrapolatory behaviour in escape test, to attenuate the emotional hyperreactivity. LPDA normalized EEG power spectrum, decreased interhemispheric asymmetry. This substance attenuated the disbalance evoked by prenatal alcoholization.     

Catecholaminergic component of the action of a heptapeptide analog of ACTH4-10 on the open-field behavior of rats

Heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro (ACTH4-10 analog) at a dose of 0.015 mg/kg failed to alter open field behaviour of rats in the first test series. The peptide abolished amphetamine-induced stimulation of the exploratory and grooming behaviour. Extinction of the rats' exploratory behaviour during second test series in the open field (7 days later) was disturbed when haloperidol or apomorphine were injected before the first test series. When the peptide was administered with haloperidol or apomorphine, the extinction tended to become normal. Heptapeptide failed to change noradrenaline, dopamine or 5-hydroxytryptamine content in the rat forebrain. However, this peptide at a concentration of 10(-4) M moderately diminished tyrosine hydroxylation velocity in the rat striatal or hypothalamic synaptosomes, the effect depending on tyrosine concentration. These data suggest the involvement of catecholaminergic component into the heptapeptide action on the behaviour of rats.     

Dopamine depletion and subsequent treatment with L-DOPA, but not the long-lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum

Dysregulation of signaling pathways is believed to contribute to Parkinson's disease pathology and l-DOPA-induced motor complications. Long-lived dopamine (DA) agonists are less likely to cause motor complications by virtue of continuous stimulation of DA receptors. In this study, we compared the effects of the unilateral 6-hydroxydopamine lesion and subsequent treatment with l-DOPA and DA agonist pergolide on signaling pathways in rats. Pergolide caused less pronounced behavioral sensitization than l-DOPA (25 mg/kg, i.p., 10 days), particularly at lower dose (0.5 and 0.25 mg/kg, i.p.). Pergolide, but not l-DOPA, reversed lesion-induced up-regulation of preproenkephalin and did not up-regulate preprodynorphine or DA D3 receptor in the lesioned hemisphere. Pergolide was as effective as l-DOPA in reversing the lesion-induced elevation of ERK2 phosphorylation in response to acute apomorphine administration (0.05 mg/kg, s.c.). Chronic l-DOPA significantly elevated the level of Akt phosphorylation at both Thr(308) and Ser(473) and concentration of phosphorylated GSK3alpha, whereas pergolide suppressed the lesion- and/or challenge-induced supersensitive Akt responses. The data indicate that l-DOPA, unlike pergolide, exacerbates imbalances in the Akt pathway caused by the loss of DA. The results support the hypothesis that the Akt pathway is involved in long-term actions of l-DOPA and may be linked to l-DOPA-induced dyskinesia.     

Differential effects of l-DOPA on monoamine metabolism, cell survival and glutathione production in midbrain neuronal-enriched cultures from parkin knockout and wild-type mice

