Functional and histological consequences of quinolinic and kainic acid-induced seizures on hippocampal somatostatin neurons.

Changes in endogenous somatostatin after quinolinic and kainic acids were investigated by measuring somatostatin-like peaks by in vivo voltammetry and by assessing the distribution of somatostatin-positive neurons by immunocytochemistry. Kainic acid (0.19 nmol/0.5 microliter) or quinolinic acid (120 nmol/0.5 microliter) in doses inducing comparable electroencephalographic seizure patterns, were injected into the hippocampus of freely moving rats. Somatostatin-like peaks were measured every 6 min for 3 h by a carbon fiber electrode implanted in the proximity of the injection needle. Kainic acid kept somatostatin-like peaks significantly higher than saline from 48 min after the injection till the end of the recording. Somatostatin-like peaks were dramatically elevated by quinolinic acid, reaching a maximum of 482% 60 min after the injection. Three days later, administration of kainic acid resulted in selective degeneration of CA3 pyramidal neurons but did not affect the number of somatostatin-positive cells, while quinolinic acid induced cell loss in all pyramidal layers and complete degeneration of somatostatin-positive cells in the whole hippocampus. Thus, the quantitative difference in somatostatin release in response to doses of kainic and quinolinic acids inducing comparable electroencephalographic seizure patterns was reflected in a substantial difference in the neurodegenerative consequences. In both models, the release of somatostatin in response to seizures may be interpreted as a "defense" mechanism aimed at reducing the spread of excitation in the tissue.

Modulation of striatal dopamine metabolism by the activity of dorsal raphe serotonergic afferences.

Serotonin (5-HT)-dopamine (DA) interaction was studied in the caudate nucleus after electrical stimulation of the dorsal raphe (DR), an area containing 5-HT cell bodies and sending afferences to nigrostriatal dopaminergic neurons. The DR was stimulated by means of a bipolar stainless steel electrode for 16 min (10 Hz, 0.6 ms, 200 microA). 5-HT and DA metabolism were monitored before, during and after stimulation by in vivo differential pulse voltammetry. This electrochemical technique uses carbon fiber electrodes implanted in brain areas to record oxidation peaks corresponding to extracellular 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC). Changes in the concentrations of the metabolites were recorded every 2 min in freely moving rats. Both 5-HIAA and DOPAC increased in the first minutes after the beginning of stimulation, the rise lasting 30 min after the end. That DR was closely involved was borne out by the fact that stimulation in the surrounding areas had no effect on either metabolite. Classical biochemical determinations in tissue samples were also used to study the effect on DA release: 3-methoxytyramine (3-MT) levels, measured in basal conditions and after blockade of its degradation by pargyline, were not changed, indicating that DR stimulation, though increasing DA metabolism, does not affect release. However, modulation of DA transmission by 5-HT afferences seems possible in certain circumstances. This 5-HT-DA interaction appears to be presynaptic (on dopaminergic terminals or cell bodies) since it is not prevented by kainic acid degeneration of striatal neurons.

Functional meaning of tryptophan-induced increase of 5-HT metabolism as clarified by in vivo voltammetry.

Differential pulse voltammetry with carbon fiber electrodes was used to study serotonin (5-HT) metabolism in freely moving rats. The electrodes implanted in the striatum recorded the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak after oral tryptophan (150 mg/kg). This 5-HT precursor did not modify the 5-HIAA peak in any rat tested, but it raised 5-HIAA levels determined in total tissue by a classical biochemical method (HPLC). The administration of 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.) induced an increase of 5-HIAA detectable both in the extracellular medium by voltammetry and in tissue samples. As previously shown, dorsal raphe electrical stimulation raises extracellular 5-HIAA in the striatum and this effect is enhanced by pretreatment with tryptophan. The results suggest that tryptophan in 'normal' conditions enhances 5-HT metabolism without affecting 5-HT release unless such release is stimulated. 5-HTP increases 5-HT metabolism and release.

Repeated treatment with fluoxetine decreases the number of spontaneously active cells per track in frontal cortex.

Repeated (10 mg/kg i.p. x 14 days, once daily), but not acute (10 and 40 mg/kg i.p., 30 min), treatment with fluoxetine decreased the number of active neurons in the frontal cortex 30 min (-55%) or 24 h (-62%) after the last drug injection. This result supports the view that repeated, but not acute, treatment with fluoxetine decreases the function of the frontal cortex.

Different effects of fenfluramine isomers and metabolites on extracellular 5-HIAA in nucleus accumbens and hippocampus of freely moving rats.

The effects of optical isomers of fenfluramine and their metabolites, d- and l-norfenfluramine on the serotonergic system were studied in the nucleus accumbens and hippocampus of freely moving rats by in vivo voltammetry. Both isomers and the metabolites induced a slow, sustained decrease in 5HIAA but only d-fenfluramine and its metabolite, d-norfenfluramine, increased the 5HIAA levels in nucleus accumbens shortly after injection, the increase being greater after the metabolite. No effect could be detected in the hippocampus after the higher dose of d-fenfluramine.

Effect of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine on hippocampal serotoninergic system, studied in freely moving rats.

The effects of the anxiolytic drug buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1PP) were studied on the serotoninergic system in the hippocampus of freely moving rats. Pulse voltammetry was used in association with chronically implanted carbon fiber microelectrodes to record 5HIAA, the serotonin metabolite in the extracellular space, almost continuously. Buspirone, 2.5 mg/kg i.p. was ineffective, but the dose of 10 mg/kg lowered 5HIAA between about 45 and 150 min; the same decrease was obtained with 40 mg/kg. This effect can be explained by an agonistic action on 5HT1 A receptors. The metabolite 1PP, which displays alpha 2 adrenoceptor blocking properties, either had no effect or raised extracellular 5HIAA, depending on the dose (1.5 or 6 mg/kg). The rapid metabolization of buspirone to 1PP can thus explain the short time course of the drug effect. Pretreatment with 1PP could only partially prevent buspirone's effect on the serotoninergic system.

Aspartame and the rat brain monoaminergic system.

A high dose of aspartame (APM) was administered to rats to study possible effects on brain monoaminergic systems. APM and its metabolite phenylalanine (Phe) were given orally at doses of 1000 and 500 mg/kg, respectively. Significant increases were seen in brain Phe and tyrosine (Tyr) levels. Two different approaches were used to study monoaminergic systems: whole tissue measurements by HPLC-ED and in vivo voltammetry in freely moving rats. Dopamine, serotonin and their metabolites were taken as indexes of neuronal activity. In spite of the high dose used, no modification was found in monoamines or their metabolites in striatum, hippocampus and nucleus accumbens.

Effects of cerestat and NBQX on functional and morphological outcomes in rat focal cerebral ischemia.

This study investigated the ability of NBQX, an AMPA receptor antagonist, and cerestat, a NMDA receptor antagonist, to counteract neurological deficits and morphological damage induced by permanent occlusion of the left middle cerebral artery (MCAO model) in the rat. NBQX (3, 10, and 30 mg/kg, ip) injected at 10, 60, and 120 min postocclusion did not reduce the volume of infarct in the MCAO model of cerebral ischemia and had marginal effects on sensory dysfunctions (vibrissae stimulation and body proprioception) and no effects on motor dysfunctions (forelimb flexion and footfault test). Conversely, cerestat (0.3, 1, and 3 mg/kg, sc) injected at 10 and 120 min postocclusion significantly reduced the ischemic volume at the dose of 1 mg/kg, and, at the same dose, significantly attenuated behavioural deficits in the body proprioception and in the forelimb flexion tests.

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex.

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.