LSP4-2022 is a novel, orthosteric agonist of mGlu receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT 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-HT antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT 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 other's 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-HT 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 μM). LSP4-2022 (2.5; 5 and 10 μm) 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 mGlu-5-HT 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'.

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.

New psychoactive “designer drugs” are synthetic compounds developed to provide similar effects to illicit drugs of abuse, but not subjected to legal control. The rapidly changing legal status of novel psychoactive drugs triggers the development of new compounds, analogs of well-known amphetamine or mescaline. New designer drugs used as substitutes in ecstasy pills are the least investigated and can cause life-threatening effects on users. The aim of our research was to examine the effects of acute administration of 4-methoxyamphetamine (PMA, 5 and 10 mg/kg), 4-methoxy-N-methylamphetamine (PMMA, 5 and 10 mg/kg), and mephedrone (MEPH, 5, 10 and 20 mg/kg) on extracellular and tissue level of dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites in rat brain, by microdialysis method in freely moving animals and HPLC. Similarly to 3,4-methylenedioxymethamphetamine (MDMA, 5 and 10 mg/kg) PMA, PMMA and MEPH enhanced the release of DA and 5-HT in rat striatum, nucleus accumbens, and frontal cortex. DA tissue content was increased by MEPH and PMMA in striatum, by MEPH, PMA, and PMMA in nucleus accumbens, and by PMA in frontal cortex. Instead, cortical DA level was decreased by MEPH and PMMA. MEPH did not influence 5-HT tissue level in striatum and nucleus accumbens, but decreased its level in frontal cortex. PMMA increased 5-HT content in striatum, while PMA enhanced it in nucleus accumbens and frontal cortex. Observed changes in brain monoamines and their metabolites by new psychoactive drugs suggest that these drugs may be capable of development of dependence. Further experiments are needed to fully investigate the neurotoxic and abuse potential of those drugs.

Rationale According to psychological theories, cognitive distortions play a pivotal role in the aetiology and recurrence of mood disorders. Although clinical evidence for the coexistence of depression and altered sensitivity to performance feedback is relatively coherent, we still do not know whether increased or decreased sensitivity to positive or negative feedback is associated with ‘pro-depressive’ profile in healthy subjects. Objective Our research has been designed to answer this question, and here, we present the first steps in that direction. Methods Using a rat version of the probabilistic reversal-learning (PRL) paradigm, we evaluated how sensitivity to negative and positive feedback influences other cognitive processes associated with mood disorders, such as motivation in the progressive ratio schedule of reinforcement (PRSR) paradigm, hedonic status in the sucrose preference (SP) test, locomotor and exploratory activity in the open field (OF) test, and anxiety in the light/dark box (LDB) test. Results The results of our study demonstrated for the first time that in rodents, sensitivity to negative and positive feedback could be considered a stable and enduring behavioural trait. Importantly, we also showed that these traits are independent of each other and that trait sensitivity to positive feedback is associated with cognitive flexibility in the PRL test. The computational modelling results also revealed that in animals classified as sensitive to positive feedback, the α learning rates for both positive and negative reward prediction errors were higher than those in animals classified as insensitive. We observed no statistically significant interactions between sensitivity to negative or positive feedback and the parameters measured in the PRSR, SP, OF or LDB tests. Conclusions Further studies using animal models of depression based on chronic stress should reveal whether sensitivity to feedback is a latent trait that when interacts with stressful life events, could produce correlates of depressive symptoms in rats.

RationaleDiverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia.ObjectivesTo begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated.ResultsThe effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release.ConclusionsThe actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-014-3657-4) contains supplementary material, which is available to authorized users.

The present study demonstrates that co-administration of risperidone and escitalopram may be used to treat positive and negative symptoms of schizophrenia and will allow to minimize the drugs' side effects.

The study shows effects of the nonselective adenosine A1/A2A receptor antagonist caffeine and the selective A2A receptor antagonist KW6002 on LPS-induced changes in the extracellular levels of dopamine (DA), glutamate, adenosine, hydroxyl radical, and A2A receptor density in the rat striatum. Intrastriatal LPS (10 μg) injection decreased extracellular level of DA and increased the level of adenosine, glutamate, and hydroxyl radical on the ipsilateral side 24 h after LPS administration. Caffeine (10 and 20 mg/kg i.p.) and KW6002 (1.5 and 3 mg/kg i.p.) given once daily for 6 days and on the 7th day 2 h before and 4 h after LPS injection reversed the LPS-induced changes in extracellular levels of DA, adenosine, glutamate, and hydroxyl radical production. Moreover, LPS-induced decrease in the striatal A2A receptor density was increased by caffeine and KW6002. In order to show the late LPS effect on oxidative damage of DA neurons, the contents of DA, DOPAC, HVA, and hydroxyl radical were determined 72 h after LPS (10 μg) administration into both striata. LPS decreased striatal and substantia nigra content of DA, DOPAC, and HVA while increased striatal but not nigral content of hydroxyl radical. Caffeine (20 mg/kg) and KW60002 (3 mg/kg) given once daily for 6 days and on the 7th day 2 h before and 4 h after intrastriatal injection of LPS normalized the content of DA and its metabolites in both brain regions as well as decreased LPS-induced increase in the striatal level of hydroxyl radical. In conclusion, our data demonstrated antioxidant effects of caffeine and KW6002 in the inflammatory model of PD.

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