Aging of brain cholinergic neurons: pharmacological interventions.
Explore the source record for details and available documents.
Acetylcholine↗
Biomedical subjects
F Casamenti
Publications and source records attributed to F Casamenti.
Phosphatidylserine reverses the age-dependent decrease in cortical acetylcholine release: a microdialysis study.
In vivo basal acetylcholine (ACh) and choline (Ch) output from the parietal cortex of 3- and 19-month-old freely moving rats was measured by microdialysis. A dialysis tubing was inserted transversally through the parietal cortex 24 h before the experiment. ACh and Ch concentrations were determined in the same perfusate samples by HPLC with electrochemical detection. In 19-month-old rats treated with Tris buffer, ACh and Ch outputs were 39 and 16% lower, respectively, than in 3-month-old rats. Phosphatidylserine (PtdSer) administration (15 mg/kg i.p. daily) for 8 days to 19-month-old rats markedly attenuated the decrease in ACh release. The same treatment did not affect ACh and Ch outputs in 3-month-old rats. ACh and Ch outputs in 19-month-old rats administered either phosphatidylcholine (PtdCho) or o-phospho-dl-serine (P-Ser) (15 mg/kg i.p. daily) for 8 days were as low as in 19-month-old rats receiving Tris buffer only. It is possible that chronic PtdSer treatment improve ACh release in aging rats by increasing the availability of Ch for ACh synthesis.
Acetylcholine↗
Effect of thyrotropin releasing hormone (TRH) on acetylcholine release from different brain areas investigated by microdialysis.
1. The effect of thyrotropin releasing hormone (TRH) administration upon acetylcholine (ACh) release in freely moving rats was investigated by means of transversal microdialysis coupled to h.p.l.c. TRH administered either s.c. or via local perfusion increased the ACh release from cortex and hippocampus but not from the striatum. The increase in ACh release was maintained after 7 days of s.c. administration of TRH. 2. After s.c. injection of the neuropeptide, the increase in ACh release was dose-dependent and reached a maximum at 40 min after administration. The maximal percentage increases were 18, 52, 66 and 89% at doses of 1, 2.5, 5 and 10 mg kg-1 and 35, 48 and 54% at doses of 2.5, 5 and 10 mg kg-1 in the cortex and hippocampus, respectively. The effect of TRH was dependent on neuronal activity since it was completely inhibited by perfusion with tetrodotoxin (TTX), 5 X 10(-7) M. 3. Perfusion with TRH, 2.5 micrograms microliters-1, caused 198% and 150% increase in ACh release 60 and 80 min after the beginning of the perfusion in the cortex and hippocampus, respectively. After this initial peak, a 100% increase in ACh release persisted throughout the perfusion. 4. Systemic TRH administration was followed by marked hyperactivity and stereotyped behaviour that showed a time course shorter than that of the increase in ACh release. 5. These findings demonstrate that TRH exerts a strong stimulant action on cortical and hippocampal cholinergic pathways.
Acetylcholine↗
Principal aspects of the regulation of acetylcholine release in the brain.
Explore the source record for details and available documents.
Acetylcholine↗
Decrease of acetylcholine release from cortical slices in aged rats: investigations into its reversal by phosphatidylserine.
The release of total acetylcholine (ACh) and [3H]ACh was investigated in electrically stimulated cortical slices prepared from 4- and 18-month-old male Wistar rats. The slices were prelabeled with [3H]choline ([3H]Ch) and perfused with Krebs solution containing physostigmine. Total ACh was measured and the nature of the tritium efflux identified by HPLC. The total tritium content in the slices at the end of the incubation period was half as great in the old as in young rats. A linear relationship was found between stimulation frequencies (2, 5, and 10 Hz) and fractional [3H]ACh release in both young and old rats. In the latter the release was significantly smaller. At 10 Hz stimulation frequency the ratio between the two 2-min stimulation periods, S2/S1, was higher in the 18-month-old rats than in the young rats. Specific activity of the evoked ACh release was significantly smaller in S2 than in S1 in 4-month-old rats only. These findings indicate that the young synthetize ACh from endogenous unlabeled Ch more than older rats. In 18-month-old rats both the evoked total ACh and [3H]ACh release, expressed as picograms per minute, showed an approximately 50% decrease in both S1 and S2 stimulation periods, with no significant difference in specific activity. Phosphatidylserine (PtdSer) administration (15 mg/kg, i.p. daily) for 1 week to 18-month-old rats prevented the reduction in total evoked ACh release but not the reduction in evoked [3H]ACh release. The specific activity of ACh release was therefore significantly smaller than that of the young and untreated old rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
The validity of animal models in the search for drugs for the aging brain.
