Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

Environmental enrichment (EE) has been largely used to investigate behavioral modifications and neuroplasticity in the adult brain both in normal and pathological conditions. The interaction between individual behavioral traits with EE responsiveness has not been investigated within the same strain. By using two extremes of CF1 mice that differ by their exploratory behavior in the Open Field (OF) task (Kazlauckas V, 2005), denominated as Low (LE) and High (HE) Exploratory Mice, the present study evaluated if EE during adulthood could modify the putative differences between LE and HE mice on exploratory behavior, memory performance and hippocampal BDNF levels. To this end, we investigated the effect of adult LE and HE mice after 2 months of enriched or standard housing conditions on the open field, on novel object recognition, on the inhibitory avoidance task and on hippocampal BDNF immunocontent. LE showed low exploratory behavior, less retention in the inhibitory avoidance and lower hippocampal BDNF levels. EE enhanced exploratory behavior, memory performance and hippocampal BDNF levels both in LE and HE mice. Importantly, the general profile of LE mice submitted to EE was similar to HE mice housed in standard conditions. These results show that internalized behavior of LE mice can be significantly modified by exposure to an enriched environment even during adulthood. These observations may contribute to investigate biological mechanisms and therapeutical interventions for individuals with internalized psychiatric disorders.

Aging is a major risk factor for cognitive deficits and neurodegenerative disorders, and impaired brain insulin receptor (IR) signaling is mechanistically linked to these abnormalities. The main goal of this study was to investigate whether brain insulin infusions improve spatial memory in aged and young rats. Aged (24 months) and young (4 months) male Wistar rats were intracerebroventricularly injected with insulin (20 mU) or vehicle for five consecutive days. The animals were then assessed for spatial memory using a Morris water maze. Insulin increased memory performance in young rats, but not in aged rats. Thus, we searched for cellular and molecular mechanisms that might account for this distinct memory response. In contrast with our expectation, insulin treatment increased the proliferative activity in aged rats, but not in young rats, implying that neurogenesis-related effects do not explain the lack of insulin effects on memory in aged rats. Furthermore, the expression levels of the IR and downstream signaling proteins such as GSK3-β, mTOR, and presynaptic protein synaptophysin were increased in aged rats in response to insulin. Interestingly, insulin treatment increased the expression of the brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptors in the hippocampus of young rats, but not of aged rats. Our data therefore indicate that aged rats can have normal IR downstream protein expression but failed to mount a BDNF response after challenge in a spatial memory test. In contrast, young rats showed insulin-mediated TrkB/BDNF response, which paralleled with improved memory performance.

Quinolinic acid (QA) is an N-methyl-D-aspartate receptor agonist that also promotes glutamate release and inhibits glutamate uptake by astrocytes. QA is used in experimental models of seizures studying the effects of overstimulation of the glutamatergic system. The guanine-based purines (GBPs), including the nucleoside guanosine, have been shown to modulate the glutamatergic system when administered extracellularly. GBPs were shown to inhibit the binding of glutamate and analogs, to be neuroprotective under excitotoxic conditions, as well as anticonvulsant against seizures induced by glutamatergic agents, including QA-induced seizure. In this work, we studied the electrophysiological effects of guanosine against QA-induced epileptiform activity in rats at the macroscopic cortical level, as inferred by electroencephalogram (EEG) signals recorded at the epidural surface. We found that QA disrupts a prominent basal theta (4-10 Hz) activity during peri-ictal periods and also promotes a relative increase in gamma (20-50 Hz) oscillations. Guanosine, when successfully preventing seizures, counteracted both these spectral changes. MK-801, an NMDA-antagonist used as positive control, was also able counteract the decrease in theta power; however, we observed an increase in the power of gamma oscillations in rats concurrently treated with MK-801 and QA. Given the distinct spectral signatures, these results suggest that guanosine and MK-801 prevent QAinduced seizures by different network mechanisms.

Nandrolone decanoate (ND), an anabolic androgenic steroid (AAS), induces an aggressive phenotype by mechanisms involving glutamate-induced N-methyl-d-aspartate receptor (NMDAr) hyperexcitability. The astrocytic glutamate transporters remove excessive glutamate surrounding the synapse. However, the impact of supraphysiological doses of ND on glutamate transporters activity remains elusive. We investigated whether ND-induced aggressive behavior is interconnected with GLT-1 activity, glutamate levels and abnormal NMDAr responses. Two-month-old untreated male mice (CF1, n=20) were tested for baseline aggressive behavior in the resident-intruder test. Another group of mice (n=188) was injected with ND (15mg/kg) or vehicle for 4, 11 and 19days (short-, mid- and long-term endpoints, respectively) and was evaluated in the resident-intruder test. Each endpoint was assessed for GLT-1 expression and glutamate uptake activity in the frontoparietal cortex and hippocampal tissues. Only the long-term ND endpoint significantly decreased the latency to first attack and increased the number of attacks, which was associated with decreased GLT-1 expression and glutamate uptake activity in both brain areas. These alterations may affect extracellular glutamate levels and receptor excitability. Resident males were assessed for hippocampal glutamate levels via microdialysis both prior to, and following, the introduction of intruders. Long-term ND mice displayed significant increases in the microdialysate glutamate levels only after exposure to intruders. A single intraperitoneal dose of the NMDAr antagonists, memantine or MK-801, shortly before the intruder test decreased aggressive behavior. In summary, long-term ND-induced aggressive behavior is associated with decreased extracellular glutamate clearance and NMDAr hyperexcitability, emphasizing the role of this receptor in mediating aggression mechanisms.

