Stress, neurotransmitters, corticosterone and body-brain integration.

Stress can be defined as a brain-body reaction towards stimuli arising from the environment or from internal cues that are interpreted as a disruption of homeostasis. The organization of the response to a stressful situation involves not only the activity of different types of neurotransmitter systems in several areas of the limbic system, but also the response of neurons in these areas to several other chemicals and hormones, chiefly glucocorticoids, released from peripheral organs and glands. Thus, stress is probably the process through which body-brain integration plays a major role. Here we review first the responses to an acute stress in terms of neurotransmitters such as dopamine, acetylcholine, glutamate and GABA in areas of the brain involved in the regulation of stress responses. These areas include the prefrontal cortex, amygdala, hippocampus and nucleus accumbens and the interaction among those areas. Then, we consider the role of glucocorticoids and review some recent data about the interaction of these steroids with several neurotransmitters in those same areas of the brain. Also the actions of other substances (neuromodulators) released from peripheral organs such as the pancreas, liver or gonads (insulin, IGF-1, estrogens) are reviewed. The role of an environmental enrichment on these same responses is also discussed. Finally a section is devoted to put into perspective all these environmental-brain-body-brain interactions during stress and their consequences on aging. It is concluded that the integrative perspective framed in this review is relevant for better understanding of how the organism responds to stressful challenges and how this can be modified through different environmental conditions during the process of aging. This article is part of a Special Issue entitled: Brain Integration.

Aging increases basal but not stress-induced levels of corticosterone in the brain of the awake rat.

The main purpose of this study was to evaluate the effect of aging on plasma and free corticosterone (CORT) levels in the brain in basal conditions and in response to an acute stressor. Microdialysis experiments were performed in the hippocampus (HC) and the prefrontal cortex (PFC) of young adult (6 months) and aged (24 months) male Wistar rats. Basal free levels of CORT in the HC and the PFC were higher in aged animals. Restraint stress increased plasma CORT and free CORT levels in the HC and the PFC both in young and aged animals. However, while the increase of plasma CORT was higher in aged rats compared with young rats, the increases of free CORT in the HC and the PFC were not different between these two groups of rats. These results suggest that the changes produced by aging in the brain may be related to the enhanced basal levels of free CORT and not to the CORT increases in response to stress.

Aging impairs the control of prefrontal cortex on the release of corticosterone in response to stress and on memory consolidation.

This study investigated the role of the dorsomedial prefrontal cortex (dmPFC) on the activity of the hypothalamus-pituitary-adrenal axis and memory consolidation in young and aged rats. The messenger RNA (mRNA) expression of several gamma-aminobutyric acid (GABA) and glutamate receptor subunits were also evaluated in the prefrontal cortex (PFC) of young and aged rats. Microinjections of picrotoxin (GABA(A) antagonist), muscimol (GABA(A) agonist), or vehicle were performed into the dmPFC of young adult (3 months) and aged (27 months) male Wistar rats. Plasma corticosterone was measured under acute stress (30-minute restraint) conditions following microinjections. The retention of an inhibitory avoidance response was also evaluated in response of the same treatments. Picrotoxin microinjections into the dmPFC reduced the stress-induced corticosterone concentrations on young but not on aged animals. Aging did not modify the mRNA content of any of the receptor subunits analyzed. Picrotoxin into the dmPFC reduced inhibitory avoidance response in young but not aged animals. Muscimol treatment did not modify any of the parameters evaluated. These results suggest that prefrontal cortex loses its capacity to control hypothalamo-pituitary-adrenal (HPA) axis activity and the consolidation of emotional memory during aging.

Prefrontal cortex, caloric restriction and stress during aging: studies on dopamine and acetylcholine release, BDNF and working memory.

This study was designed to investigate whether long-term caloric restriction during the life span of the rat changes the effects of an acute mild stress on the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and on working memory performance. Spontaneous motor activity was also monitored and levels of BDNF measured in the prefrontal cortex, amygdala and hippocampus. Male Wistar rats (3 months of age) were housed during 3, 12, 21 and 27 months (6, 15, 24 and 30 months of age at the end of housing) in caloric restriction (CR; 40% food intake restriction) or control conditions. After behavioural testing, animals were further subdivided into two other groups. In one of the groups BDNF protein levels were determined. In the other group rats were implanted with guide cannulas into the PFC to perform microdialysis experiments. In CR rats the release of dopamine produced by handling stress did not differ from the response found in control rats of 6, 15 and 24 months of age. The release of acetylcholine was not changed at the ages of 6 and 15 months but reduced at the age of 24 months. Stress did not change dopamine or acetylcholine release in CR and control rats of 30 months of age. BDNF levels were increased in the hippocampus and amygdala, but not in the PFC, of 6 and 15 months CR rats. Spontaneous motor activity was increased in all groups of CR rats. Age, however, decreased motor activity in CR and control rats. Both experimental groups showed similar working memory performance in a delayed alternation task in basal conditions and after a situation of acute stress. These results suggest that CR does not modify the function of the PFC in response to an acute stress nor the changes found as a result of the normal process of aging.

Environmental enrichment increases the in vivo extracellular concentration of dopamine in the nucleus accumbens: a microdialysis study.