The search for drugs of use in the treatment of age-associated memory impairment, multi-infarct dementia, and Alzheimer's disease is frustrated by the expense or inadequacy of animal models of these conditions. We hope that this critical review of existing models will stimulate the use and proper interpretation of the best of these models, and encourage thinking in devising new models.
Aging↗
Lesions of the nucleus basalis magnocellularis in the rat: morphological, biochemical and behavioral reparative effect of nerve growth factor and ganglioside GM1.
Three- and fifteen-month old rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM) were used. In 3-month old rats, 4 days after the lesion a 34 and 33% decrease in high affinity choline uptake (HACU) rate was found in the ipsilateral frontal and parietal cortices, respectively. Twenty-one days later the lesioned rats showed a loss in the NBM choline acetyltransferase (ChAT)-positive cells, a marked decrease in ipsilateral cortical ChAT activity and an impairment of the acquisition of a passive avoidance conditioned response. If the lesioned rats received nerve growth factor (NGF) (10 micrograms i.c.v.) twice a week or daily administration of ganglioside GM1 (GM1) (30 mg/kg i.p.), beginning immediately after surgery, the decreases in the HACU rate and ChAT activity were significantly smaller and the behavioral performance was normal. A potentiation by GM1 of NGF effects on the cholinergic neurons of the NBM occurred since no differences were detected between sham-operated rats and rats trated with NGF plus either the active (30 mg/kg) or inactive (10 mg/kg) dose of GM1. The loss in the number of NBM ChAT-positive neurons was reduced by GM1 or prevented by NGF administrations, indicating that the two drugs prevent the cholinergic deficit by protecting the cholinergic neurons of the NBM from ibotenic acid neurotoxicity. GM1 had no effect on ChAT activity decrease and behavioral impairment in 15-month old rats. The latter finding indicates an age-related loss of the ability of GM1 to enhance neurotrophic activity in the NBM.
Animals↗
Effects of nerve growth factor and GM1 ganglioside on the number and size of cholinergic neurons in rats with unilateral lesion of the nucleus basalis.
Four groups of rats with a unilateral ibotenic acid lesion of the nucleus basalis were treated with saline, nerve growth factor (NGF) 10 micrograms administered intracerebroventricularly twice per week, sialoganglioside GM1 30 m/kg daily i.p. and NGF twice per week plus GM1 10 mg/kg i.p. daily, respectively, beginning immediately after lesioning. Twenty-one days later the rats treated with saline showed a marked impairment in negotiating a 'step through' passive avoidance conditioned response, a 32% decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the lesioned nucleus basalis and a 12% decrease in their areas. The rats treated with NGF and NGF plus GM1 showed no difference from sham-operated rats. In the GM1-treated rats a 12% decrease only in the number of ChAT-positive neurons was detected while performance and neuronal areas were normal. These findings indicate that NGF and GM1 prevent the cholinergic deficit by protecting the cholinergic neurons of the nucleus basalis from ibotenic acid neurotoxicity.
Animals↗
Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis.
Monosialoganglioside GM1 and nerve growth factor (NGF) were administered alone or concomitantly to adult male rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM). High-affinity choline uptake (HACU) rate and choline acetyltransferase (ChAT) activity were measured, 4 and 21 days after surgery, respectively, in the frontal and parietal cortices of both hemispheres. A 33-34% decrease in HACU rate and a 43-39% decrease in ChAT activity was found in the ipsilateral cortices 4 and 21 days, respectively, after the lesion. If the lesioned rats received NGF (10 micrograms i.c.v.) twice a week or daily administrations of GM1 (30 mg/kg, i.p.), beginning immediately after surgery the decrease in HACU rate and ChAT activity was smaller. If NGF and GM1 were given concomitantly no decrease in HACU rate and ChAT activity was detected in the lesioned hemisphere and a slight increase occurred in the contralateral hemisphere. However, after the concurrent administration of NGF (10 micrograms i.c.v.) and the inactive dose of GM1 10 mg/kg i.p. no decrease in HACU and ChAT activity was also found in the lesioned rats. The latter finding indicates a potentiation by GM1 of NGF effects on the cholinergic neurons of the NBM. The two drugs may either antagonize the neurotoxic effects of ibotenic acid or stimulate a compensatory activity in the remaining neurons.
Animals↗
Local cerebral glucose utilization following unilateral and bilateral lesions of the nucleus basalis magnocellularis in the rat.
To investigate to what extent the loss of cholinergic projections to the neocortex results in functional impairment in the target areas, local rates of cerebral glucose utilization were measured following excitotoxin lesions of the nucleus basalis magnocellularis (NBM) in the rat. Both unilateral and bilateral lesions of NBM resulted in reversible depression of cerebral metabolism. The effects of unilateral lesions were limited to the cortical areas which receive most of the cholinergic projections from NBM. The metabolic defect produced by bilateral lesions was spread to the whole brain. Within 4 months, however, normal metabolic values coexisted with marked changes of the presynaptic cholinergic markers and impairment of conditioned behavior.
