Rosa Redolat

Spatial learning in male mice with different levels of aggressiveness: effects of housing conditions and nicotine administration.

The main aim of the present investigation was to evaluate the possible modulation of spatial learning ability by housing conditions and level of aggressiveness in mice, also testing whether differences in locomotion and anxiety could influence this relationship. Additionally, we have examined effects of nicotine in the acquisition and retention of a spatial learning task in groups of mice differing in these variables. NMRI male mice were either group-housed or individually housed for 30 days and then classified into mice with short (SAL) and long (LAL) attack latency after a pre-screening agonistic encounter. Locomotor activity and baseline levels of anxiety of these groups were evaluated in the actimeter and elevated plus-maze. Results indicated that SAL and LAL individually housed mice displayed higher locomotion activity than LAL group-housed mice. In the plus-maze test, SAL and LAL individually housed mice showed more total and open arm entries than group-housed LAL mice, confirming the hyperactivity of individually housed mice and suggesting that isolation had no clear anxiolytic or anxiogenic actions. In the water-maze, we compared the performance of individually housed SAL, individually housed LAL mice, and group-housed LAL mice treated with nicotine (0.35 and 0.175 mg/kg) or vehicle. Nicotine did not improve acquisition in group-housed mice and even impaired it in individually housed mice. Retention of platform position was better in vehicle-treated individually housed mice in comparison with vehicle-treated group-housed mice. The present study demonstrates that housing conditions but not level of aggressiveness modify spontaneous locomotor activity and behaviors displayed on the elevated plus-maze test, and can also influence retention of a spatial learning task.

Potential benefits and limitations of enriched environments and cognitive activity on age-related behavioural decline.

The main aim of this chapter is to review preclinical studies that have evaluated interventions which may aid in preventing or delaying age-related behavioural decline. Animal models of Environmental Enrichment (EE) are useful for evaluating the influence of cognitive, physical and social stimulation in mitigating cognitive decline at different ages. The EE paradigm has been proposed as a non-invasive treatment for alleviating age-related memory impairment and neurodegenerative diseases. While in this complex environment, rodents can be stimulated at different levels (physical, social, cognitive and sensorial), although a synergism between all these components is likely to play an important role. We will summarize available data relating to EE as a potential therapeutic strategy that slows down or counteracts age-related cognitive and behavioural changes. EE also alters physiological responses and induces neurobiological changes such as stimulation of neurogenesis and neural plasticity. At the behavioural level, EE improves learning and memory tasks and reduces anxiety. Several variables seem to influence the behavioural and cognitive benefits induced by EE, including the age at which animals are first exposed to EE, total period during which animals are submitted to EE, gender, the cognitive task evaluated, the drug administered and individual factors. Cognitive and physical stimulation of animals in enriched experimental environments may lead to a better understanding of factors that promote the formation of cognitive reserve (CR) and a healthier life in humans. In the present chapter we review the potential benefits of EE in aged rodents and in animal models of Alzheimer Disease (AD). Results obtained in preclinical models of EE may be relevant to future research into mental and neurodegenerative diseases, stress, aging and development of enviromimetics. Finally, we outline the main limitations of EE studies (variability between laboratories, difficulty of separating the different components of EE, gender of experimental subjects, individual differences in the response to EE), evaluating the potential benefits of enriched environments and the neurobiological mechanisms that underlie them. We conclude that there are experimental data which demonstrate the cognitive benefits of rearing rodents in enriched environments and discuss their implication for clarifying which variables contribute to the formation of the CR.

Effects of early spatial training on water maze performance: a longitudinal study in mice.

The aim of the present study is to establish whether in mice the effects of an early experience in the Morris water maze are maintained after a long period. A longitudinal study was performed in which mice of two different strains (NMRI and C57) received spatial training at 2 months of age and their performance was re-evaluated 8 and 16 months later. In both strains, results showed a beneficial effect of prior experience on this spatial memory task even 8 months after the initial training. At 18 months of age, performance of C57 mice that were trained at 2 months of age for the first time was similar to those who received their first training at 10 months of age. These findings suggest that the beneficial effect of previous training could be limited by time. In addition, water maze performance of 18 month-old C57 mice did not differ from their earlier performance when they were 10 months of age, which would indicate that experience in this task could prevent some of the age-related spatial learning deficits observed in mice.