Cerebral okadaic acid (OA) administration induces Alzheimer's disease (AD)-like phenotype in rats. Alterations in glutamate levels associated with hyperactivation of cyclin dependent kinase 5 (Cdk5) signaling pathway downstream Tau phosphorylation may participate in the genesis of this pathological phenotype. Here, we examined the efficacy of memantine (MN) pretreatment on reducing OA-induced AD-like phenotypes in rats. Wistar rats were given daily intraperitoneal injections of MN for 3 days and then given an intrahippocampal infusion of OA. Animals were divided into four groups: control (CO), MN, OA and MN/OA. Spontaneous locomotion and spatial memory performance were assessed by open field and Morris water maze respectively. Additionally, we measured glutamate levels in the cerebrospinal fluid (CSF) and the immunocontent of Cdk5, p35, p25 and phosphorylated Tau (pTauSer199/202) in the hippocampus. Spontaneous locomotion did not differ between groups. The OA group showed a significant decrease in spatial memory performance compared to all groups. The OA infusion also increased CSF glutamate levels and the immunocontents of Cdk5, p25 and pTauSer199/202 in the hippocampus. Conversely, pretreatment with MN prevented OA-induced spatial memory deficits and the increment of CSF glutamate level; which paralleled with normal immunocontents of Cdk5, p25 and pTau- Ser199/202 proteins. There were positive correlations between spatial memory performance and the neurochemical parameters. In summary, pretreatment with MN prevents spatial memory deficits induced by intrahippocampal OA administration in rats. The prevention of increase CSF glutamate levels, along with the reduced hippocampal phosphorylation of TauSer199/202 by Cdk5/p25 signaling pathway, are the mechanisms proposed to participate in the prophylactic effects of MN in this AD-like model.

Anxiety disorders appear to involve distinct neurobiological mechanisms and several medications are available against this mental health problem. However, pharmacological therapeutic approaches display undesirable side effects for patients, particularly when long-term therapy is required. Some evidences have suggested that Coriandrum sativum extract (CSE) provide sedative and anxiolytic effects. We investigate if CSE could attenuate anxiety-like behaviors induced by novelty and alarm substance exposures in zebrafish. Adult zebrafish were injected with vehicle, clonazepam, or CSE (25, 50 or 100 mg/kg) and submitted to novel tank test. At the end, saline or alarm substance was added and anxiety-like responses were recorded. Twenty-four hours after, fish were submitted to the light/dark test. Novelty associated with alarm substance exposure decreased distance traveled and total time mobile in novel tank, and CSE (at 50 and 100 mg/kg) prevented these alterations similarly to clonazepam. Alarm substance reduced the time spent in white compartment ( p = 0.0193 as compared with vehicle group). Clonazepam and CSE prevented this anxiogenic effect of alarm substance. CSE presents anxiolytic effects against alarm substance-induced locomotor and anxiogenic responses similarly to clonazepam. These data corroborate with the use of this plant in traditional medicine and provides a putative new pharmacological intervention for anxiety disorders.

The role of glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been extensively studied in schizophrenia; however, less is known about its role in anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype. Although astrocytes are capable of modulating NMDAR activity through glutamate uptake transporters, the relationship between astrocytic glutamate uptake and the development of an anxiety phenotype remains poorly explored. Here, we aimed to investigative whether long-term antagonism of NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake. Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy adult CF-1 mice by oral gavage at doses of 5, 10, or 20 mg/kg. The mice were submitted to a sequential battery of behavioral tests (open field, light–dark box and elevated plus-maze tests). We then evaluated glutamate uptake activity and the immunocontents of glutamate transporters in the frontoparietal cortex and hippocampus. Our results demonstrated that long-term administration of memantine induces anxiety-like behavior in mice in the light–dark box and elevated plus-maze paradigms. Additionally, the administration of memantine decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the memantine-induced reduction in glutamate uptake was correlated with enhancement of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with memantine induces anxiety-like behavior that is associated with reduced glutamate uptake activity but that is not dependent on GLT-1 or GLAST protein expression. Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to the development of conditions that fall within the category of anxiety disorders.