Eliane Kempf

Protective effect of adenosine and nicotinamide against audiogenic seizure

Abstract Intraperitoneal injection of adenosine into Swiss albino mice, RB strain, sensitive to audiogenic convulsions, rapidly produces, in proportion to the dose administered: sedation, modification of the EEG, lowering of arterial pressure and protection against audiogenic seizures. Simultaneous injection of adenosine and nicotinamide, produces the most striking protection, the effect being independent of all the others. During the protective period to convulsions, there is an elevation in the energy rich compounds, ATP and phosphocreatine, which is attributable to a reduction in their rate of degradation. During the same period, a diminution in the cerebral level of noradrenaline takes place. The pharmacological effects of adenosine appear to oppose those of its structural analogue, caffeine, with regard to mobility, arterial pressure, basal metabolic rate and body temperature.

Effects of immobilization stress on dopamine and its metabolites in different brain areas of the mouse: role of genotype and stress duration

Immobilization stress induced, in mice of both C57BL/6 (C57) and DBA/2 (DBA) strains, an increase in dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios and a reduction of 3-methoxytyramine (3-MT)/DA ratio in the caudatus putamen (CP) and nucleus accumbens septi (NAS). These effects were already evident after 30 min stress in the NAS, while in the CP 120 min were needed in order to show the effects of stress. Immobilization did not produce any effects on dopaminergic metabolism in the frontal cortex (FC) of the C57 strain either after 30 or after 120 min stress while in mice of the DBA strain a time-dependent effect of stress on the HVA/DA ratio was evident. When B6D2F1 hybrids were considered, the effects produced by 120 min immobilization in the CP and the NAS paralleled those observed in parental strains, while in the FC 120 min stress induced the same increase of HVA observed in DBA mice, thus suggesting that the pattern of response in the FC that characterizes the DBA strain may be inherited through a dominant pattern of inheritance.

Neurochemical lesion of the locus coeruleus of the rat does not suppress the sedative effect of clonidine

The locus coeruleus of male rats was destroyed bilaterally by injection of 6-hydroxydopamine. Rats injected with the vehicle and normal rats served as controls. Starting 20 days after the lesion, the locomotor activity of all rats was measured for 5 min every day. For the first 6 days, the lesioned rats were significantly less active than control rats; from the 7th to the 15th day, on the other hand, the locomotor activity of the two groups of rats was the same. From the 16th day onwards, the sedative effect of small doses of clonidine (2.5-100 micrograms/kg) was measured in lesioned and control animals. In spite of an almost total loss of noradrenaline in the cerebral cortex and hippocampus and a 33% loss of noradrenaline in the brain-stem of the lesioned rats, the sedative effect of clonidine was the same as in the control rats. This result suggests that the sedation produced by clonidine is not dependent on presynaptically located alpha 2-adrenoceptors.

Facilitation of spontaneous and learned spatial behaviours following 6-hydroxydopamine lesions of the lateral septum: a cholinergic hypothesis

Mice received injections of 6-hydroxydopamine (6-OHDA) in the lateral septum; they were tested for spontaneous alternation, acquisition and reversal of a spatial discrimination in a T-maze. In each of these tasks, performance of 6-OHDA lesioned mice was improved relative to controls. Neurochemical analysis revealed that 6-OHDA lesioned mice exhibited a significant increase in the rate of sodium-dependent high affinity choline uptake in the hippocampus. These results are discussed in relation to current theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behaviour.

Involvement of the nigral output pathways in the inhibitory control of the substantia nigra over generalized non-convulsive seizures in the rat.

Activation of GABAergic transmission within the substantia nigra has been shown to suppress several forms of generalized seizures in experimental models of epilepsy. More especially, such pharmacological manipulations suppress spontaneous and chemically-induced generalized non-convulsive seizures in the rat. The aim of the present study was to examine the role of the dopaminergic and GABAergic thalamic and collicular nigral outputs in this antiepileptic effect. For this purpose, we examined the effects of output destruction on the antiepileptic effect of intranigral injections of a GABA agonist or pharmacological blockade of the neurotransmission at the nerve terminal level in rats with spontaneous absence seizures. After selective destruction of dopaminergic neurons within the substantia nigra with 6-hydroxydopamine (5 micrograms/side) or hemisection of the ascending nigral output, bilateral intranigral injection of muscimol (2 ng/side) still significantly suppressed generalized non-convulsive seizures. Bilateral lesioning of the ventromedial nucleus of the thalamus did not abolish the antiepileptic effects of intranigral muscimol (2 ng/side) and the GABA antagonist, picrotoxin, when given into this thalamic nucleus (10 ng/side) also failed to induce suppression of spike and wave discharges. The antiepileptic effects of intranigral injection of muscimol (2 ng/side) was reversed by bilateral electrolytic lesions of the superior colliculus. Blockade of the GABAergic transmission at this level with picrotoxin (40 ng/side) significantly suppressed generalized non-convulsive seizures. Finally, excitation of collicular cell bodies with low doses of kainic acid (4 and 8 ng/side) also resulted in a suppression of spike and wave discharges. These results demonstrate that the GABAergic nigrocollicular pathway is critical for the inhibitory control of the substantia nigra over generalized non-convulsive seizures. The data further suggest that antiepileptic effects observed following potentiation of GABAergic transmission in the substantia nigra result from a disinhibition of collicular cell bodies.

