Chapter 22 Behavioral and biochemical effects of nucleus basalis magnocellularis lesions: implications and possible relevance to understanding or treating Alzheimer's disease

Bartus, Raymond T.; Flicker, Charles; Dean, Reginald L.; Fisher, Stephen K.; Pontecorvo, Michael J.; Figueiredo, Joanne C.

doi:10.1016/s0079-6123(08)64315-0

Cited by 32 publications

(17 citation statements)

References 79 publications

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“…Lesioning of the NBM in the rat by local injection of the excitotoxin ibotenic acid is known to partially mimic some of the complex behavioral and neurochemical deficits characteristic of AD, and has for this reason been widely used as a model for studying the role of central cholinergic pathways in some cognitive processes and for identifying potentially useful pharmacological treatments (Bartus et al, 1986;Pepeu et al, 1986). As expected, and as a validation of the lesioning procedure, bilateral NBM-lesioned rats showed significant performance deficits in both the passive avoidance and Morris water maze tests, in agreement with previous studies (O 'Connell et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Noradrenaline has also been found to have an important permissive role in long-term potentiation, a form of synaptic plasticity associated with memory processes (Bliss et al, 1983), and also facilitates in a synergistic manner a similar role for acetylcholine in longterm potentiation (Brocher et al, 1992). Decline in memory is one of the major symptoms of Alzheimer's disease (AD), and this impairment has been ascribed to the central cholinergic (Bartus et al, 1986;Perry et al, 1992) and noradrenergic (Reinikainen et al, 1990;Haapalinna et al, 1998) pathologies that occur in this disorder. Neuronal cell loss in the locus coeruleus (LC) and a decrease in presynaptic noradrenergic markers are commonly observed in postmortem brains of patients with AD (Cowburn et al, 1988), Parkinson's disease, and related neuropathologies (Colpaert, 1994).…”

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confidence: 99%

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Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Chopin¹,

Colpaert²,

Marien³

2002

J Pharmacol Exp Ther

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The present study examined the influence of dexefaroxan, a potent and selective ␣ 2 -adrenoceptor antagonist, on cognitive performance in rodents. In young adult rats, dexefaroxan reversed the deficits induced by UK 14304 [5-bromo-N-(4,5-dihydro-1-H-imidazol-2-yl)-6-quinoxalinamine], scopolamine, and diazepam in a passive avoidance task. In this test, dexefaroxan also attenuated the spontaneous forgetting induced by a 15-week training-testing interval. Moreover, dexefaroxan, given immediately after training, increased the memory performance of rats trained with a weak electric footshock in the passive avoidance test, facilitated spatial memory processes in the Morris water maze task in rats, and increased the performance of mice in an object recognition test. Thus, dexefaroxan appears to have a promnesic effect in these tests by facilitating the processes of memory retention, rather than acquisition or other noncognitive influences. The facilitatory effects of dexefaroxan in young adult rats persisted even after a 21-to 25-day constant subcutaneous infusion by using osmotic minipumps, indicating that tolerance to the promnesic effect of the drug did not occur during this prolonged treatment interval. Furthermore, in the passive avoidance and Morris water maze tests, dexefaroxan ameliorated the age-related memory deficits of 24-month-old rats to a level that was comparable to that of young adult animals, and reversed the memory deficits induced by excitotoxin lesions of the nucleus basalis magnocellularis region. Together, these findings support a potential utility of dexefaroxan in the treatment of cognitive deficits occurring in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Chopin¹,

Colpaert²,

Marien³

2002

J Pharmacol Exp Ther

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“…ory in monkeys (19)(20)(21)(22)(23)(24)(25). Cholinergic agonists, cholinesterase inhibitors, and hippocampal grafts of cholinergic neurons have been reported to restore memory function after these lesions and to improve memory function in normal rats and mice (26)(27)(28)(29)(30).…”

