Karolina Noworyta-Sokołowska

LPS-induced oxidative stress and inflammatory reaction in the rat striatum

BACKGROUND Inflammation-induced microglia activation and increased oxidative stress have been observed in neurodegenerative disorders, such as Parkinsons disease. The aim of our study was to determine the appropriate dose and route of LPS administration to study hydroxyl radical generation and extracellular level of dopamine (DA), glutamate (GLU) and adenosine (ADN) in the rat striatum as markers of DA neuron damage and glial cell activation. The effect of LPS administration on DA, DOPAC, HVA and hydroxyl radical tissue level was also examined. METHODS LPS was given to rats in a single dose of 10 mg/kg ip, repeatedly for 5 days in a dose of 5 mg/kg ip and intrastriatally at doses 5, 20 and 40 μg/4 μl. The extracellular level of DA, hydroxyl radical, ADN and GLU were assayed in striatal dialysates using HPLC with electrochemical, fluorescence and VIS detection, respectively. RESULTS A single ip LPS (10 mg/kg) administration increased hydroxyl radical production but did not affect extracellular DA, GLU and ADN level. Repeated ip LPS (5 × 5 mg/kg) treatment decreased extracellular level of DA, GLU, ADN and production of hydroxyl radical. LPS (5 and 10 μg) given intrastriatally increased hydroxyl radical production, extracellular GLU and ADN level from 0 to 180 min after administration, but did not influence DA level. LPS (5, 20 and 40 μg) decreased striatal DA and DOPAC content, but increased HVA and hydroxyl radical level 72 h after intrastriatal administration. CONCLUSIONS Our data indicate that local intrastriatal LPS administration activates glial cells and increases production of free radicals and secretion of GLU and ADN in early phase of inflammation. The damage of DA neurons is observed 72 h after local LPS administration.

The effect of caffeine on MDMA-induced hydroxyl radical production in the mouse striatum

BACKGROUND The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) with a strong addictive potential is widely used as a recreational drug. Neurotoxicity of MDMA is related with the generation of highly reactive free radicals. METHODS MDMA was given in doses of 20 and 40mg/kg ip alone or in combination with caffeine (CAF) 10mg/kg ip. Extracellular concentration of hydroxyl radical was measured using microdialysis in freely moving mice and was assayed by HPLC with electrochemical detection. RESULTS MDMA dose-dependently increased production of hydroxyl radical in the mouse striatum and its effect was reversed by caffeine. CONCLUSIONS The data show that caffeine may have neuroprotective properties as it decreased oxidative stress induced by MDMA.

Neurochemical and behavioral studies on the 5-HT1A-dependent antipsychotic action of the mGlu4 receptor agonist LSP4-2022.

&NA; LSP4‐2022 is a novel, orthosteric agonist of mGlu4 receptor that induces antipsychotic‐like activity in animal studies. In the present study, the involvement of 5‐HT1A receptors in LSP4‐2022‐induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5–2 mg/kg) were antagonized via the administration of the 5‐HT1A antagonist WAY100635 (0.1 mg/kg). The co‐administration of sub‐effective dose of the 5‐HT1A agonist (R)‐(S)‐8‐OH‐DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4‐2022, having no influence on the efficacy of the active doses. The co‐administration of effective doses of both compounds did not intensify each others action. In the microdialysis in vivo tests, MK‐801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4‐2022 (2 mg/kg) abolished this MK‐801‐induced effect on neurotransmitter release. Co‐administration with WAY100635 (0.1 mg/kg), a 5‐HT1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4‐2022‐induced effect. Subsequently, the patch‐clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 &mgr;M). LSP4‐2022 (2.5; 5 and 10 &mgr;m) reversed DOI‐induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4‐2022‐induced effects on sEPSCs, indicating that the mGlu4‐5‐HT1A interaction does not occur via single‐neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’. HighlightsLSP4‐2022 antagonizes MK‐801‐induced release of dopamine, serotonin, glutamate and GABAThe action of LSP4‐2022 is 5‐HT1A dependentmGlu4‐5‐HT1A interaction does not occur within a single neuron

The effect of chronic co-treatment with risperidone and novel antidepressant drugs on the dopamine and serotonin levels in the rats frontal cortex

