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Recently, several studies on pedestrian safety and particularly those addressing pedestrian crossing behaviour and decision-making have been performed using virtual reality systems. The use of simulators to assess pedestrian behaviour is conditioned by the feeling of presence and immersion, for which the sound is a determining factor. This paper presents an implementation procedure in which tyre-road noise samples are auralized and presented as auditory stimuli in a virtual environment, for assessing pedestrian crossing decision-making. The auditory samples obtained through the Close Proximity (CPX) method and subsequently auralized to represent Controlled Pass-By (CPB) recordings reproduce the sounds of a vehicle approaching a crosswalk. The auralized sounds together with the presentation of visual stimuli were used in an experiment carried out with 15 participants. Safety indicators, such as the time-to-passage at the moment that participants decided to cross a virtual crosswalk and the minimum time-to-collision were registered and compared with data obtained in real-world road crossings. The comparison of the results obtained in virtual and real environments, indicated a good suitability of the approach for studying pedestrian crossing behaviour., A preliminary indication that the simulation approach used in the experiments is able to realistically depict road crossing situations, where the CPB auralized sounds certainly played an important role. However, full validation will require more in-depth studies of multiple conditions, to assess the suitability of the implementation of the approach as a valid tool for simulation-based safety analysis of car-pedestrian interactions. FCT – Fundação para a Ciência e a Tecnologia, under grant agreement [SFRH/BD/131638/2017] attributed to the first author; by FCT/MCTES through national funds (PIDDAC) under the R&D Unit Institute for Sustainability and Innovation in Engineering Structures (ISISE) [UIDB/04029/2020]; and by the project Promoting Scientific Production and Technological Development and Thematic Networking (3599-PPCDT), supported by the European Community Fund FEDER, through the grant attributed to the project AnPeB – Analysis of pedestrians behaviour based on simulated urban environments and its incorporation in risk modelling [PTDC/ECM-TRA/3568/2014]

Neonatal exposure to general anesthetics has been associated with neurotoxicity and morphologic changes in the developing brain. Isoflurane is a volatile anesthetic widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated the effects of a single neonatal isoflurane (3% in oxygen, 2 h) exposure in rats at postnatal day (PND) 7, in short-term (24 h - PND8) and long-term (adulthood) protocols. In PND8, ex vivo analysis of hippocampal and frontal cortex slices evaluated cell viability and susceptibility to in vitro glutamate challenge. In adult rats, behavioral parameters related to anxiety-like behavior, short-term memory, and locomotor activity (PND60-62) and ex vivo analysis of cell viability, membrane permeability, glutamate uptake, and susceptibility to in vitro glutamate challenge in hippocampal and cortical slices from PND65. A single isoflurane (3%, 2 h) exposure at PND7 did not acutely alter cell viability in cortical and hippocampal slices of infant rats (PND8) per se and did not alter slice susceptibility to in vitro glutamate challenge. In rat's adulthood, behavioral analysis revealed that the neonatal isoflurane exposure did not alter anxiety-like behavior and locomotor activity (open field and rotarod tests). However, isoflurane exposure impaired short-term memory evaluated in the novel object recognition task. Ex vivo analysis of brain slices showed isoflurane neonatal exposure selectively decreased cell viability and glutamate uptake in cortical slices, but it did not alter hippocampal slice viability or glutamate uptake (PND65). Isoflurane exposure did not alter in vitro glutamate-induced neurotoxicity to slices, and isoflurane exposure caused no significant long-term damage to cell membranes in hippocampal or cortical slices. These findings indicate that a single neonatal isoflurane exposure did not promote acute damage; however, it reduced cortical, but not hippocampal, slice viability and glutamate uptake in the adulthood. Additionally, behavioral analysis showed neonatal isoflurane exposure induces short-term recognition memory impairment, consolidating that neonatal exposure to volatile anesthetics may lead to behavioral impairment in the adulthood, although it may damage brain regions differentially.

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. l-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-l-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-l-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1–42 oligomers (AβO; 1 μM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AβO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AβO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AβO, thus counteracting AD-related pathological phenotypes.

Tramadol and tapentadol, synthetic opioids commonly prescribed for moderate-to-severe pain, have a unique pharmacology that optimizes their analgesia and safety. However, they are not devoid of risks, presenting addictive, abuse, and dependence potential. While tramadol-reinforcing properties have been documented by various studies with human and animal models, including conditioned place preference (CPP) assays, no similar studies have been performed with tapentadol. In the present study, we performed CPP assays by intraperitoneally administering Wistar rats with a tramadol/tapentadol therapeutic dose. Animal permanence and the number of entries in the CPP compartments were recorded in the preconditioning phase and then 1 (T1), 7 (T7), and 14 (T14) days after conditioning. Both opioids induced a change in place preference (T1), suggesting that they have short-term reinforcing properties. However, only tramadol was associated with place preference retention (T7 and T14), with an increase in the number of entries in the opioid-paired compartment (T1 and T7), showing that it causes rewarding memory and incubation of craving. The results indicate that at therapeutic doses: (1) both drugs cause short-term rewarding effects and (2) as opposed to tramadol, tapentadol does not cause CPP retention, despite its higher central nervous system activity and stricter scheduling.