The present study was designed to elucidate the effects of environmental enrichment in adulthood (EE) on the in vivo basal and stimulated extracellular concentration of dopamine in the nucleus accumbens of awake rats. The effects of EE on novelty-induced motor activity in an open field and on the levels of brain-derived neurotrophic factor (BDNF) in the nucleus accumbens and striatum were also analysed. Male Wistar rats (3 months of age) were housed in enriched or control conditions during 12 months. After behavioural testing, animals were subdivided in two groups. In one of the groups, BDNF protein levels were determined. In the second group of rats, microdialysis experiments were performed to monitor dialysate concentrations of dopamine in the nucleus accumbens after the perfusion of the glutamatergic agonist α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA; 100 µM) or potassium (100 mM). Both basal and potassium stimulated dialysate concentrations of dopamine were higher in EE than in control rats (basal: 80%; potassium: 210%). EE did not significantly change the increases of dialysate concentrations of dopamine induced by AMPA although there was a trend towards an enhancement of the effects of AMPA. EE decreased novelty-induced locomotor activity but did not modify the levels of BDNF in the nucleus accumbens or in the striatum. These results suggest that the in vivo activity of the mesolimbic dopamine system is enhanced by housing rats in an enriched environment and that this effect is not mediated by BDNF. These findings may be relevant for the understanding of the effects of EE on motor behaviour.

Environmental enrichment reduces the response to stress of the cholinergic system in the prefrontal cortex during aging.

The present study was designed to evaluate the release of acetylcholine in the prefrontal cortex (PFC) induced by handling stress during aging and also to investigate whether this response changed as a result of the animals living in an enriched environment. Male Wistar rats of 3 months of age were housed in control and enriched conditions during the entire period of their adult life and experiments were performed at 6, 15 and 24 months of age. Spontaneous motor activity was first monitored in an open field arena. Then, rats were stereotaxically implanted with guide cannula to perform microdialysis experiments in the PFC and to evaluate the effects of stress on extracellular concentrations of acetylcholine. Handling stress increased the extracellular concentrations of acetylcholine in the PFC of control and enriched rats. These increases were not modified by aging in control rats. However, environmental enrichment (EE) reduced the effects of stress on acetylcholine concentrations in all groups of age. Spontaneous motor activity in the open field was reduced by aging. EE also decreased motor activity in all groups of age. These results suggest that EE reduces the reactivity to stress of the cholinergic system in the prefrontal cortex during aging.

Effects of an enriched environment on the release of dopamine in the prefrontal cortex produced by stress and on working memory during aging in the awake rat.

The present study was designed to investigate the effects of a mild acute stress on the in vivo release of dopamine in the prefrontal cortex (PFC) during aging and whether housing animals in an enriched environment changes these effects. Behavioural parameters such as spontaneous motor activity (open-field) and working memory performance in a delayed alternation task (water T-maze) were also studied. Male Wistar rats (3 months of age) were housed during 3, 12, and 21 months (6, 15 and 24 months of age at the end of housing) in enriched or control conditions. After behavioural testing, animals were subdivided in two groups. In one of the groups BDNF protein levels were determined in PFC, hippocampus and amygdala. Rats of the second group were implanted with guide cannula in the PFC to perform microdialysis experiments and to monitor extracellular concentrations of dopamine. The release of dopamine in the PFC produced by handling stress (40 min) was significantly reduced in both enriched and control 24 months animals. However, the increases of dopamine produced by stress were significantly lower in enriched animals when compared to controls. Similarly, the increases of dopamine produced by perfusing K(+) 100 mM into the PFC were also reduced by aging and environmental enrichment. Both spontaneous motor activity and working memory performance were significantly reduced by aging. Moreover, animals housed in an enriched environment did show a lower spontaneous motor activity at all ages studied, though they did not show any change in performing the working memory task, either in basal conditions or after an acute stress. The BDNF protein levels were increased by environmental enrichment in the hippocampus and amygdala, but not in the PFC. These results suggest that both environmental enrichment and aging reduces the activity of the mesocortical dopamine system.

Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats.

The aim of the present study was to investigate whether environmental enrichment changes the effects of acute stress on both the release of dopamine and acetylcholine in the prefrontal cortex (PFC) and working memory performance. Male Wistar rats (3 months of age) were housed in enriched or control conditions during 12 months. Behavioural testing was carried out to assess working memory performance in a delayed alternation task (water escape T-maze). Horizontal and vertical motor activity were also monitored in the open field. After behavioural testing (open field and water T-maze), animals were implanted with guide cannula in the PFC to perform microdialysis experiments and to monitor dopamine and acetylcholine extracellular concentrations. Handling stress (40min) produced similar increases of extracellular concentrations of dopamine in the PFC of both enriched and control animals. In contrast, handling stress increased significantly the extracellular concentrations of acetylcholine in the PFC of control, but not enriched, animals. Exposing animals to a lit open field during 10min significantly reduced working memory performance assessed immediately in the water T-maze just in control animals, though these effects were not significantly different between both groups of animals. Spontaneous motor activity in the open field was lower in enriched compared to control animals. These results suggest that environmental enrichment changes acetylcholine, but not dopamine, reactivity to stress in the PFC.