Selective decline of 5-HT1A receptor binding sites in rat cortex, hippocampus and cholinergic basal forebrain nuclei during aging

The effect of aging on 5-HT1A receptor binding in several forebrain areas associated with the basal forebrain cholinergic system was investigated in rats of 3-, 24- and 30-months-old by receptor autoradiography and biochemical binding assay using [H-3]8-OH-DPAT as a ligand. Autoradiographic measurements demonstrated a marked region-specific decline of ligand binding in: (i) regions of the basal forebrain cholinergic cell groups, i.e. the medial septum, diagonal band nuclei and magnocellular nucleus basalis, (ii) the frontal and parietal neocortex and (iii) the dentate gyrus of the hippocampus. No change or- only a slight decrease of the 5-HT1A receptor density was found in other areas investigated: the CA1 and CA3 sectors of hippocampus, the cingular and perirhinal cerebral cortex and the lateral septum. The autoradiographic findings were substantiated by the biochemical binding assay, which revealed a comparable loss of 5-HT1A receptor in the hippocampus and neocortex at the age of 30 months. The results clearly show that with increasing age the decrement of 5-HT1A receptor binding in the rat forebrain is remarkably region-selective and particularly affects the cholinergic cell groups that innervate cortex and hippocampus. This phenomenon appears to be especially significant in relation to the neuronal substrates underlying the age-related alterations of mood and cognition. (C) 1997 Elsevier Science B.V

BENEFICIAL EFFECT OF CHRONIC NIMODIPINE TREATMENT ON BEHAVIORAL DYSFUNCTIONS OF AGED RATS EXPOSED TO PERINATAL ETHANOL TREATMENT

The long-term effects of prenatal and early postnatal ethanol exposure were assessed in adult (5-month), aged (24-month), and senescent (30-month) rats on non-aggressive intermale social behavior, and on black-white discrimination and spatial learning behaviors. Furthermore, the effects of chronic application of the Ca2+ channel blocker nimodipine, which reportedly improves behavioral function in aging, were studied on the ethanol-induced behavioral deficits during aging, The results showed that the perinatal alcohol treatment suppressed social behavior by reducing the frequency and duration of social interactions at all ages. Black-white discrimination behavior and appetitively motivated learning in a hole-board were also markedly disturbed, Several measures of social and spatial learning behaviors of ethanol-exposed rats revealed progressive functional decline with aging. Chronic oral treatment with nimodipine improved the social activity and normalized the cognitive behavioral capabilities of aged and senescent rats exposed to ethanol. We concluded that: (1) the behavioral disabilities caused by perinatal ethanol toxicity are persistent in the rat lifespan and become more pronounced with aging; and (2) administration of nimodipine in the aging period improves, with a long-lasting efficacy, the ethanol-induced behavioral dysfunctions in aged rats

Early postnatal treatment with ACTH4-9 analog ORG 2766 improves adult spatial learning but does not affect behavioural stress reactivity

Studies on adult animals and humans have shown that the ACTH4-9 analog ORG 2766 influences cognitive performance and possibly has neurotrophic effects. For this reason we studied the effect of ORG 2766 applied in early postnatal life when brain structures and neuronal pathways are still developing. Our aim was to see whether such treatment during development would result in permanent changes in adult behavioural performance. Pups received subcutaneous injections of 1 µg/g bodyweight ACTH4-9 analog ORG 2766 on day 1, 3 and 5 after birth. Control animals in the same nest received saline injections. When the animals had reached an adult age of 3 months they were subjected to a series of tests to measure their behavioural performance. In the first experiment, behavioural stress responses and anxiety were measured by subjecting the rats to the following tests: open field, defensive burying, elevated plus maze, and conditioned fear test. In a second experiment, adult cognitive function was measured in the Morris water-maze, a hippocampus-related spatial learning test, and in the active avoidance test, a more amygdala-related nonspatial test. The results showed that animals treated with ORG 2766 during early postnatal life learned faster in the spatial Morris water-maze. The treatment had a positive effect on performance during the acquisition phase of the learning task, while memory retrieval was not affected. Learning in the nonspatial active avoidance task did not change due to the postnatal ACTH4-9 treatment. In addition, there were no differences in the open field test, the defensive burying test, elevated plus maze and the conditioned fear test. The latter supports the conclusion that the differences in water-maze performance was due to a difference in learning speed, rather than a difference in anxiety or behavioural stress reactivity. Analysis of [3H]CORT binding capacity measured after the learning tests revealed no differences in the hippocampal MR and GR concentration between non-treated and treated animals.