The controlled study of pedestrians' crossing decision-making is relevant to the search for better safety conditions for this class of vulnerable road users. Several risk factors have been identified in the literature related to the crosswalks' surrounding environment, the socio-demographic characteristics of the pedestrians crossing the road and the place where the crosswalks are inserted, as well as situational variables, such as speed and distance of the approaching vehicle during the crossing. In this work, the roles of visual and auditory cues in crossing decisions were analysed, comparing different speeds and distances, and taking into consideration different speed patterns of the approaching vehicle, aiming to identify what can affect pedestrians' crossing behaviour. Experiments were performed in a virtual environment. Participants were presented with 10 different stimuli featuring a vehicle approaching with different speeds and movement patterns, combined with 2 auditory conditions: one concerning a vehicle with a gasoline combustion engine and another one with no sound cues. Participants were tasked with indicating the moment they decided to cross the street when they thought it was safe to do so by pressing a response button. Percentage of crossings, response time (RT), and time-to-passage (TTP) were recorded and subsequently analysed. The results showed that lower speeds and higher distances lead to higher percentages of crossings and RTs. The auditory condition did not significantly affect participants' responses, leading to the conclusion that participants' crossing decision was especially based on their visual perception of the movement characteristics of the approaching vehicle, particularly its speed and distance. These results may have relevance for the development of communication strategies between the vehicles, especially the automated ones, and pedestrians., This work was partially financed by national funds through FCT - Fundacao para a Ciencia e a Tecnologia, under grant agreement [SFRH/BD/131638/2017] attributed to the first author; by FCT/MCTES through national funds (PIDDAC) under the R&D Unit Institute for Sustainability and Innovation in Engineering Structures (ISISE) [UIDB/04029/2020]; and by the project Promoting Scientific Production and Technological Development and Thematic Networking (3599-PPCDT), supported by the European Community Fund FEDER, through the grant attributed to the project AnPeB -Analysis of pedestrians behaviour based on simulated urban environments and its incorporation in risk modelling [PTDC/ECM-TRA/3568/2014].

Introduction: Drug use related deaths are increasing and the lack of effective treatment for psychostimulants can be largely held responsible. Particularly, no pharmacotherapy is approved for methamphetamine (METH) use disorder despite decades of research. Only psychosocial interventions are clinically used, with limited long-term recovery and relapse.Areas covered: This review aims to select and describe the most relevant findings to date. Selected clinical trials were found in PubMed using the following keywords ('methamphetamine') and ('addiction' OR 'withdrawal' OR 'treatment' OR 'pharmacotherapy'). Randomized placebo-controlled trials enrolling treatment-seeking METH-dependent subjects and inherent secondary analysis were included.Expert opinion: Overall, end-of-treatment abstinence, reduced METH use or lower relapse rates were seen on METH dependent subgroups or attained significance only following post hoc analysis, irrespective of the medication tested. For example, light and heavy METH users seem to respond differently to pharmacotherapy. This together with the heterogeneous nature of the METH dependent population strongly suggests that some drugs herein described (e.g. mirtazapine, methylphenidate) should be further tested in clinical trials focused on subgroups. Lastly, objective measures, such as urinalysis, are mandatory to include in clinical trials and early treatment response and/or medication compliance should be carefully monitored and considered as predictors of success/failure.

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions.

Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.

Cuprizone (CPZ) is a copper chelator used to produce a reversible oligodendrocytopathy in animals, which has some similarities to the pathology found in human multiple sclerosis (MS). This model is attractive to study remyelination.To demonstrate that a two-week period after cessation of CPZ exposure is sufficient to establish changes compatible with remyelination, without accompanying behavior or brain magnetic resonance imaging (MRI) disturbances.Two groups of male C57BL/6 mice were fed an oral solution of CPZ (0.2%) for 5 weeks (W5); half of the animals were kept under the vehicle for another 2 weeks (W7). After 5 and 7 weeks, animals were subjected to a battery of behavioural tests and 18 animals to brain MRI. Animals' cerebellar samples were studied for gene expression and/or protein levels of GFAP, myelin proteolipid protein (PLP), TNF-α and IL-1β.No differences were observed between CPZ-exposed and control animals, regarding behavior and MRI, both at W5 and W7. However, myelin PLP levels decreased in CPZ (W5) treated animals, and these changes reverted at W7. GFAP levels varied in the opposite direction.Observed changes validate the use of W5 and W7 temporal moments for the study of demyelination and early remyelination in this model.

Mitochondrial deregulation has emerged as one of the earliest pathological events in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. Improvement of mitochondrial function in AD has been considered a relevant therapeutic approach. L-carnitine (LC), an amino acid derivative involved in the transport of long-chain fatty acids into mitochondria, was previously demonstrated to improve mitochondrial function, having beneficial effects in neurological disorders; moreover, acetyl-L-carnitine (ALC) is currently under phase 4 clinical trial for AD (ClinicalTrials.gov NCT01320527). Thus, in the present study, we investigated the impact of different forms of carnitines, namely LC, ALC and propionyl-L-carnitine (PLC) on mitochondrial toxicity induced by amyloid-beta peptide 1-42 oligomers (AβO; 1 μM) in mature rat hippocampal neurons. Our results indicate that 5 mM LC, ALC and PLC totally rescued the mitochondrial membrane potential and alleviated both the decrease in oxygen consumption rates and the increase in mitochondrial fragmentation induced by AβO. These could contribute to the prevention of neuronal death by apoptosis. Moreover, only ALC ameliorated AβO-evoked changes in mitochondrial movement by reducing the number of stationary mitochondria and promoting reversal mitochondrial movement. Data suggest that carnitines (LC, ALC and PLC) may act differentially to counteract changes in mitochondrial function and movement in neurons subjected to AβO, thus counteracting AD-related pathological phenotypes.

(1) Background: One mechanism through which physical activity (PA) provides benefits is by triggering activity at a molecular level, where neurotrophins (NTs) are known to play an important role. However, the expression of the circulating levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4/5), in response to exercise, is not fully understood. Therefore, the aim was to provide an updated overview on the neurotrophin (NT) variation levels of BDNF and NT-4/5 as a consequence of a long-term aerobic exercise intervention, and to understand and describe whether the upregulation of circulating NT levels is a result of neurotrophic factors produced and released from the brain, and/or from neurotrophic secreting peripheral organs. (2) Methods: The articles were collected from PubMed, SPORTDiscus, Web of Science, MEDLINE, and Embase. Data were analyzed through a narrative synthesis. (3) Results: 30 articles studied humans who performed training protocols that ranged from 4 to 48 weeks; 22 articles studied rodents with an intervention period that ranged from 4 to 64 weeks. (4) Conclusions: There is no unanimity between the upregulation of BDNF in humans; conversely, concerning both BDNF and NT-4/5 in animal models, the results are heterogeneous. Whilst BDNF upregulation appears to be in relative agreement, NT-4/5 seems to display contradictory and inconsistent conclusions.

