Correlations among central serotonergic parameters and age-related emotional and cognitive changes assessed through the elevated T-maze and the Morris water maze.

Emotion and spatial cognitive aspects were assessed in adult and middle-aged rats using the elevated T-maze (ETM) and the Morris water maze (MWM) tasks. Both adult and middle-aged rats were able to acquire inhibitory avoidance behaviour, though the middle-aged subjects showed larger latencies along the trials, including the baseline, which was significantly longer than that showed by adult rats. Further, compared to adult rats, middle-aged rats had longer escape latency. In spite of the worse performance in the second session of the spatial cognitive task, the middle-aged rats were able to learn the task and remember the information along the whole probe trial test. Both thalamic serotonin (5-HT) concentration and amygdala serotonergic activity (5-HIAA/5-HT) are significantly correlated, respectively, to escape latency and behavioural extinction in the MWM only for middle-aged rats. A significant correlation between the 5-HIAA/5-HT ratio in the amygdala and behavioural extinction for middle-aged, but not for adult, rats was observed. This result suggests that serotonergic activity in the amygdala may regulate behavioural flexibility in aged animals. In addition, a significant negative correlation was found between hippocampal 5-HIAA/5-HT ratio and the path length at the second training session of the MWM task, although only for adult subjects. This was the only session where a significant difference between the performance of middle-aged and adult rats has occurred. Although the involvement of the hippocampus in learning and memory is well established, the present work shows, for the first time, a correlation between a serotonergic hippocampal parameter and performance of a spatial task, which is lost with ageing.

Age-related deficit in behavioural extinction is counteracted by long-term ethanol consumption: correlation between 5-HIAA/5HT ratio in dorsal raphe nucleus and cognitive parameters.

We investigated age-related changes in learning and memory performance and behavioural extinction in the water maze; and in endogenous levels of serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) in the neocortex, hippocampus, thalamus and dorsal raphe nucleus of Wistar rats. Another aim was to assess the correlation between behavioural and biochemical parameters, which were measured in rodents of two different ages: 5 months (adults) and 16 months (middle-aged). The middle-aged subjects succeeded in learning the behavioural task, albeit with significantly worse performance when compared to adult animals. Aging also had significant main effects on memory and extinction. An age-dependent decrease in 5-HIAA levels was observed in both hippocampus and dorsal raphe nucleus (DRN). The decrease in DRN 5-HIAA was paralleled by a decrease in 5-HIAA/5-HT ratio in this brain area, which was significantly correlated to the animals' spatial memory performance and behavioural extinction. In addition, using middle-aged rats, a 2x2 factorial study was carried out to examine the effects of food restriction and chronic ethanol consumption on rat's performance in a spatial behavioural task and on central serotonergic parameters. None of these two treatments had a significant effect on the behavioural and biochemical parameters assessed, with the exception of extinction index, which was significantly affected by ethanol consumption. Long-term ethanol ameliorated the impairment in behavioural flexibility caused by aging. In conclusion, long-term ethanol consumption may have a role in protecting against age-related deficit in behavioural extinction. Moreover, the present results also indicate that DRN serotonergic system is involved in spatial memory and behavioural extinction.

Correlation between phosphorylation level of a hippocampal 86kDa protein and extinction of a behaviour in a model of Wernicke-Korsakoff syndrome.

The effects of chronic ethanol and thiamine deficiency, alone or associated, on hippocampal protein phosphorylation profiles ranging in molecular weight from 30 to 250kDa molecular weight, in stimulated (high K(+) concentration) and unstimulated (basal) conditions were investigated. These treatments significantly changed the phosphorylation level of an 86kDa phosphoprotein. Thiamine deficiency, but not chronic ethanol, induced a decrease in a behavioural extinction index, which is significantly correlated to the phosphorylation level of the p86 protein. These data add to and extend previous findings by our laboratory implicating the involvement of hippocampal neurotransmission components in extinction of a behaviour which involves learning of environmental spatial cues.

Thiamine deficiency decreases glutamate uptake in the prefrontal cortex and impairs spatial memory performance in a water maze test.