Animals↗
Effect of BM-5, a presynaptic antagonist-postsynaptic agonist, on cortical acetylcholine release.
The effect of N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl) acetamide (BM-5) on acetylcholine release from the cerebral cortex was investigated in unanaesthetized and urethane-anaesthetized rats. BM-5 at doses ranging from 0.3 to 5 mg/kg i.p. enhanced acetylcholine output in both groups of rats. The maximum increase occurred with 0.5 mg/kg in the unanaesthetized and 2 mg/kg in the anaesthetized rats. The effect lasted approximately 60 min. At the largest doses peripheral muscarinic effects including salivation, chromodachryorrhea and rhinorrhea were also seen. These results demonstrate that BM-5 exerts presynaptic antagonistic and postsynaptic agonistic effects on muscarine receptors in vivo also.
Acetylcholine↗
Are the neurochemical and behavioral changes induced by lesions of the nucleus basalis in the rat a model of Alzheimer's disease?
A review of the work on the neurochemical, electroencephalographic and behavioral changes induced in the rat by lesions of the nucleus basalis is presented. The similarities and differences between the effects of the lesions and the neurochemical and clinical alterations characterizing senile dementia of Alzheimer type are pointed out. The decrease in choline acetyltransferase (ChAT) activity in the cortex following unilateral or bilateral electrolytic or neurotoxic lesions of the nucleus basalis are described and compared with the decrease in ChAT activity found in the cortex and hippocampus of patients affected by senile dementia. At variance with the latter condition, in rats with lesions of the nucleus basalis a spontaneous recovery in cortical ChAT activity has been observed 3-6 months after the lesion. The lesions of the nucleus basalis decrease high affinity choline uptake activity which, however, undergoes a rapid recovery. Lesions also decrease spontaneous and drug-stimulated ACh release from the cerebral cortex. Transitory changes in the number of muscarinic binding sites have been reported in the cerebral cortex of the lesioned rats while a decrease in the number of muscarinic binding sites has generally been found in the cerebral cortex of patients with senile dementia. [3H] glutamate uptake in the striatum of the lesioned rats was not affected. In both lesioned rats and patients affected by senile dementia, a decrease of low voltage high frequency electrocortical activity has been reported. Unilateral and bilateral lesions of the nucleus basalis bring about an impairment of the acquisition of active and passive avoidance responses and of the rewarded alternation discriminatory tasks involving working memory and spatial memory. On the other hand, memory impairment is a typical symptom of senile dementia. In conclusion, the lesions of the nucleus basalis only partly mimic the complex clinical picture of senile dementia of Alzheimer type. They offer, nevertheless, a useful tool for understanding the critical role of the central cholinergic pathways in some of the cognitive processes and identifying potentially useful pharmacological treatments.
Alzheimer Disease↗
Effect of phosphatidylserine on acetylcholine output from the cerebral cortex of the rat.
Explore the source record for details and available documents.
Acetylcholine↗
Stimulation of acetylcholine output from brain slices caused by the ionophores BrX-537A and A23187.
1 The effect of two ionophores, BrX-537A (Bromolasolacid) and A 23187, on acetylcholine (ACh) output from brain slices was studied. 2 The slices were prepared from rat cerebral cortex, incubated in Krebs solution containing physostigmine and ACh output determined by bioassay. 3 Both ionophores enhanced ACh output. BrX-537A exerted its maximal effect, a six fold increase, at a concentration of 1.8 micron, while A 23187 caused a three fold increase at a concentration of 58 micron. 4 When the slices were incubated in a Ca-free medium, the effect of A 23187 on ACh output was only reduced, BrX-537A was abolished while that of BrX-537A was also active when disodium edetate (EDTA) was added to the the Ca-free medium. 5 The activity of BrX-537A was not affected by the presence of tetrodotoxin in the incubation medium. 6 The stimulation of ACh output elicited by KCl (25 mM) was increased further by hyoscine, but not by BrX-537A. Hyoscine however had no effect when ACh output was stimulated by BrX-537A. 7 The effect of BrX-537A on ACh output was potentiated by the addition of Mg2+ (9.3 mM) to the incubation medium and was reduced in a Mg-free medium. 8 It is concluded that A 23187 stimulates ACh output by transporting extracellular Ca2+ into cholinergic nerve endings. The effect of BrX-537A does not depend only on Ca2+ but also on other mechanisms.
Acetylcholine↗