Virtual reality is becoming an important tool for studying the interaction between pedestrians and road vehicles, by allowing the analysis of potentially hazard situations without placing subjects in real risk. However, most of the current simulators are unable to accurately recreate traffic sounds that are congruent with the visual scene. This has been recognized as a fault in the virtual audio-visual scenarios used in such contexts. This study proposes a method for delivering a binaural auralization of the noise generated by a moving vehicle to an arbitrarily located moving listener (pedestrian). Building on previously developed methods, the proposal presented here integrates in a novel way a dynamic auralization engine, thus enabling real-time update of the acoustic cues in the binaural signal delivered via headphones. Furthermore, the proposed auralization routine uses Close ProXimity (CPX) tyre-road noise signal as sound source input, facilitating the quick interchangeability of source signals, and easing the noise collection procedure. Two validation experiments were carried out, one to quantitatively compare field signals with CPX-derived virtual signal recordings, and another to assess these same signals through psychoacoustic models. The latter aims to assure that the reproduction of the synthesized signal is perceptually similar to one occurring on pedestrian/vehicle interactions during situations of street crossing. Discrepancies were detected, and emphasized when the vehicle is within close distance from the receiver (pedestrian). However, the analysis indicated that these pose no hindrance to the study of vehicle–pedestrian interaction. Improvements to the method are identified and further developments are proposed., This work was supported by the ‘‘Fundação para a Ciência e a Tecnologia” [PTDC/ECM-TRA/3568/2014, SFRH/BD/131638/2017, UIDB/04029/2020] This work is part of the activities of the research project AnPeB – ‘‘ANalysis of PEdestrians Behaviour based on simulated urban environments and its incorporation in risk modelling” (PTDC/ECM TRA/3568/2014), funded by the ‘‘Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáti cas” (3599-PPCDT) project and supported by the ‘‘European Com munity Fund FEDER” and the doctoral scholarship SFRH/ BD/131638/2017, funded by ‘‘Fundação para a Ciência e a Tecnolo gia (FCT)”.

Depression is associated with an increased risk of aging-related diseases. It is also seemingly a common psychological reaction to pandemic outbreaks with forced quarantines and lockdowns. Thus, depression represents, now more than ever, a major global health burden with therapeutic management challenges. Clinical data highlights that physical exercise is gaining momentum as a non-pharmacological intervention in depressive disorders. Although it may contribute to the reduction of systemic inflammation associated with depression, the mechanisms underlying the beneficial physical exercise effects in emotional behavior remain to be elucidated. Current investigations indicate that a rapid release of extracellular vesicles into the circulation might be the signaling mediators of systemic adaptations to physical exercise. These biological entities are now well-established intercellular communicators, playing a major role in relevant physiological and pathophysiological functions, including brain cell–cell communication. We also reviewed emerging evidence correlating depression with modified circulating extracellular vesicle surfaces and cargo signatures (e.g., microRNAs and proteins), envisioned as potential biomarkers for diagnosis, efficient disease stratification and appropriate therapeutic management. Accordingly, the clinical data summarized in the present review prompted us to hypothesize that physical exercise-related circulating extracellular vesicles contribute to its antidepressant effects, particularly through the modulation of inflammation. This review sheds light on the triad “physical exercise–extracellular vesicles–depression” and suggests new avenues in this novel emerging field.

When crossing a road, pedestrians must detect traffic, combine data coming from different perceptual modalities, evaluate the time envelope for safely cross the street, and monitor the position of oncoming vehicles to perform corrective actions if needed. This study analyzed the influence of noise emitted by vehicles, or its absence, on pedestrians&rsquo, crossing decision-making. Experiments were performed in a virtual environment using two road scenarios. Participants were presented with stimuli of approaching vehicles that varied regarding speed, movement patterns, and auditory condition: one concerning the approaching of an electric vehicle, another regarding the approaching of a gasoline combustion vehicle, and, finally, a condition regarding the absence of auditory cues. Participants were tasked with indicating the moment when they decided to cross the street. The results show that, despite the noise variations caused by the type of vehicle and its speed pattern, the participants&rsquo, decision to cross was mostly based on vehicle distance. When a vehicle approaches the crosswalk from a short distance and with no occlusion to the pedestrian&rsquo, s visibility, the sound does not seem to influence the pedestrians&rsquo, crossing decision-making.

The neonatal exposure to general anesthetics has been associated with neuronal apoptosis and dendritic spines morphologic changes in the developing brain. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated short- and long-term effects of a single ketamine (20 mg/kg, s.c.) neonatal exposure at postnatal day 7 in rats on the hippocampal and frontal cortical cellular viability. Additionally, putative neurochemical alterations and neurobehavioral impairments were evaluated in the adulthood. Ketamine neonatal administration selectively decreased cellular viability in the hippocampus, but not in the frontal cortex, 24 h after the treatment. Interestingly, a single ketamine neonatal exposure prevented the vulnerability to glutamate-induced neurotoxicity in the frontal cortex of adult rats. No short- or long-term damage to cellular membranes, as an indicative of cell death, was observed in hippocampal or cortical slices. However, ketamine induced a long-term increase in hippocampal glutamate uptake. Regarding behavioral analysis, neonatal ketamine exposure did not alter locomotor activity and anxiety-related parameters evaluated in the open-field test. However, ketamine administration disrupted the hippocampal-dependent object recognition ability of adult rats, while improved the motor coordination addressed on the rotarod. These findings indicate that a single neonatal ketamine exposure induces a short-term reduction in the hippocampal, but not in cortical, cellular viability, and long-term alterations in hippocampal glutamate transport, improvement on motor performance, and short-term recognition memory impairment.

GPR37 is an orphan G protein-coupled receptor highly expressed in the brain. The precise function of GPR37 is still unknown, but a number of evidences indicate it modulates the dopaminergic system. Here, we aimed to determine the role of GPR37 on the control of cocaine-mediated electrophysiological effects (synaptic transmission and short-term plasticity) in corticostriatal synapses. Accordingly, we evaluated basal synaptic transmission and paired-pulse stimulation (PPS) in wild-type and GPR37KO mice slices. Regardless of the genotype, a low concentration of cocaine (2μM) did not modify basal synaptic transmission. Conversely, a higher dose of cocaine (30μM) decreased synaptic transmission in both genotypes, although with different intensities: approximately 30% in slices from wild-type mice and 45% in slices from GPR37-KO mice. On the other hand, no differences in PPS ratio were observed between wild-type and GPR37-KO cocaine-treated mice. Overall, our data suggest that GPR37 is involved in cocaine-induced modification of basal synaptic transmission without modifying cocaine effects in short-term plasticity.