Using an animal model of Wernicke-Korsakoff syndrome, in which rats were submitted to a chronic ethanol treatment with or without a thiamine deficiency episode, the glutamate uptake in the prefrontal cortex and spatial memory aspects were studied. It was found that (i) thiamine deficiency, but not chronic ethanol consumption, induced a significant decrease of glutamate uptake; (ii) thiamine-deficient subjects showed an impaired performance in the water maze spatial memory test though these animals were able to learn the task during the acquisition. In spite of the fact that thiamine deficiency affects both glutamate uptake and spatial reference memory, there was no significant correlation between these two data. The present results show that, although prefrontal cortex is considered by some authors a not vulnerable area to lesions caused by thiamine deficiency, this vitamin deficiency does cause a neurochemistry dysfunction in that region.

Dietary restriction protects against chronic-ethanol-induced changes in exploratory behavior in Wistar rats.

Chronic ethanol intake causes various types of neural damage and behavioral impairments, probably acting through oxidative stress and excitotoxicity, while dietary restriction is considered by some authors to protect the central nervous system from these kinds of damage. In the present study, a factorial experimental design was used to investigate the effects of chronic ethanol and dietary restriction treatments, associated or not, on Wistar rats' exploratory behavior, spatial memory aspects and cortical and hippocampal acetylcholinesterase (AChE) activity. Dietary restriction lasted for the whole experiment, while ethanol treatment lasted for only 3 weeks. Despite the short ethanol treatment duration, for two behavior categories assessed, moving and rearing, an interaction was observed between the effects of chronic ethanol and dietary restriction. There were no significant differences in AChE activities among the groups. Cerebellar neural nitric oxide synthase (nNOs) activity was measured as a first step to assess oxidative stress. Dietary restriction significantly reduced NO formation. The present results indicate that dietary restriction might exert a protective effect against chronic-ethanol-induced changes in exploratory behavior. It is hypothesized that the mechanisms underlying this protection can involve prevention of oxidative stress.

Cholinergic parameters and the retrieval of learned and re-learned spatial information: a study using a model of Wernicke-Korsakoff Syndrome.

This is a factorial (2 x 2 x 2) spatial memory and cholinergic parameters study in which the factors are chronic ethanol, thiamine deficiency and naivety in Morris water maze task. Both learning and retention of the spatial version of the water maze were assessed. To assess retrograde retention of spatial information, half of the rats were pre-trained on the maze before the treatment manipulations of pyrithiamine (PT)-induced thiamine deficiency and post-tested after treatment (pre-trained group). The other half of the animals was only trained after treatment to assess anterograde amnesia (post-trained group). Thiamine deficiency, associated to chronic ethanol treatment, had a significant deleterious effect on spatial memory performance of post-trained animals. The biochemical data revealed that chronic ethanol treatment reduced acetylcholinesterase (AChE) activity in the hippocampus while leaving the neocortex unchanged, whereas thiamine deficiency reduced both cortical and hippocampal AChE activity. Regarding basal and stimulated cortical acetylcholine (ACh) release, both chronic ethanol and thiamine deficiency treatments had significant main effects. Significant correlations were found between both cortical and hippocampal AChE activity and behaviour parameters for pre-trained but not for post-trained animals. Also for ACh release, the correlation found was significant only for pre-trained animals. These biochemical parameters were decreased by thiamine deficiency and chronic ethanol treatment, both in pre-trained and post-trained animals. But the correlation with the behavioural parameters was observed only for pre-trained animals, that is, those that were retrained and assessed for retrograde retention.

Animal models for evaluation of behavior and molecular neurobiological changes with emphasis on spatial memory and cholinergic system impairments in chronic alcohol abuse

In this article we outline the use of experimental animal models to study aspects of memory processes. We describe some results obtained by our group and other laboratories in studies on memory aspects, using rats chronically treated with alcohol. At behavioral and biochemical levels, we focused respectively, on retrograde amnesia and central nervous cholinergic system. We also compare, at both levels, the direct and indirect (those related to thiamine deficiency) effects induced by chronic alcohol treatment.