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Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer's disease, but the mechanisms are not fully explored. In the male animal models of DM, the development of cognitive impairment seems to be the result of the concomitance of different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and aberrant synaptogenesis. However, even if diabetic encephalopathy shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, in an experimental model of type 1 DM (T1DM), we explored the impact of one month of pathology on memory abilities by the novel object recognition test and on neuroinflammation, synaptogenesis and mitochondrial functionality. Moreover, given that steroids are involved in memory and learning, we also analysed their levels and receptors. We reported that memory dysfunction can be associated with different features in the female hippocampus and cerebral cortex. Indeed, in the hippocampus, we observed aberrant synaptogenesis and neuroinflammation but not mitochondrial dysfunction and oxidative stress, possibly due to the results of locally increased levels of progesterone metabolites (i.e., dihydroprogesterone and allopregnanolone). These observations suggest specific brain-area effects of T1DM since different alterations are observed in the cerebral cortex. [ABSTRACT FROM AUTHOR]

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy. [ABSTRACT FROM AUTHOR]

4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25B-NBOMe) is a hallucinogen exhibiting high binding affinity for 5-HT2A/C serotonin receptors. In the present work, we investigated its effect on dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release in the rat frontal cortex, striatum, and nucleus accumbens. Hallucinogenic activity, impact on cognitive and motor functions, and anxiogenic/anxiolytic properties of this compound were also tested. The release of DA, 5-HT, ACh, and glutamate was studied using microdialysis in freely moving animals. Hallucinogenic activity was investigated using head and body twitch response (WDS), cognitive functions were examined with the novel object recognition test (NOR), locomotor activity was studied in the open field (OF), while anxiogenic/anxiolytic effect was tested using the light/dark box (LDB). Neurotoxicity was evaluated with the comet assay. 25B-NBOMe increased DA, 5-HT, and glutamate release in all studied brain regions, induced hallucinogenic activity, and lowered the recognition index (Ri) vs. control in the NOR test. It also decreased locomotor activity of rats in the OF test. The effect of 25B-NBOMe in the NOR test was inhibited by scopolamine. In the LDB test, the time spent in the dark zone was longer in comparison to control and was dose-dependent. In contrast to MDMA, 25B-NBOMe showed subtle genotoxic effect observed in the comet assay. Our findings indicate that 25B-NBOMe shows hallucinogenic activity in the wide range of doses. The changes in neurotransmitter levels may be related to 25B-NBOMe affinity for 5-HT2A receptor. Alterations in the NOR, OF, and LDB indicate that 25B-NBOMe impacts short-term memory, locomotion, and may be anxiogenic. [ABSTRACT FROM AUTHOR]

NBOMes are N-benzylmethoxy derivatives of the 2C family hallucinogens. 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is one of the commonly used illicit drugs. It exhibits high binding affinity for 5-HT2A/C and 5-HT1A serotonin receptors. Activation of 5-HT2A receptor induces head-twitch response (HTR) in rodents, a behavioral marker of hallucinogen effect in humans. There is not much data on neurochemical properties of NBOMes. Therefore, we aimed to investigate the effect of 25I-NBOMe on extracellular level of dopamine (DA), serotonin (5-HT), and glutamate (GLU) in the rat frontal cortex, tissue contents of monoamines, and hallucinogenic activity in rats. The extracellular levels of DA, 5-HT, and GLU were studied using microdialysis in freely moving animals. The tissue contents of DA, 5-HT and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the rat frontal cortex. We also tested a drug-elicited HTR. 25I-NBOMe at doses 1, 3, and 10 mg/kg (sc) increased extracellular DA, 5-HT, and GLU levels, enhanced tissue content of 5-HT and 5-HIAA, but did not affect tissue level of DA and its metabolites. The compound exhibited an inverted U-shaped dose-response curve with respect to the effect on extracellular DA and 5-HT levels, but a U-shaped dose-response curve was observed for its effect on GLU release and HTR. The data from our study suggest that hallucinogenic activity of 25I-NBOMe seems to be related with the increase in extracellular GLU level-mediated via cortical 5-HT2A receptors. The influence of 25I-NBOMe on 5-HT2C and 5-HT1A receptors may modulate its effect on neurotransmitters and HTR. [ABSTRACT FROM AUTHOR]