Convincing evidence indicates that advanced glycation end-products and danger-associated protein S100B play a role in Parkinson's disease (PD). These agents operate through the receptor for advanced glycation end-products (RAGE), which displays distinct isoforms playing protective/deleterious effects. However, the nature of RAGE variants has been overlooked in PD studies. Hence, we attempted to characterize RAGE regulation in early stages of PD striatal pathology. A neurotoxin-based rodent model of PD was used in this study, through administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice. Animals were killed 6 h post-MPTP to assess S100B/RAGE contents (RT-qPCR, ELISA) and RAGE isoform density (WB) and cellular distribution (immunohistochemistry). Dopaminergic and gliotic status were also mapped (HPLC-ED, WB, immunohistochemistry). At this preliminary stage of MPTP-induced PD in mice, RAGE inhibitory isoforms were increased whereas full-length RAGE was not affected. This putative cytoprotective RAGE phenotype paired an inflammatory and pro-oxidant setting fueling DAergic denervation. Increased RAGE inhibitory variants occur in astrocytes showing higher S100B density but no overt signs of hypertrophy or NF-κB activation, a canonical effector of RAGE. These findings expand our understanding of the toxic effect of MPTP on striatum and offer first in vivo evidence of RAGE being a responder in early stages of astrogliosis dynamics, supporting a protective rather tissue-destructive phenotype of RAGE in the initial phase of PD degeneration. These data lay the groundwork for future studies on the relevance of astrocytic RAGE in DAergic neuroprotection strategies. We report increased antagonistic RAGE variants paralleling S100B up-regulation in early stages of MPTP-induced astrogliosis dynamics . We propose that selective RAGE regulation reflects a self-protective mechanism to maintain low levels of RAGE ligands , preventing long-term inflammation and oxidative stress arising from sustained ligands/flRAGE activation . Understanding loss of RAGE protective response to stress may provide new therapeutic options to halt or slow down dopaminergic axonopathy and, ultimately, neuronal death .

Stress has been considered determinant in the etiology of depression. The adrenal medulla plays a key role in response to stress by releasing catecholamines, which are important to maintain homeostasis. We aimed to study the adrenal medulla in a mouse model of depression induced by 21 days of unpredictable chronic stress (UCS). We observed that UCS induced a differential and time-dependent change in adrenal medulla. After 7 days of UCS, mice did not show depressive-like behavior, but the adrenal medullae show increased protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DβH and PNMT), Neuropeptide Y, the SNARE protein SNAP-25, the catecholamine transporter VMAT2 and the chromaffin progenitor cell markers, Mash1 and Phox2b. Moreover, 7 days of UCS induced a decrease in the chromaffin progenitor cell markers, Sox9 and Notch1. This suggests an increased capacity of chromaffin cells to synthesize, store and release catecholamines. In agreement, after 7 days, UCS mice had higher NE and EP levels in adrenal medulla. Opposite, when mice were submitted to 21 days of UCS, and showed a depressive like behavior, adrenal medullae had lower protein and/or mRNA levels of catecholamine biosynthetic enzymes (TH, DβH, PNMT), catecholamine transporters (NET, VMAT1), SNARE proteins (synthaxin1A, SNAP25, VAMP2), catecholamine content (EP, NE), and lower EP serum levels, indicating a reduction in catecholamine synthesis, re-uptake, storage and release. In conclusion, this study suggests that mice exposed to UCS for a period of 21 days develop a depressive-like behavior accompanied by an impairment of adrenal medullary function.

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. Coriolus versicolor (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.

Background/Aims: Several guidelines for neuropathic pain management and various effective drugs are available; however, neuropathic pain remains undertreated. This retrospective study aimed to evaluate the efficacy of topical capsaicin 8% in peripheral neuropathic pain in a routine clinical setting. Methods: Therapeutic efficacy was evaluated through pain intensity, using numerical pain rating scale at baseline and 7–14 days after each treatment, and using pain treatment area (PTA) assessed immediately before each treatment. Results: A total of 43 patients with either post-herpetic neuralgia or post-traumatic/post-surgical neuropathic pain were enrolled. The median percentage reduction in numerical pain rating scale score and in PTA was –40.0 (–50.0 to –33.3; 95% CI, bootstrap) and –35.1 (–50.9 to 3.4; 95% CI, bootstrap), respectively. Pain intensity and PTA were equally improved and reduced in both treated conditions. Conclusion: This study suggests that topical capsaicin 8% reduces peripheral neuropathic pain as well as treatment pain area.

The purpose of this study was to evaluate the impact of prebifurcation renal denervation in a swine model and assess its safety through optical coherence tomography (OCT). Prebifurcation renal denervation with a multi-electrode catheter was performed in one renal artery of 12 healthy pigs, with the contralateral artery and kidney being used as controls. Angiograms and OCT pullbacks were obtained peri-procedurally and 1 month post procedure. Renal tissue catecholamines were quantified, and the arterial wall and peri-adventitial tissue were analyzed histologically. Intraluminal changes (endothelial swelling, spasm, and thrombus formation) were observed acutely by OCT in most of the treated arteries and were no longer visible at follow-up. Histology revealed a statistically significant accumulation of collagen (fibrosis) and a near absence of tyrosine hydroxylase labeling in the denervated artery, suggesting a clear reduction in nervous terminals. Renal tissue catecholamine levels were similar between both sides, probably due to the low number of ablation points and the renorenal reflex. The present study demonstrates that renal denervation is associated with acute intimal disruptions, areas of fibrosis, and a reduction in nervous terminals. The lack of difference in renal tissue catecholamine levels is indicative of the need to perform the highest and safest number of ablation points in both renal arteries. These findings are important because they demonstrate the histological consequences of radiofrequency energy application and its medium-term safety.