Previous training in the water maze: differential effects in NMRI and C57BL mice.

It has been shown that acquisition rates in the water maze vary across strains of mice, although the differential effects of previous experience in this spatial task have been scarcely evaluated. The aim of the present study was to evaluate the effects of training in the water maze at an early age (2 months) in two strains of mice (NMRI and C57BL) using a longitudinal study. Mice with or without previous training were tested when they were 6 months, and retested when 10 months old. The results showed that trained NMRI mice performed better than all the other groups, both at test and retest, indicating that previous training had more beneficial effects in NMRI than in C57BL mice. These results demonstrate that the effects of an early training in the water maze may be influenced by the characteristics of the strain of mice. It could have implications in longitudinal studies evaluating effects of pharmacological or behavioral manipulations.

Time estimation and aging: a comparison between young and elderly adults.

Studies about effects of aging on the estimation of short temporal intervals are not conclusive. The aim of the present research was to evaluate age-related differences in the reproduction of a short interval (10 s) using a computerized method. The sample comprised thirteen young adults (M = 26.15 years) and twelve elderly adults (M = 79.1 years). Three parameters of time estimation were measured: estimated time, absolute error, and standard deviation. Results showed that time estimates performed by elderly participants were shorter than those of younger ones, although there were no significant differences between the two age groups in the percentage of absolute errors or standard deviations. These findings could be explained by changes in the rate of the internal clock or to an interaction between more general changes in cognitive processes.

Effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in mice

There is evidence that the cholinergic nicotinic system is involved in the modulation of anxiety. Anxiolytic and anxiogenic effects of nicotine agonists have been reported in mice. Bupropion is an antidepressant drug which may alleviate some symptoms of nicotine withdrawal, although its effects on anxiety are not clear. It has been suggested that the interaction between bupropion and nicotinic mechanisms could be complex. The aim of the present study was to investigate acute effects of co-administration of bupropion and nicotinic agonists on the elevated plus-maze test in NMRI mice. Effects of nicotine, lobeline, and cytisine (0.35 and 0.175 mg/kg), administered alone or combined with bupropion (20 mg/kg) were tested in the plus-maze. Results indicated that nicotine (0.35 mg/kg) decreased number and percentage of entries and time spent in open arms, and increased percentage of protected stretched attend posture. Bupropion (20 mg/kg) plus lobeline (0.175 mg/kg) increased percentage of time spent in open arms, without altering total or closed arm entries. Our findings suggest that the highest dose of nicotine induces anxiogenic effects, which are counteracted when co-administered with bupropion. The combination of bupropion with a low dose of lobeline seems to have an anxiolytic profile in the conventional parameters of the plus-maze, although ethological measures do not support it clearly.

Environmental Enrichment Improves Novel Object Recognition and Enhances Agonistic Behavior in Male Mice

Environmental enrichment (EE) is an experimental paradigm in which rodents are housed in complex environments containing objects that provide stimulation, the effects of which are expected to improve the welfare of these subjects. EE has been shown to considerably improve learning and memory in rodents. However, knowledge about the effects of EE on social interaction is generally limited and rather controversial. Thus, our aim was to evaluate both novel object recognition and agonistic behavior in NMRI mice receiving EE, hypothesizing enhanced cognition and slightly enhanced agonistic interaction upon EE rearing. During a 4-week period half the mice (n = 16) were exposed to EE and the other half (n = 16) remained in a standard environment (SE). On PND 56-57, animals performed the object recognition test, in which recognition memory was measured using a discrimination index. The social interaction test consisted of an encounter between an experimental animal and a standard opponent. Results indicated that EE mice explored the new object for longer periods than SE animals (P < .05). During social encounters, EE mice devoted more time to sociability and agonistic behavior (P < .05) than their non-EE counterparts. In conclusion, EE has been shown to improve object recognition and increase agonistic behavior in adolescent/early adulthood mice. In the future we intend to extend this study on a longitudinal basis in order to assess in more depth the effect of EE and the consistency of the above-mentioned observations in NMRI mice.

