The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat.

The effects of selective cholinergic cell loss within the basal forebrain (BF) were determined using a task that requires shifting of attention between two visual stimuli. Discriminability between two stimuli and response bias were determined in young and old F-344 rats given BF injections of IgG-192 saporin (100 ng). The lesion reduced ChAT activity in the frontal and parietal cortices, hippocampus, and olfactory bulbs. The lesion did not significantly alter Na+/K(+)-ATPase activity in cortex, hippocampus, or olfactory bulbs, or endogenous levels of neuropeptide Y and neurokinin B within the BF. The BF lesions impaired both stimulus discriminability and response bias in young and old rats. The BF lesions had a significantly greater effect upon stimulus discriminability and response bias in aged rats, compared to young rats, only when the stimulus duration was very brief, i.e., when the task was most difficult to solve. At longer stimulus durations, aging and lesions showed no interaction. The results suggest that the selective loss of cholinergic cells in the BF, but not normal aging, impairs the ability to discriminate between independent sensory stimuli. The loss of these cells confers a response bias in simple operant tasks involving motor responses to reward-related visual stimuli.

Choline acetyltransferase activity and vesamicol binding in Rett syndrome and in rats with nucleus basalis lesions.

The decline in choline acetyltransferase activity has been identified previously within the brains of patients with Rett syndrome and Alzheimer's disease. The level of [3H]vesamicol binding to a terminal vesicular acetylcholine transporter is inversely related to the decline in cortical choline acetyltransferase activity in Alzheimer's disease, which may be due to compensatory processes within surviving cholinergic terminals. In order to investigate whether similar cholinergic compensatory processes are present in the Rett syndrome brain and are altered by normal aging, we investigated the density of cholinergic vesicular transporters in (i) the brains of Rett syndrome patients, and (ii) young and old rats with experimentally-induced cholinergic cell loss. In Rett syndrome, a significant decline in choline acetyltransferase activity within the putamen and thalamus was directly correlated with a decline in [3H]vesamicol binding. In both young and old rats, basal forebrain lesions decreased cortical choline acetyltransferase activity significantly, while [3H]vesamicol binding was unchanged. In contrast to young and old lesioned rats and patients with Alzheimer's disease, cholinergic cells in the brains of patients with Rett syndrome do not compensate for the loss of cholinergic cells by increasing acetylcholine vesicular storage.

Age-related decrease in vulnerability to excitatory amino acids in the nucleus basalis.

The present study investigated the effects of nucleus basalis magnocellularis (NBM) lesions in young (3 months), adult (9 months), and aged (24 months) rats by injections of either NMDA or AMPA upon performance of a delayed alternation task on a T maze. During phase 1 of testing, the interchoice interval (ICI) was 5 s and each rat was given 10 trials per day during phase 2, the ICI was 30 s across 10 trials per day; during phase 3, the ICI was 5 s across 20 trials per day. Analyses of variance revealed (a) a significant effect of age during phase 1 (i.e., 24-month-old rats performed worse than 3-month-old rats); (b) a significant effect of age and lesion in phase 2 (i.e., the lesions impaired choice accuracy equally in all age groups when the ICIs were 30 s); (c) a significant effect of age and lesions, and a significant interaction in phase 3 (i.e., young rats were more impaired by the lesions than were aged rats.

MK-801, memantine and amantadine show neuroprotective activity in the nucleus basalis magnocellularis.

The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.

Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat.

The nucleus basalis magnocellularis (NBM) contains cholinergic neurons that project to the neocortex and is densely innervated by excitatory amino acid-containing terminals. A dysfunction in the balance of excitatory inputs or an alteration in the sensitivity of NBM cells to glutamate may underlie the selective vulnerability to aging. Some large NBM neurons contain neurokinin B (NKB) mRNA. The present study investigated whether alpha-2-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA) differentially destroy NKB-containing, NKB-receptive, or cholinergic NBM cells, and whether this vulnerability is altered by aging. Injections of AMPA or NMDA significantly decreased neocortical ChAT activity, as compared to control levels, across all three age groups, with no interaction between lesion and age group. The results of in situ hybridization histochemistry and NKB receptor studies suggest that NKB-containing neurons in the NBM, and the neurons they innervate, are not vulnerable to NMDA or AMPA in either young or old rats. While NKB mRNA-positive cells were diffusely distributed throughout the basal forebrain, only a small proportion of the large NBM cells contained NKB mRNA. The results suggest that NKB does not extensively colocalize with acetylcholine within the basal forebrain of rats and that NBM NKB neurons do not directly innervate cholinergic cells.

Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat.

The present study investigated the specific ways by which cytotoxicity due to glutamate receptor stimulation could be attenuated by the administration of agonists and antagonists of the ionotropic and metabotropic glutamate receptors within the nucleus basalis magnocellularis (NBM) of rats as measured by cortical choline acetyltransferase activity. The results of these studies suggest that (1) the cytotoxicity of ibotenate to NBM cholinergic cells is not dependent upon stimulation of metabotropic glutamate receptors, but results from activation of N-methyl-D-aspartate (NMDA) receptors, (2) the cytotoxicity of quisqualate to cholinergic cells within the NBM is not dependent upon stimulation of NMDA or metabotropic receptors, and (3) the cytotoxicity of NMDA was prevented by administration (i.p.) of the un-competitive NMDA antagonist memantine (30 mg/kg), resulting in plasma levels of 2.5 micrograms/ml, a concentration known to block efficiently NMDA receptors in vitro. Finally, performance of a food-motivated, delayed-alternation task on a T-maze was impaired by injections of NMDA into the NBM, but was prevented by co-administration of NMDA with memantine.

Nitric oxide formation does not underlie the memory deficits produced by ibotenate injections into the nucleus basalis of rats.

Basal forebrain (BF) injections of ibotenic (IBO) acid impair memory, whereas quisqualic (QUIS) acid injections do not. The authors investigated whether the cytotoxicity and differential behavioral effects of IBO and QUIS in rats depend on the generation of nitric oxide (NO). Injections of IBO or sodium nitroprusside (NP), but not QUIS, significantly increased BF NO formation, as determined by guanosine 3,5-cyclic monophosphate levels. IBO, alone or coinjected with methylene blue (MB), and QUIS, alone or coinjected with NP, decreased cortical choline acetyltransferase (ChAT) activity and the number of ChAT-positive BF neurons. The BF levels of galanin or neuropeptide Y were unchanged in all lesion groups. QUIS, but not IBO, dose-dependently destroyed NO-producing BF cells. Injections of IBO, with or without MB, impaired choice accuracy in a T-maze alternation task. The results suggest that the generation of NO in the BF does not underlie the spatial working memory deficit produced by IBO.

Relationship among weight change, body condition and reproductive performance of range beef cows.

A 5-yr study involving 45 to 78 pregnant Hereford range cows each year evaluated relationships among prepartum nutrition, body condition scores, BW changes and reproductive performance. Four prepartum nutritional treatments were imposed. One group of cows were fed to maintain (M) their November BW until calving in March and April. The other three groups of cows were fed to lose about 5% of their November BW by 8 wk before parturition, then to maintain BW (LM), lose an additional 5% of their BW (LL) or gain 5% of their BW (LG). After calving, all cows were fed to maintain BW. Body condition scores and BW were recorded every 14 d throughout the trial. Linear regression analyses were conducted to examine treatment effects on BW, body condition score and measures of reproductive performance. A discriminant analysis was performed on pregnancy rate and percentage of cows with ovarian luteal activity by 85 d after parturition. The M cows had a greater pregnancy rate (71%) than cows on other treatment groups. The LL cows had a reduced pregnancy rate (42%) compared with LM (51%) and LG (58%) cows. Prepartum nutritional treatment did not affect the days from parturition to conception. Precalving body condition score and November to January BW changes influenced pregnancy rate (P less than .001). A cubic response curve described the relationship between pregnancy rate and precalving body condition score for cows with condition scores of 3 through 7.(ABSTRACT TRUNCATED AT 250 WORDS)