Methamphetamine (METH) is the primary drug within amphetamine-type stimulants which are the second most abused group of drugs worldwide. There is no pharmacological treatment addressed specifically to METH addiction, and behavioral therapy is shadowed by poor long-term recovery and relapse. Therefore, novel approaches to manage METH addiction are an urgent need. This review aims to describe the current state of physical exercise use on methamphetamine addiction management. The following searching terms in PubMed were used: ("physical exercise" OR "exercise") AND "methamphetamine." Relevant references from key publications and gray literature were also reviewed to identify additional citations for inclusion. Original investigation regarding physical exercise and methamphetamine addiction (clinical data) or neurobiological mechanisms of physical exercise in animal models of methamphetamine administration (preclinical data) was included. Overall, METH users demonstrated improvements, including better fitness and emotional measures, lower relapse rates, and sustained abstinence when compared to nonexercised individuals. The neurobiological mechanisms of physical exercise in METH users seem to reflect an interplay of several agents, including neurochemicals, oxidative stress, neurogenesis, gliogenesis, and blood-brain barrier as disclosed by preclinical data. Exercise-based interventions alone or as a conjoint therapy may be a useful tool for managing METH addiction.

Parkinson's disease (PD) prodromal stages comprise neuropsychiatric perturbations that critically compromise a patient’s quality of life. These nonmotor symptoms (NMS) are associated with exacerbated innate immunity, a hallmark of overt PD. Physical exercise (PE) has the potential to improve neuropsychiatric deficits and to modulate immune network including receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in distinct pathological settings. Accordingly, the present study aimed to test the hypothesis that PE 1) alleviates PD NMS and 2) modulates neuroimmune RAGE network in experimental PD. Adult Wistar rats subjected to long-term mild treadmill were administered intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probed for PD NMS before the onset of motor abnormalities. Twelve days after MPTP, neuroimmune RAGE network transcriptomics (real-time quantitative PCR) was analyzed in frontal cortex, hippocampus, and striatum. Untrained MPTP animals displayed habit-learning and motivational deficits without gross motor impairments (cued version of water-maze, splash, and open-field tests, respectively). A suppression of RAGE and neuroimmune-related genes was observed in frontal cortex on chemical and physical stressors (untrained MPTP: RAGE, TLR5 and -7, and p22 NADPH oxidase; saline-trained animals: RAGE, TLR1 and -5 to -11, TNF-α, IL-1β, and p22 NADPH oxidase), suggesting the recruitment of compensatory mechanisms to restrain innate inflammation. Notably, trained MPTP animals displayed normal cognitive/motivational performances. Additionally, these animals showed normal RAGE expression and neuroprotective PD-related DJ-1 gene upregulation in frontal cortex when compared with untrained MPTP animals. These findings corroborate PE efficacy in improving PD NMS and newly identify RAGE network as a neural substrate for exercise intervention. Additional research is warranted to unveil functional consequences of PE-induced modulation of RAGE/DJ-1 transcriptomics in PD premotor stages. NEW & NOTEWORTHY This study newly shows that physical exercise (PE) corrects nonmotor symptoms of the intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of experimental parkinsonism. Additionally, we show that suppression of neuroimmune receptor for advanced glycation end products (RAGE) network occurs in frontal cortex on chemical (MPTP) and physical (PE) interventions. Finally, PE normalizes frontal cortical RAGE transcriptomics and upregulates the neuroprotective DJ-1 gene in the intranasal MPTP model of experimental parkinsonism.

Alterations in microtubule-dependent transport, mitochondrial dysfunction, and autophagic pathology are involved in neurodegeneration observed in sporadic Parkinson's disease. However, the mechanistic link connecting these events remains elusive. We observed that NAD+ metabolism is altered in sporadic Parkinson's disease patient-derived cells, which contributes to Sirtuin-2 activation and subsequent decrease in acetylated-α-tubulin levels. Pharmacological inhibition of sirtuin-2 deacetylase activity selectively enhanced α-tubulin acetylation and facilitated the trafficking and clearance of misfolded proteins. Sirtuin-2 knock-out mice neurons had no alteration in microtubule assembly after exposure to MPP+, allowing the maintenance of a normal autophagic flux. These data were validated using MPTP-treated sirtuin-2 knock-out mice, where no alterations in motor behavior were observed. Biochemical analysis of sporadic Parkinson's disease patient brains supports the in vitro and in vivo data. Our data provide strong evidence that sirtuin-2 controls the functional ability of the autophagic system through acetylation and highlight the association between mitochondrial metabolism and neurodegeneration in sporadic Parkinson's disease.

Neuroinflammation is a two-edged sword in Alzheimer's disease (AD). A certain degree of neuroinflammation is instrumental in the clearance of amyloid-β (Aβ) peptides by activated microglia, although a sustained neuroinflammation might accelerate Aβ deposition, thus fostering the neurodegenerative process and functional decline in AD. There is an increasing body of evidence suggesting that the innate immune system via Toll-like receptor 4 (TLR4) finely orchestrates the highly regulated inflammatory cascade that takes place in AD pathology. Herein we critically review pre-clinical (in vitro and in vivo approaches) and clinical studies showing that monophosphoryl lipid A (MPL), a partial TLR4 agonist, may have beneficial effect on AD physiopathology. The in vivo data elegantly showed that MPL enhanced Aβ plaque phagocytosis thus decreasing the number and the size of Aβ deposits and soluble Aβ in brain from APPswe/PS1 mice. Furthermore, MPL also improved their cognition. The mechanism underlying this MPL effect was proposed to be microglial activation by recruiting TLR4. Additionally, it was demonstrated that MPL increased the Aβ antibody titer and showed a safe profile in mice and primates, when used as a vaccine adjuvant. Clinical studies using MPL as an adjuvant in Aβ immunotherapy are currently ongoing. Overall, we argue that the TLR4 partial agonist MPL is a potentially safe and effective new pharmacological tool in AD.