Behavioural, pharmacological and biochemical effects of acute and chronic administration of ketamine in the rat

The effects of N-methyl-D-aspartate (NMDA) antagonist ketamine given acutely or chronically were investigated on dopamine-related motor functions. Acute administration (15, 22.5, 30 mg/kg, i.p.) reversed the catalepsy induced by a dopamine (DA) antagonist (haloperidol, 0.25 mg/kg, i.p.) in the rat. When given orally and chronically (15 mg/kg per day) during at least 60 days, no alteration of spontaneous motor behaviour was observed, but the responsiveness to a DA agonist (apomorphine, 0.125 or 0.25 mg/kg s.c.) and to haloperidol was enhanced, suggesting an hypersensitivity of the DA receptors following the chronic blockade of NMDA receptors. However, following prolonged administration of ketamine there were no alteration of DA levels and turnover. Taken together these results suggest that the mechanisms involved in this DA receptor hypersensitivity should be postsynaptic.

Different effects of acute and chronic stress on two dopamine-mediated behaviors in the mouse.

After two hours of immobilization stress, C57BL/6 mice presented a significant reduction of spontaneous locomotion and a slight reduction of spontaneous climbing. The effect of stress on locomotor activity disappeared after ten daily sessions of immobilization while this chronic treatment increased the effect of stress on spontaneous climbing. Twenty-four hr after the last stressful experience the mice showed an increase of spontaneous locomotion and a decrease of spontaneous climbing in comparison with unstressed mice. Following a single exposure to immobilization stress, an increase of DOPAC/DA and HVA/DA ratios was found in the striatum and in the nucleus accumbens. These effects were still evident following repeated exposure to this stressor but disappeared 24 hr after the last of ten daily stressful experiences. Finally, chronically stressed mice, tested 24 hr after the last stressful experience, showed an increased sensitivity to the inhibitory effects of low doses of apomorphine on climbing behavior and a decreased sensitivity to the inhibitory effects of the same doses of the dopamine agonist on locomotion. These results are discussed in terms of altered sensitivity of different populations of dopamine receptors following chronic stress.

Involvement of the GABAergic System on Shock-induced Aggressive Behavior in Two Strains of Mice

The effects of drugs that antagonize or potentiate the action of brain gamma-aminobutyric acid (GABA) on shock-induced aggressive behavior in mice were investigated. In previous studies it has been shown that in C57 BL/6 strain shock-induced aggressive behavior is absent up to the 10th week of age and rises to the highest intensity after the 20th week, while at the same ages aggressive responses are lowest or absent in DBA/2 strain. GABA antagonist, picrotoxin and glutamic acid decarboxylase (GAD) inhibitor, D, L-allylglycine induced aggressive responses in non-aggressive 10 week old C57 BL/6 and 20 week old DBA/2 mice. GABA agonist muscimol hydrobromide, and GABA-T inhibitor sodium n-dipropylacetate inhibited aggressive responses in 20 week old C57 BL/6 mice. These effects were not related to changes in shock sensitivity and motor activity. The results strongly suggest that the GABAergic system is involved in the control of shock-induced aggressive behavior in mice and that this control is related to developmental and genetic factors.

Serotonin levels and turnover in different brain areas of isolated aggressive or non-aggressive strains of mice

After eight weeks of individual housing DBA/2 but not C57 B1/6 (C57) mice showed high levels of aggressive responses in comparison with grouped mice. Social isolation did not modify serotonin (5-HT) levels in either strain of mice, while it produced a decrease of turnover rate in amygdala, lateral hypothalamus and pons in C57 mice and in lateral hypothalamus and pons of DBA mice. When isolated mice of both C57 and DBA strains are compared, no differences in turnover rate in amygdala and pons are evident, while isolated DBA mice show significant lower turnover values in lateral hypothalamus in comparison with isolated C57 mice. A possible suggestion emerging from our results is that aggressive responses exhibited by isolated DBA mice but not by isolated C57 mice may be related to lower 5-HT turnover rate in lateral hypothalamus.

Neurochemical lesion of the nucleus locus coeruleus increases neophobia in a specific exploration task but does not modify endocrine response to moderate stress

In order to test more specifically the role of the nucleus locus coeruleus (LC) in reaction to novelty, rats with bilateral 6-hydroxydopamine lesions of this nucleus, vehicle injected rats and non-operated animals were tested in the open-field and in the Hughes apparatus where motor activity is recorded in both a familiar and a non-familiar environment. In the open-field, the LC lesioned animals were significantly less active. A similar decrease of locomotor activity was observed in the Hughes test: the number of passages between the two boxes of the LC lesioned rats was significantly decreased. Likewise when the locomotor activities in the two boxes were pooled, the activity of the rats with lesions was significantly lower than the activity of the control rats, but in this case the locomotor deficit appeared only in the familiar box, the locomotor activity in the novel enclosure being the same in both LC lesioned and control animals. This result suggests that exploratory induced locomotion is not disturbed by the locus coeruleus lesion. The significant locomotor deficit showed by the LC lesioned rats in the familiar box could be due to an increased immobility induced by the stressful situation. Moreover, the deficit observed was the same whether the behavioral test began 4 days or 4 weeks after the lesion. Finally, at the end of the experiment, all rats were submitted to a moderate novel environmental stress and blood samples collected to measure the plasma levels of different stress hormones (ACTH, glucocorticoids, PRL, catecholamines).(ABSTRACT TRUNCATED AT 250 WORDS)