l-DOPA is the most effective treatment for Parkinson's disease but in isolated neuronal cultures it is neurotoxic for dopamine (DA) neurones. Experiments in vivo and clinical studies have failed to show toxicity of l-DOPA in animals or patients but that does not exclude the possibility of a toxic effect of l-DOPA on patients with certain genetic risk factors. Mutations of the parkin gene are the most frequent cause of hereditary parkinsonism. Parkin null mice have a mild phenotype that could be modified by different neurotoxins. The aim of this study was to investigate whether the toxic effects of l-DOPA on DA neurones are amplified in parkin null mice. We have measured the effects of l-DOPA on cell viability, tyrosine hydroxylase (TH) expression, DA metabolism and glutathione levels of parkin knockout (PK-KO) midbrain cultures. Neuronal-enriched cultures from PK-KO mice have similar proportions of the different cell types with the exception of a significant increment of microglial cells. l-DOPA (400 microm for 24 h) reduced the number of TH-immunoreactive cells to 50% of baseline and increased twofold the percentage of apoptotic cells in cultures of wild-type (WT) animals. The PK-KO mice, however, are not only resistant to the l-DOPA-induced pro-apoptotic effects but they have an increased number of TH-immunoreactive neurones after treatment with l-DOPA, suggesting that l-DOPA is toxic for neurones of WT mice but not those of parkin null mice. MAPK and phosphatidylinositol-3 kinase signalling pathways are not involved in the differential l-DOPA effects in WT and PK-KO cultures. Intracellular levels of l-DOPA were not different in WT and parkin null mice but the intracellular and extracellular levels of DA and 3-4-dihydroxyphenylacetic acid, however, were significantly increased in parkin null animals. Furthermore, monoamine oxidase activity was significantly increased in parkin null mice, suggesting that these animals have an increased metabolism of DA. The levels of glutathione were further increased in parkin null mice than in controls both with and without treatment with l-DOPA, suggesting that a compensatory mechanism may protect DA neurones from neuronal death. This study opens new avenues for understanding the mechanisms of action of l-DOPA on DA neurones in patients with Park-2 mutations.     

Individual characteristics of spontaneous locomotor activity and adaptive behavior in the rat

Spontaneous locomotor activity (SLA) of the male rats possesses significant individual differences. The daily volume of this activity is sufficiently stable for each separate individual. Animals with high and low SLA also differ in daily dynamics of this parameter. The behaviour of the rats with low SLA was characterized by lesser orienting activity and greater emotional reactivity in comparison to the rats with high SLA. By means of factor analysis it was established that, along with searching activity, emotional reactivity and alimentary motivation, the need in motor activity is one of the main inner factors, determining various manifestations of adaptive behaviour.     

Effect of chronic cadmium exposure on locomotor behaviour of rats

Growing male rats were exposed to cadmium (Cd, 100 micrograms/kg, ip) for 51 days and the effect on the different components of locomotor behaviour was assessed on days 38, 46 and 51 of Cd exposure. Significant decrease in distance travelled, stereotypic time and movements, ambulatory time and vertical movements were observed in Cd-exposed rats, whereas the time of rest was increased. The number of entries into the inner as well as the outer squares and the total time spent in the inner squares of the floor area were significantly reduced. Results indicate that Cd exposure results in a general depression in all aspects of motor behaviour leading to decrease in gross locomotor activity. The involvement of an exaggerated emotional reactivity in the behavioural expression of the Cd-treated animals is also emphasized.     

Two types of "spike-wave" discharges in the electrocorticogram of WAG/Rij rats, the genetic model of absence epilepsy

WAG/Rij rats were injected with apomorphine (0.5 mg/kg, i.p.), an agonist of D2 receptors. Two types of spike-wave discharges (generalized and local) were found in the baseline ECoG of the intact and injected rats. Injections of apomorphine led to a suppression of the generalized (type 1) for about 30 minutes and a 8-10-fold increase in the local spike-wave discharges (type 2) within 4-6 minutes. Since it has been shown earlier that haloperidol, which acts on dopamine receptors oppositely to apomorphine, enhance the generalized spike-wave activity and suppress the local discharges. Thus, the different pharmacological characteristics of the two types of spike-wave activity suggest the controlling role of the dopaminergic system in the processes of spike-wave generation.     

Effect of a 3-hydroxypyridine-class antioxidant on the functional activity of the central nervous system in mice of different age groups

Characteristics of emotional reactivity, orienting-investigating behaviour and of preservation of conditioned reflex of passive avoidance were used for estimation of the functional activity of animals CNS and also of psychotropic effect of antioxidant 2-ethyl-6-methyl-3-oxypyridine (3-OP) on mice of different age. Studies were carried out on white outbred young (3 months) and elderly (15 months) male mice. Different character was observed of the emotional reactions of different age mice to aversive stimuli and to the open field conditions. Differences were noted of psychotropic effects of 3-OP in 3 and 15-months animals.