Methamphetamine leads to functional changes in basal ganglia that are linked to impairment in motor activity. Previous studies from our group and others have shown that a single high-methamphetamine injection induces striatal dopaminergic changes in rodents. However, striatal glutamatergic, GABAergic and serotoninergic changes remain elusive under this methamphetamine regimen. Moreover, nothing is known about the participation of the receptor for advanced glycation end-products (RAGE), which is overexpressed upon synaptic dysfunction and glial response, on methamphetamine-induced striatal dysfunction. The aim of this work was to provide an integrative characterization of the striatal changes in amino acids, monoamines and astroglia, as well as in the RAGE levels, and the associated motor activity profile of C57BL/6 adult mice, 72 h after a single-high dose of methamphetamine (30 mg/kg, i.p.). Our findings indicate, for the first time, that methamphetamine decreases striatal glutamine, glutamate and GABA levels, as well as glutamine/glutamate and GABA/glutamate ratios, while serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels remain unchanged. This methamphetamine regimen also produced dopaminergic terminal degeneration in the striatum, as evidenced by dopamine and tyrosine hydroxylase depletion. Consistently, methamphetamine decreased the locomotor activity of mice, in the open field test. In addition, increased levels of glutamine synthase and glial fibrillary acidic protein were observed. Nevertheless, methamphetamine failed to change RAGE levels. Our results show that acute methamphetamine intoxication induces pronounced changes in the striatal glutamatergic/GABAergic and dopaminergic homeostasis, along with astrocyte activation. These neurochemical and glial alterations are accompanied by impairment in locomotor activity.

Amphetamines exert their persistent addictive effects by activating brain's reward pathways, perhaps through the release of dopamine in the nucleus accumbens (and/or in other places). On the other hand, there is a relationship between dopamine and all behavioural aspects that involve motor activity and it has been demonstrated that exercise leads to an increase in the synthesis and release of dopamine, stimulates neuroplasticity and promotes feelings of well-being. Moreover, exercise and drugs of abuse activate overlapping neural systems. Thus, our aim was to study the influence of chronic exercise in the mechanism of addiction using an amphetamine-induced conditioned-place-preference in rats.Adult male Sprague-Dawley rats were randomly separated in groups with and without chronic exercise. Chronic exercise consisted in a 8 week treadmill running program, with increasing intensity. The conditioned place preference test was performed in both groups using a procedure and apparatus previously established. A 2 mg.kg(-1) amphetamine or saline solution was administered intraperitonially according to the schedule of the conditioned place preference. Before conditioning none of the animals showed preference for a specific compartment of the apparatus. The used amphetamine dose in the conditioning phase was able to produce a marked preference towards the drug-associated compartment in the group without exercise. In the animals with exercise a significant preference by the compartment associated with saline was observed. These results lead us to conclude that a previous practice of regular physical activity may help preventing amphetamine addiction in the conditions used in this test.

Tramadol, a central analgesic acting on serotonin neurotransmission, is often co-used with ondansetron, a 5-HT3 antagonist, for the management of postoperative pain to decrease nausea and vomiting. The aim of the study is to test the hypothesis that this drug combination raises tramadol requirement by patient-controlled analgesia (PCA). Forty patients undergoing hernioplasty or thyroidectomy were enrolled in a randomized, controlled study and allocated to receive ondansetron 4 mg i.v. (n = 20) or saline (n = 20). At 0, 1, 2, 4 and 24 h of PCA, tramadol consumption was evaluated. Tramadol consumption (mg × kg–1 × h–1) was higher in the ondansetron group at the 2-hour time point compared to the control group (0.24 ± 0.1 vs. 0.17 ± 0.16; p = 0.01). Our study suggests that ondansetron acutely reduces the analgesic efficacy of tramadol.

Methamphetamine (METH) abuse and addiction present a major problem in the United States and globally. Oxidative stress associated with exposure to METH mediates to the large extent METH-evoked neurotoxicity. While there are currently no medications approved for treating METH addiction, its pharmacology provides opportunities for potential pharmacotherapeutic adjuncts to behavioral therapy in the treatment of METH addiction. Opioid receptor agonists can modulate the activity of dopamine neurons and could, therefore, modify the pharmacodynamic effects of METH in the dopaminergic system. Efficacy of the adjunctive medication with buprenorphine has been demonstrated in the treatment of cocaine addiction extending beyond opiate addiction. We investigated the interactions of morphine (10 mg/kg) and buprenorphine (0.01 and 10 mg/kg) with METH (2 mg/kg) affecting striatal dopaminergic transmission. The extracellular concentration of dopamine (DA) and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined using brain microdialysis coupled with high performance liquid chromatography with electrochemical detection (HPLC-ED) in the caudate nucleus of adult, awake, male Sprague-Dawley rats. Compared to METH alone, extracellular DA release was prolonged for 140 min without changes in DA peak-effect by combined treatment with morphine/METH. Morphine did not change DOPAC efflux evoked by METH. On the other hand, both buprenorphine doses attenuated the METH-induced DA peak-effect. However, whereas high buprenorphine dose extended DA outflow for 190 min, the low-dose abbreviated DA release. High buprenorphine dose also shortened METH-induced decrease in DOPAC efflux. Data confirm that opiates modulate dopaminergic neurotransmission evoked by METH. Alteration of dopaminergic response to METH challenge under buprenorphine may suggest effectiveness of buprenorphine treatment in METH addiction.

Methamphetamine (METH) is a powerful psychostimulant whose noxious effects depend largely on the pattern of abuse. METH-induced glutamate release may overactivate N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (NMDAR and AMPAR, respectively) causing excitotoxicity. In the brain, these receptors are also known for their essential role in mediating memory consolidation. Therefore, we assessed glial fibrillary acidic protein (GFAP) expression as a marker for astrogliosis and neurodegeneration by using Fluoro-Jade C (F-J C) staining. Moreover, we investigated the effect of two METH regimens on NMDAR NR1 and NR2A and on AMPAR GluR2 subunit expression in the rat striatum and frontal cortex 24 h after drug treatment. Adult Sprague-Dawley rats were injected subcutaneously (s.c.) on six consecutive days with saline (control and acute groups) or with an increasing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the seventh day, both METH groups were given a "bolus" of 30 mg/kg METH, whereas controls received saline. We evaluated the expression levels of GFAP by both Western blot and immunohistochemical assays and concluded that there was no difference from control levels. In addition, neither drug regimen resulted in neurodegeneration within 24 h of last METH administration. In the frontal cortex of the acute group, NR1 expression level was decreased, and both NR2A and GluR2 were increased. Also, in the striatum of the acute group, the expression level of GluR2 was significantly increased, and both GluR2 and NR2A levels were augmented in the striatum of the ED group. Taken together, these results suggest a protective mechanism by decreasing permeability and/or functionality of AMPAR and NMDAR to counteract METH-induced glutamate overflow in the brain. Moreover, these results may explain, in part, the mnemonic deficits and psychotic behavior associated with METH abuse.