Developmental docosahexaenoic and arachidonic acid supplementation improves adult learning and increases resistance against excitotoxicity in the brain

Through metabolic imprinting mechanisms a number of bioactive molecules including polyunsaturated fatty acids affect brain functions in the developmental age and longer-lasting beneficial effects are expected. In this study pregnant rats were offered diets either containing no docosahexaenoic acid (DHA) and arachidonic acid (AA) (Placebo diet) or an excess amount of these long chain polyunsaturated fatty acids (LC-PUFA) (Supplement diet) up to the time of weaning. Bilateral N-methyl-D-aspartate (NMDA) induced neurodegeneration in the entorhinal cortex of offspring in the age of 4 months was used as a tool to investigate the neuroprotective property of the developmentally supplemented DHA and AA treatments. Hippocampus-dependent spatial learning was measured in Morris water maze and the extent of neuronal lesion in the injected brain area was evaluated. Under baseline condition, in intact or sham-lesioned rats, the Morris water maze performance was superior in the supplemented group compared to the placebo controls. NMDA-lesion in the entorhinal cortex area decreased spatial learning in the supplement-treated rats while insignificantly diminished it in the placebo controls. The same supplementation attenuated the lesion size induced by the NMDA injection into the entorhinal and ventral hippocampal areas. We concluded that LC-PUFA supplementation during fetal and early postnatal development results in long-term enhancement of spatial learning ability of the offspring and offers resistance against excitotoxic brain lesion which lasts up to the adult age

Chronic Excess of Corticosterone Increases Serotonergic Fibre Degeneration in Aged Rats

Evidence is presented for the potentiating role of corticosterone on axonal degeneration of serotonergic neurones during ageing. Aged rats, 24 months old, were implanted subcutaneously with 2 × 100 mg pellets of corticosterone. Serotonergic and cholinergic (ChAT- and NADPHd-positive) fibre degenerations in the anteroventral thalamic nucleus (AVT) were measured 2 months after corticosterone implantation. Numbers of immunoreactive serotonergic raphe and mesolimbic cholinergic neurones were also quantified. Basal plasma corticosterone and adrenocorticotropin (ACTH) concentrations were assayed at 2, 4, 6, and 8 weeks after implantation in the plasma and at 1, 2, 4 and 6 weeks in urine. The degree of serotonergic fibre aberrations in the AVT increased significantly after corticosterone exposure, while that of ChAT-positive and NADPHd-stained axon aberrations showed a modest but nonsignificant increase. A positive correlation between the magnitudes of serotonergic and cholinergic fibre aberrations appeared in the AVT, but only in the corticosterone-treated rats. The number of serotonin immunopositive neurones in the raphe nuclei after corticosterone decreased marginally, while that of mesopontine ChAT-positive neurones was not influenced. Measurements of basal plasma corticosterone and ACTH, as well as urine corticosterone, revealed that the steroid implantation increased the plasma corticosterone level for at least 4 weeks and decreased ACTH level for at least 6 weeks. By the week 8, the pituitary-adrenal function was apparently restored. However, at sacrifice, both the weight of adrenal glands and that of thymus remained reduced, indicating the long-lasting effects of corticosterone on target tissues. It is concluded that the raphe serotonergic neurones and their projecting fibres are sensitive to corticosterone excess in aged rats and become more vulnerable to degeneration processes than under normal ageing conditions. Cholinergic neurones of brainstem origin, which also express massive NADPHd activity, are more resistant against corticosterone, but their axon degeneration correlates to serotonergic fibre degeneration.

Developmental docosahexaenoic and arachidonic acid supplementation improves adult learning and increases resistance against excitotoxicity in the brain

Through metabolic imprinting mechanisms a number of bioactive molecules including polyunsaturated fatty acids affect brain functions in the developmental age and longer-lasting beneficial effects are expected. In this study pregnant rats were offered diets either containing no docosahexaenoic acid (DHA) and arachidonic acid (AA) (Placebo diet) or an excess amount of these long chain polyunsaturated fatty acids (LC-PUFA) (Supplement diet) up to the time of weaning. Bilateral N-methyl-D-aspartate (NMDA) induced neurodegeneration in the entorhinal cortex of offspring in the age of 4 months was used as a tool to investigate the neuroprotective property of the developmentally supplemented DHA and AA treatments. Hippocampus-dependent spatial learning was measured in Morris water maze and the extent of neuronal lesion in the injected brain area was evaluated. Under baseline condition, in intact or sham-lesioned rats, the Morris water maze performance was superior in the supplemented group compared to the placebo controls. NMDA-lesion in the entorhinal cortex area decreased spatial learning in the supplement-treated rats while insignificantly diminished it in the placebo controls. The same supplementation attenuated the lesion size induced by the NMDA injection into the entorhinal and ventral hippocampal areas. We concluded that LC-PUFA supplementation during fetal and early postnatal development results in long-term enhancement of spatial learning ability of the offspring and offers resistance against excitotoxic brain lesion which lasts up to the adult age