Behavioral effects of combined environmental enrichment and chronic nicotine administration in male NMRI mice

Environmental enrichment (EE) is an experimental paradigm which provides sensory, social, physical and cognitive stimulation for rodents. Experimental evidence indicates that this type of housing induces different neurobiological and behavioral changes. However, few studies have evaluated the consequences of combined exposure to an enriched environment and nicotine administration during a critical period of development such as adolescence. Taking into account previous studies, it can be hypothesized that a chronic treatment with nicotine would modulate the effects of rearing animals in enriched environments. In the current study, our main aim was to evaluate the effects of EE and chronic nicotine administration on physiological parameters (weight, fluid intake and cotinine levels), motor activity, exploratory behavior, anxiety and learning in male NMRI mice. Half of the mice (n=32) were exposed to an enriched environment (EE) and the other half (n=32) were housed in standard environments (SE) with or without oral nicotine administration (100 μg/ml). After 3 weeks, mice were evaluated in a behavioral battery that included an elevated plus-maze, a hole board, an actimeter and an inhibitory avoidance task. Blood cotinine levels were measured in an additional group of 32 mice in order to confirm nicotine intake. Results indicated that mice reared in an enriched environment gained less body weight and displayed higher fluid intake than those maintained in a standard environment. EE reduced motor activity, exploratory behavior and anxiety, whereas it enhanced inhibitory avoidance learning. In relation to the effects of chronic nicotine treatment, the data reflected a lower increase in body weight and a reduced fluid intake in nicotine-treated mice. In the elevated plus-maze, nicotine induced a reduction of total arm entries and rearings. Cotinine levels were higher in mice that received oral nicotine than in the control group. We conclude that the EE paradigm applied in this study induces physiological and behavioral changes in NMRI mice. Chronic nicotine treatment diminished motor activity displayed by mice in the elevated plus-maze but did not have significant effects on inhibitory avoidance learning. Future studies should explore in greater depth the interaction between environmental factors and nicotine administration using longer periods of EE, a wider range of doses and/or other cholinergic agonists, acute drug administration, and sequential exposure to nicotine and EE.

Differential sensitivity to the effects of nicotine and bupropion in adolescent and adult male OF1 mice during social interaction tests

Few studies have compared the action of both nicotine (NIC) and bupropion (BUP), an antidepressant used to treat NIC dependence, on social and aggressive behavior at different ages. This study aims to determine whether these drugs produce differential effects in adolescent (postnatal day: 36-37) and adult (postnatal day: 65-66) mice that have been housed individually for 2 weeks in order to induce aggressive behavior. Mice received BUP (40, 20, or 10 mg/kg), NIC (1, 0.5, and 0.25 mg/kg as base), or vehicle earlier to a social interaction test. BUP (40 mg/kg) decreased social investigation and increased nonsocial exploration in both adolescent and adult mice. The same effects were also observed in adult mice administered with a lower dose of the same drug (20 mg/kg). In adolescents, NIC (1 mg/kg) decreased social investigation, but this effect did not reach statistical significance in adults. In conclusion, a differential sensitivity to the effects of NIC or BUP emerged in some of the behavioral categories when the two age groups were compared.

Effects of bupropion, alone or coadministered with nicotine, on social behavior in mice.

Bupropion, administered alone or combined with nicotine, is presently used to treat nicotine dependence. Despite experimental evidence of the complex behavioral actions of this drug, there have been little data reported about its effects on social behavior. Our main aim was to investigate the effects of acute administration of bupropion, alone or plus nicotine, on social interaction in mice. OF1 group‐housed male mice were confronted in a neutral cage with an anosmic opponent during a 10 minutes encounter. Time allocated to body care and digging was reduced by administration of bupropion (40 mg/kg) both when administered alone and with nicotine (1 and 0.5 mg/kg). The lowest dose of bupropion (10 mg/kg) also reduced digging when combined with 1 mg/kg of nicotine. Time spent on non‐social exploration and exploration from a distance was significantly higher in mice treated with bupropion (40 mg/kg) alone or combined with nicotine (1 and 0.5 mg/kg). The lowest dose of bupropion (10 mg/kg) increased non‐social exploration when combined with 0.5 mg/kg of nicotine and exploration from a distance when combined with 1 mg/kg of nicotine. Ethopharmacological assessment of the behavior of groups of mice treated with different combinations of the two drugs indicates that nicotine can potentiate some of the behavioral effects of low doses of bupropion. Results also indicate that bupropion, either alone or combined with nicotine, has no significant effects on social investigation, suggesting that this drug does not induce a clear anxiolytic profile in OF1 mice.