The glutamate-glutamine cycle between neurons and glia is tightly related to excitatory glutamatergic and inhibitory GABAergic regulation in brain. The role of this neuron-astrocyte cross-talk on the neurotoxicity induced by amphetamines is not understood. Also, the impact of neurotoxic doses of amphetamines on the balance between glutamatergic and GABAergic circuits is largely unknown. The aim of this work was to assess the acute effect of a neurotoxic regimen of amphetamine (AMPH) on glutamine (GLN, an astrocytic marker) levels and on glutamine/glutamate (an index for glutamate-glutamine cycle) and GABA/glutamate ratios in rat brain. Sprague-Dawley rats were sacrificed 4 and 24 h after a single-dose regimen of AMPH (30 mg/kg, i.p.), and the caudate-putamen (CPu), frontal cortex (FC), and hippocampus (Hp) were dissected for analysis of glutamate (GLU), gamma-aminobutyric acid (GABA), and GLN. The total content of these amino acids was measured using a microbore HPLC electrochemical detector. Although AMPH did not change GLU levels, it increased both GLN content and GLN/GLU ratio (160-469%) at 4 h, but not at 24 h, in all regions after injection. Striatal GABA levels and GABA/GLU ratio were increased (46 and 100%, respectively) at 24 h. In hippocampus the GABA/GLU increase (60%) occurred as early as 4 h after treatment. To the contrary, AMPH exerted no effect in GABA/GLU balance in frontal cortex. These data strongly suggest that this neurotoxic AMPH regimen provoked an early increase in the glutamate-glutamine cycle between neurons and glia. This increase may ultimately lead to an upregulation of the inhibitory system as a compensatory response.

The aim of this study was to verify the effect of chronic exercise on the striatal dopamine (DA) outflow induced by low and high single doses of amphetamine (AMPH), and verify the existence of an exercise protective role on neurodegeneration. Adult male Sprague-Dawley rats were randomly separated into six groups: chronic exercise, saline; chronic exercise, 5 mg kg(-1) AMPH; chronic exercise, 30 mg kg(-1) AMPH; without exercise, saline; without exercise, 5 mg kg(-1) AMPH; without exercise, 30 mg kg(-1) AMPH. Chronic exercise consisted of an 8-week running program on a treadmill, with increasing intensity. Animals were anesthetized, placed into a stereotaxic frame and an intracerebral guide cannula implanted into the caudate-putamen. When indicated, microdialysis was performed. Dialysate samples were collected during 30-min intervals for 6 h, before and after the intraperitonial administration of AMPH or saline solution. HPLC with electrochemical detection was used to quantify DA. Chronic exercise did not significantly change the extracellular DA basal values. Regarding the maximal DA levels in the dialysates, in the rats treated with 5 mg kg(-1) AMPH, there was no significant difference between groups with and without chronic exercise; on the contrary, in animals treated with 30 mg kg(-1) AMPH, the DA release was lower in the group with chronic exercise. Moreover, the maintenance of higher levels of DA along time in the training group suggests a diminished reuptake of DA. By using the Fluoro-Jade C staining technique, we did not find neuronal death in any of the groups. In conclusion, these results suggest that chronic exercise leads to a diminished release and reuptake of DA after administration of a high dose of AMPH, whereas neither chronic exercise nor AMPH seems to induce neurodegeneration.

SummaryIntroduction We recently showed that a single high dose of methamphetamine (METH) induces a persistent frontal cortical monoamine depletion that is accompanied by helpless-like behavior in mice. However, brain metabolic alterations underlying both neurochemical and mood alterations remain unknown. Aims Herein, we aimed at characterizing frontal cortical metabolic alterations associated with early negative mood behavior triggered by METH. Adult C57BL/6 mice were injected with METH (30 mg/kg, i.p.), and their frontal cortical metabolic status was characterized after probing their mood and anxiety-related phenotypes 3 days postinjection. Results Methamphetamine induced depressive-like behavior, as indicated by the decreased grooming time in the splash test and by a transient decrease in sucrose preference. At this time, METH did not alter anxiety-like behavior or motor functions. Depolarization-induced glucose uptake was reduced in frontocortical slices from METH-treated mice compared to controls. Consistently, astrocytic glucose transporter (GluT1) density was lower in the METH group. A proton high rotation magic angle spinning (HRMAS) spectroscopic approach revealed that METH induced a significant decrease in N-acetyl aspartate (NAA) and glutamate levels, suggesting that METH decreased neuronal glutamatergic function in frontal cortex. Conclusions We report, for the first time, that a single METH injection triggers early self-care and hedonic deficits and impairs frontal cortical energetics in mice.

Methamphetamine (METH) is a powerful psychostimulant that increases glutamate (Glu) levels in the mammalian brain and it is currently known that hippocampi are particularly susceptible to METH. Moreover, it is well established that the overactivation of N-methyl-d-aspartate (NMDA) and AMPA ionotropic Glu receptors causes excitotoxicity. In the present study, we investigated the effect of acute (30 mg/kg) versus escalating dose (ED) administration of METH on NMDA receptor 1, NMDA receptor 2 and glutamate receptor 2 (GluR2) subunit expression in the hippocampus and on memory. Adult Sprague-Dawley rats were injected s.c. during six consecutive days with saline (control and acute groups) or with a growing dose of METH (10, 15, 15, 20, 20, 25 mg/kg/day; ED group). On the 7th day, both METH groups were injected with a 'bolus' of 30 mg/kg METH whereas controls received saline. Western blot analysis showed an increase of GluR2 and NR2A expression levels and no alterations on NR1 subunit in the acute group. On the other hand, in the ED group, GluR2 and NR2A expression levels were unaltered and there was a decrease on NR1 levels. Moreover, we did not observe neurodegeneration with both administration paradigms, as assessed by Fluoro-Jade C staining, but we did observe a strong astrogliosis in the acute administration group by using both immunohistochemistry and Western blot analysis. The impact of METH on working memory was evaluated using the Y maze test and revealed significant mnemonic deficit in the rats acutely treated with the drug. Overall, our results suggest a protection mechanism under conditions of METH administration by decreasing permeability and/or functionality of NMDA and AMPA receptors, which has implications on memory. So, the participation of the glutamatergic system should be considered as an important pharmacological target to design new strategies to prevent or diminish the harmful effect of drug consumption.

