Nandrolone-induced aggressive behavior is associated with alterations in extracellular glutamate homeostasis in mice.

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.

Caffeine consumption prevents memory impairment, neuronal damage, and adenosine A2A receptors upregulation in the hippocampus of a rat model of sporadic dementia.

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-ß-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.

Impairment of the organization of locomotor and exploratory behaviors in bile duct-ligated rats.

Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to several problems, including motor impairment. Animal models of chronic liver disease have extensively investigated the mechanisms of this disease. Impairment of locomotor activity has been described in different rat models. However, these studies are controversial and the majority has primarily analyzed activity parameters. Therefore, the aim of the present study was to evaluate locomotor and exploratory behavior in bile duct-ligated (BDL) rats to explore the spatial and temporal structure of behavior. Adult female Wistar rats underwent common bile duct ligation (BDL rats) or the manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent open-field, plus-maze and foot-fault behavioral tasks. The BDL rats developed chronic liver failure and exhibited a decrease in total distance traveled, increased total immobility time, smaller number of rearings, longer periods in the home base area and decreased percentage of time in the center zone of the arena, when compared to the control rats. Moreover, the performance of the BDL rats was not different from the control rats for the elevated plus-maze and foot-fault tasks. Therefore, the BDL rats demonstrated disturbed spontaneous locomotor and exploratory activities as a consequence of altered spatio-temporal organization of behavior.

Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice.

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.

Distinctive effects of unpredictable subchronic stress on memory, serum corticosterone and hippocampal BDNF levels in high and low exploratory mice.

Stress affects learning and memory processes and sensitivity to stress greatly varies between individuals. We studied behavioral and neurobiological effects of unpredictable subchronic stress (USCS) in two behavioral extremes of mice from the same strain (CF1) selected by their exploratory behavior of the central arena of an open field. The top and bottom 25% explorers were classified as low exploratory (LE) and high exploratory (HE) mice, respectively. The open field task, the novel object recognition task (NOR), sucrose intake and tail suspension task were evaluated in LE and HE groups exposed to USCS for two weeks or control conditions. Also serum corticosterone and hippocampal BDNF and S100B levels were analyzed. Both stressed groups exhibited less exploratory activity when submitted to USCS, but their difference in exploratory behavior remained. This short stress protocol did not induce changes in sucrose intake or immobility in the tail suspension task. Also, LE mice exhibited impaired NOR performance after USCS, whereas HE mice changed their pattern of exploration towards less exploration of the familiar object. HE had lower corticosterone levels than LE mice, but corticosterone levels increased after stress only in HE mice. Hippocampal BDNF in LE was lower than in HE but decreased after USCS only in HE mice, whereas S100B levels were not different between groups and did not change with USCS. In conclusion, our results suggest that individual differences in exploratory behavior in rodents from the same strain influence cognitive and biochemical response to stress.

Adenosine A1 receptors are modified by acute treatment with methylphenidate in adult mice.

In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that influences the dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5mg/kg, i.p.) and to model misuse, they received an acute overdosage (50mg/kg, i.p). The involvement of adenosine A(1) receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A(1) receptor antagonist (DPCPX 1mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50mg/kg increased 88% adenosine A(1) receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A(1) receptor density. Our findings ruled out the participation of adenosine A(1) receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A(1) receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.

Diphenyl diselenide exerts anxiolytic-like effect in Wistar rats: putative roles of GABAA and 5HT receptors.

Diphenyl diselenide [(PhSe)2] is an organoselenium compound which presents pharmacological antioxidant, anti-inflammatory, antinociceptive and antidepressant properties. The present study was designed to investigate the anxiolytic effect of (PhSe)2 in rats, employing the elevated plus maze task. The involvement of 5HT and GABA receptors in the anxiolytic-like effect was also evaluated. (PhSe)2 (5, 25 and 50 micromol/kg, i.p.) did not affect locomotor activity as evaluated in the open open-field test, and learning and memory when assessed in the inhibitory foot-shock avoidance task. However, (PhSe)2 at the 50 micromol/kg dose produced signs of an anxiolytic action, namely a decreased number of fecal boli in the open-field arena and an increased time spent in as well as an increased number of entries to the open arms of the elevated plus maze test. To evaluate the role of GABA and 5HT receptors in the anxiolytic-like effect of (PhSe)2, a selective GABAA receptor antagonist bicuculline, (0.75 mg/kg, i.p.), a non-selective 5HT2A/2C receptor antagonist, ritanserin (2 mg/kg, i.p.), a selective 5HT2A receptor antagonist, ketanserin (1 mg/kg, i.p.), and a selective 5HT1A receptor antagonist, WAY100635 (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic effect of (PhSe)2 suggesting that GABAA and 5HT receptors may play a role in the pharmacological property of this selenocompound in the central nervous system.

A simple webcam-based approach for the measurement of rodent locomotion and other behavioural parameters.

We hereby describe a simple and inexpensive approach to evaluate the position and locomotion of rodents in an arena. The system is based on webcam registering of animal behaviour with subsequent analysis on customized software. Based on black/white differentiation, it provides rapid evaluation of animal position over a period of time, and can be used in a myriad of behavioural tasks in which locomotion, velocity or place preference are variables of interest. A brief review of the results obtained so far with this system and a discussion of other possible applications in behavioural neuroscience are also included. Such a system can be easily implemented in most laboratories and can significantly reduce the time and costs involved in behavioural analysis, especially in developing countries.

Behavioral and cognitive profile of mice with high and low exploratory phenotypes.

Temperament is the heritable and relatively stable pattern of basic emotions, such as fear and anger. We explored behavioral features in mice to select distinct phenotypes with extremes of temperament. In a new environment (open-field) with a central object, two groups of 15 mice from 79 screened were separated according to high or low exploration of the object to compose the high and low exploratory groups, respectively. Their performance was mostly identical in the same task 1 week later and still distinguishable 8 months later, suggesting the presence of trait or temperamental features. These mice were further tested in other behavioral tasks. Compared to low exploratory mice, high exploratory mice were less anxious in the light/dark task and the elevated plus maze, showed increased locomotion in an open-field, improved their performance along trials in the Lashley maze (with appetitive stimulus) and had higher latency to step-down in the inhibitory avoidance task (with aversive stimulus). High exploratory mice were aggressive in the intruder test, whereas low exploratory mice were non-aggressive or submissive. These results show that individual differences in temperament influence a range of behaviors in mice. The behavioral profile of low and high exploratory mice resembled the depressive and hyperthymic temperaments of patients with unipolar depression and bipolar disorders, respectively, which may be relevant for modeling mood disorders.