Section: Methodsmentioning

confidence: 99%

Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

Mastropaolo

Nadi

Ostrowski

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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Galanin coexists with acetylcholine in medial septal neurons projecting to the ventral hippocampus, a projection thought to modulate memory functions. Neurochemical lesions of the nucleus basalis-medial septal area in rats impaired choice accuracy on a delayed alternation t-maze task. Acetylcholine (7.5 or 10 ,sg intraventricularly or 1 ,.g microinjected into the ventral hippocampus) significantly improved performance in the lesioned rats. Atropine (5 mg/kg intraperitoneally or 10 ,.g intraventricularly), but not mecamylamine (3 mg/kg intraperitoneally or 20 ,ug intraventricularly), blocked this action of acetylcholine, suggesting involvement of a muscarinic receptor. Galanin (100-500 ng intraventricularly or 200 ng into the ventral hippocampus) attenuated the ability of acetylcholine to reverse the deficit in working memory in the lesioned rats. The antagonistic interaction between galanin and acetylcholine suggests that endogenous galanin may inhibit cholinergic function in memory processes, particularly in pathologies such as Alzheimer disease that involve degeneration of basal forebrain neurons.Galanin (GAL) is a 29-amino acid peptide (1) localized in many regions of the mammalian central nervous system (2-5). Immunohistochemical studies revealed the coexistence of GAL and choline acetyltransferase (ChAT), the synthetic enzyme for acetylcholine (ACh), in the medial septal nucleus and nucleus basalis/diagonal band complex of primates (6, 7).In the rat, GAL coexists with ACh in the medial septal neurons projecting to the ventral hippocampus but not in the nucleus basalis neurons projecting to the cerebral cortex (8, 9). The localization of this peptide in the septo-hippocampal pathway, and the high density of GAL binding sites labeled with 1251I-labeled GAL in the ventral hippocampus (10), raise the possibility of a functional role for GAL in memory processes. To investigate the functional significance of the GAL-ACh coexistence, rats were microinjected with GAL, ACh, GAL plus ACh, or saline before behavioral testing with a t-maze delayed alternation task, in which performance was disrupted by lesions of the nucleus basalis-medial septal area (11). MATERIALS AND METHODSMale Sprague-Dawley rats, 200 g (starting weight), were housed in a temperature and humidity controlled vivarium, with lights on from 0700 to 1900. Lesions of the nucleus basalis magnocellularis (NBM) and medial septal area (MSA) were performed according to the methods of Wenk and coworkers (12). Briefly, rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and intracerebrally microinjected through 31-gauge hypodermic tubing with ibotenic acid (in isotonic phosphate-buffered saline, pH 7.7, shielded from light; Sigma), at five individual stereotaxic sites: 1.3 and 1.7 mm posterior to bregma, bilaterally 2.6 mm lateral to the midline, and 7.5 mm ventral to the surface of the skull with 4 ,ug in 0.4 ,ul over 2.5 min for NBM, and 0.8 mm anterior to bregma, at the midline, and 6.5 mm ventral to the surface of the skull with 6 ,u...

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“…This brain area is of wide clinical interest because some of its cell populations have been found to be severely affected in a number of neurological maladies such as Alzheimer's disease, Parkinson's disease and schizophrenia (Davies and Maloney 1976;Whitehouse et al 1982; Bartus et al 1986;Heimer et al 1991;Geula and Mesulam 1994;Sarter and Parikh 2005).…”

Section: Introductionmentioning

confidence: 99%

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons

et al. 2007

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The basal forebrain (BF) contains cholinergic as well as different types of non-cholinergic corticopetal neurons and interneurons, including neuropeptide Y (NPY) containing cells. BF corticopetal neurons constitute an extrathalamic route to the cortex and their activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with low voltage fast cortical EEG activity. It has been shown in previous studies (Duque et al. in J Neurophysiol 84:1627-1635, 2000) that in anesthetized rats BF cholinergic neurons fire mostly during low voltage fast cortical EEG epochs, while increased NPY neuronal firing is accompanied by cortical slow waves. In this paper, electrophysiologically and neurochemically characterized cholinergic and NPY-containing neurons were 3D reconstructed from serial sections and morphometrically analyzed. Cholinergic and NPY-containing neurons, although having roughly the same dendritic surface areas and lengths, were found to differ in dendritic thickness and branching structure. They also have distinct patterns of dendritic endings. The subtle differences in dendritic arborization pattern may have an impact on how synaptic integration takes place in these functionally distinct neuronal populations. Cholinergic neurons exhibited cortically projecting axons and extensive local axon collaterals. Elaborate local axonal arbors confined to the BF also originated from NPY-containing neurons. The presence of local axon collaterals in both cholinergic and NPY neurons indicates that the BF is not a mere conduit for various brainstem inputs to the cortex, but a site where substantial local processing must take place.

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Chapter 22 Behavioral and biochemical effects of nucleus basalis magnocellularis lesions: implications and possible relevance to understanding or treating Alzheimer's disease

Cited by 32 publications

References 79 publications

Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons

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Chapter 22 Behavioral and biochemical effects of nucleus basalis magnocellularis lesions: implications and possible relevance to understanding or treating Alzheimer's disease

Cited by 32 publications

References 79 publications

Effects of Acute and Subchronic Administration of Dexefaroxan, an α2-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Effects of Acute and Subchronic Administration of Dexefaroxan, an α2-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Galanin antagonizes acetylcholine on a memory task in basal forebrain-lesioned rats.

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons

Contact Info

Product

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Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents

Effects of Acute and Subchronic Administration of Dexefaroxan, an α₂-Adrenoceptor Antagonist, on Memory Performance in Young Adult and Aged Rodents