Summary Aims Astrocytic S100B and receptor for advanced glycation endproducts (RAGE) have been implicated in Parkinson׳s disease (PD) pathogenesis through yet unclear mechanisms. This study attempted to characterize S100B/mRAGE (signaling isoform) axis in a dying-back dopaminergic (DAergic) axonopathy setting, which mimics an early event of PD pathology. Methods C57BL/6 mice were submitted to a chronic MPTP paradigm (20 mg/kg i.p., 2 i.d-12 h apart, 5 days/week for 2 weeks) and euthanized 7 days posttreatment to assess mRAGE cellular distribution and S100B/mRAGE density in striatum, after probing their locomotor activity (pole test and rotarod). Dopaminergic status, oxidative stress, and gliosis were also measured (HPLC-ED, WB, IHC). Results This MPTP regimen triggered increased oxidative stress (augmented HNE levels), gliosis (GS/Iba1-reactive morphology), loss of DAergic fibers (decreased tyrosine hydroxylase levels), and severe hypodopaminergia. Biochemical deficits were not translated into motor abnormalities, mimicking a presymptomatic PD period. Remarkably, striatal neurotrophic S100B/mRAGE levels and major neuronal mRAGE localization coexist with compensatory responses (3-fold increase in DA turnover), which are important to maintain normal motor function. Conclusion Our findings rule out the involvement of S100B/mRAGE axis in striatal reactive gliosis, DAergic axonopathy and warrant further exploration of its neurotrophic effects in a presymptomatic compensatory PD stage, which is a fundamental period for successful implementation of therapeutic strategies.

Parkinson's disease (PD) is characterized by motor dysfunction associated with dopaminergic degeneration in the dorsolateral striatum (DLS). However, motor symptoms in PD are often preceded by short-term memory deficits, which have been argued to involve deregulation of medial prefrontal cortex (mPFC). We now used a 6-hydroxydopamine (6-OHDA) rat PD model to explore if alterations of synaptic plasticity in DLS and mPFC underlie short-term memory impairments in PD prodrome. The bilateral injection of 6-OHDA (20μg/hemisphere) in the DLS caused a marked loss of dopaminergic neurons in the substantia nigra (>80%) and decreased monoamine levels in the striatum and PFC, accompanied by motor deficits evaluated after 21 days in the open field and accelerated rotarod. A lower dose of 6-OHDA (10μg/hemisphere) only induced a partial degeneration (about 60%) of dopaminergic neurons in the substantia nigra with no gross motor impairments, thus mimicking an early premotor stage of PD. Notably, 6-OHDA (10μg)-lesioned rats displayed decreased monoamine levels in the PFC as well as short-term memory deficits evaluated in the novel object discrimination and in the modified Y-maze tasks; this was accompanied by a selective decrease in the amplitude of long-term potentiation in the mPFC, but not in DLS, without changes of synaptic transmission in either brain regions. These results indicate that the short-term memory dysfunction predating the motor alterations in the 6-OHDA model of PD is associated with selective changes of information processing in PFC circuits, typified by persistent changes of synaptic plasticity.

The co-administration of methamphetamine (METH) and MOR (MOR)-like compounds is becoming increasingly popular among drug abusers. Recently, it was demonstrated that rats would self-inject METH–heroin combination and that this combination produced a greater rewarding effect than the identical doses of METH alone and it was further suggested that enhanced reward might underlie the popularity of this combination. However, there is null information on the effects of the MOR–METH combination on striatal dopaminergic transmission. In the present article, in vivo brain microdialysis was used to examine the effects of two METH doses (1 and 5 mg/kg, i.p.; [METH1: hyperlocomotion-inducing] and [METH5: stereotypy-inducing], respectively) and MOR (10 mg/kg, i.p. [MOR10]) either alone or in combination on dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) release in caudate putamen (CPu) in freely moving rats. METH1 evoked a transient threefold increase in DA overflow in only one-third of dosed rats. On the contrary, METH5 elicited a 11-fold increase in the extracellular DA levels 30 min after dosing and stayed significantly (P < 0.05) above control levels up to 1.5 h. On the other hand, MOR10 did not significantly change DA extracellular levels. MOR10–METH1 combination prolonged DA outflow for 1 h in all rats dosed without changing peak effect compared to METH1. On the other hand, MOR10–METH5 combination did not change the peak effect nor the DA outflow profile compared to METH5 alone. Consistently, there is a concentration-dependent decrease in DOPAC efflux evoked by METH: METH1 evoked a smaller decrease in DOPAC outflow showing a tendency for returning to basal values whereas METH5 kept DOPAC extracellular levels reduced throughout the experiment. Again, MOR10 did not significantly change DOPAC extracellular levels. MOR delayed the onset without changing METH effect on the DOPAC output. These findings provide suggestive evidence that MOR potentiated the increase in extracellular DA levels induced by a low dose of METH. Thus, this combination yields a profile of action that might underlie the reinforcing properties sought by drug addicts.

The most widely accepted concept of oxidative damage centers on the formation of hydroxyl radical (*OH) which has an extremely short-life and is the major damaging free radical. It was suggested that methamphetamine (METH) toxicity is mediated via production of *OH, as measured by 2,3-dihydroxybenzoic acid (2,3-DHBA). In this study we compared the effects of local caudate nucleus perfusion of METH with systemic administration of METH on *OH generation in relation to DA release. Local perfusion of METH (5 mM, 140 min) induced a higher level of dopamine (DA) release compared to the first METH injection (10 mg/kg, 3 times, i.p.). No significant correlation was found between changes in extracellular DA levels and *OH generation when perfusing METH locally; however, both increased after systemic METH administration.