BACKGROUND Preclinical and clinical studies have suggested a beneficial effect of combination treatment with atypical antipsychotic drugs and antidepressants (ADs) in schizophrenia and in drug-resistant depression. METHODS In the present study, we investigated the effect of chronic administration of risperidone and ADs (escitalopram or mirtazapine), given separately or jointly on the extracellular levels of dopamine (DA) and serotonin (5-HT) in the rat frontal cortex. The animals were administered risperidone (0.2 mg/kg) and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) repeatedly for 14 days. The release of monoamines in the rat frontal cortex was evaluated using a microdialysis, and DA and 5-HT levels were assayed by HPLC. We also measured the locomotor activity, catalepsy and recognition memory in these rats. RESULTS Chronic risperidone treatment (0.2 mg/kg) increased the extracellular levels of DA and 5-HT. Co-treatment with risperidone and escitalopram (5 mg/kg) or mirtazapine (10 mg/kg) more efficiently increased the release of 5-HT but not DA in the rat frontal cortex, as compared to drugs given alone. Moreover, risperidone, escitalopram and mirtazapine given alone or in combination significantly decreased the locomotor activity and only mirtazapine increased the catalepsy evoked by risperidone. Combined treatment with risperidone and ADs impaired recognition memory in these rats. CONCLUSIONS The obtained results suggest that chronic co-administration of risperidone and escitalopram or mirtazapine more efficiently increased 5-HT release in the rat frontal cortex as compared to drugs given alone and suggest that this effect may be of importance to the pharmacotherapy of schizophrenia and drug-resistant depression.BACKGROUND Preclinical and clinical studies have suggested a beneficial effect of combination treatment with atypical antipsychotic drugs and antidepressants (ADs) in schizophrenia and in drug-resistant depression. METHODS In the present study, we investigated the effect of chronic administration of risperidone and ADs (escitalopram or mirtazapine), given separately or jointly on the extracellular levels of dopamine (DA) and serotonin (5-HT) in the rat frontal cortex. The animals were administered risperidone (0.2mg/kg) and escitalopram (5mg/kg) or mirtazapine (10mg/kg) repeatedly for 14days. The release of monoamines in the rat frontal cortex was evaluated using a microdialysis, and DA and 5-HT levels were assayed by HPLC. We also measured the locomotor activity, catalepsy and recognition memory in these rats. RESULTS Chronic risperidone treatment (0.2mg/kg) increased the extracellular levels of DA and 5-HT. Co-treatment with risperidone and escitalopram (5mg/kg) or mirtazapine (10mg/kg) more efficiently increased the release of 5-HT but not DA in the rat frontal cortex, as compared to drugs given alone. Moreover, risperidone, escitalopram and mirtazapine given alone or in combination significantly decreased the locomotor activity and only mirtazapine increased the catalepsy evoked by risperidone. Combined treatment with risperidone and ADs impaired recognition memory in these rats. CONCLUSIONS The obtained results suggest that chronic co-administration of risperidone and escitalopram or mirtazapine more efficiently increased 5-HT release in the rat frontal cortex as compared to drugs given alone and suggest that this effect may be of importance to the pharmacotherapy of schizophrenia and drug-resistant depression.

Effects of exposure to 5-MeO-DIPT during adolescence on brain neurotransmission and neurotoxicity in adult rats

PurposeTryptamine hallucinogen 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a serotonin transporter inhibitor with high affinity for serotonin 5-HT1A and 5-HT2A/C receptors. We showed previously that 5-MeO-DIPT in a single dose increased neurotransmitter release in brain regions of rats and elicited single- and double-strand DNA breaks. Herein we investigated the effects of repeated-intermittent 5-MeO-DIPT administration in adolescence on dopamine (DA), serotonin (5-HT) and glutamate release in brain regions of adult rats. Furthermore, we examined caspase-3 activity, oxidative DNA damage, the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels, and cell viability.MethodsNeurotransmitter release was measured by microdialysis in freely moving animals. Caspase-3 activity was assessed colorimetrically, and oxidative DNA damage with the comet assay, while the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels were assessed by real-time polymerase chain reaction. Cell viability was studied in SH-SY5Y and Hep G2 cells by the MTT test.ResultsWe observed changed responses of DA, 5-HT and glutamate neurons to a challenge dose of 5-MeO-DIPT when animals were treated repeatedly in adolescence with this hallucinogen. The basal extracellular levels of DA and 5-HT were decreased in the striatum and nucleus accumbens, while glutamate level was increased in the nucleus accumbens and frontal cortex. The damage of cortical DNA, increased Gpx3 and Sod1 mRNA expression and affected caspase-3 activity were also observed. Furthermore, decreased Ht1a and Ht2a mRNA expression in the frontal cortex and marked cytotoxicity of 5-MeO-DIPT were found.ConclusionsThese results suggest that 5-MeO-DIPT given repeatedly during adolescence affects brain neurotransmission and shows neurotoxic potential observed in adult animals.