Basal forebrain cholinergic functions

The behavioral data indicate that both xanomeline and CDD-0102 can reverse memory deficits associated with a loss of basal forebrain cholinergic function. This is particularly important since decreased choline acetyltransferase activity is a consistent neurochemical finding in Alzheimer s disease (Perry et al., 1977 Whitehouse et al., 1982 Coyle et al., 1983). Xanomeline showed some efficacy in clinical trials in Alzheimer s patients, yet beneficial effects were limited due to the prevalence of unwanted side effects (Bymaster et al., 1997). While both xanomeline and CDD-0102 were effective in improving memory function at the 1.0 mg/kg dose, further studies using a wide range of doses are necessary to compare the effectiveness of these muscarinic agonists on memory function. 

Lesions of the basal forebrain cholinergic system using a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) result in impaired attentional, but not mnemonic, function in rats (Muir et al., 1995) and monkeys (Voytko et al., 1994), an effect which has been confirmed using more selective IgG-saporin lesions (Baxter et al., 1995 Everitt 8c Robbins, 1997). 

The brain of AD patients is also characterized by the degeneration of basal forebrain cholinergic neurons, which innervates central regions involved in cognitive functions such as the cortex amygdala and hippocampus (1,3). The decline of cortical cholinergic activity as measured in postmortem brains... 

Voytko, M. L. (1996). Cognitive functions of the basal forebrain cholinergic system in monkeys Memory or attention Behavioral Brain Research, 75, 13-25. 

Neurotrophins play an important role in the normal development of the nervous system, but their function in the mature central nervous system is poorly understood. Nerve growth factor (NGF) is necessary for the survival and maintenance of the basal forebrain cholinergic system. 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

The basal forebrain is an important way station in the activation of the cerebral cortex from the reticular activating system. AMPA and NMDA injections into the basal forebrain increase wakefulness and reduce sleep (Cape Jones, 2000 Manfridi et al, 1999), effects that are blocked by AMPA and NMDA receptor antagonists (Manfridi et al, 1999). The excitatory cortical projections of the basal forebrain have long been considered purely cholinergic, but many basal forebrain neurons that project to the cortex are now known to contain Glu, which may function as a co-transmitter or even as the primary excitatory neurotransmitter (Manns et al, 2001). The basal forebrain also affects vigilance via synapses to HCT cells in the lateral hypothalamus some of these synapses are glutamatergic (Henny Jones, 2006). 

I and II and also layers IV. Activity of the basal forebrain neurons is necessary for maintaining wakefulness and, functions of these and brainstem cholinergic nuclei include arousal, selective attention and REM sleep (Ch. 2). 

NGF is the prototypic neurotrophin. The mature NGF polypeptide contains 120 amino acids, exhibits a molecular mass of 26 kDa and a pi of approximately 10. It contains three intra-chain disulphide linkages, which are essential for activity. NGF is synthesized and released from target tissues of sympathetic neurons and cholinergic basal forebrain neurons. It is also synthesized by non-neuronal tissue, including salivary glands, the prostate and mast cells. It functions to... 

Muir JL, Dunnett SB, Robbins TW, et al Attentional functions of the forebrain cholinergic systems effects of intraventricular hemichohnium, physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task. Exp Brain Res 89 611-622, 1992 Mukherjee S Mechanisms of the antimanic effect of electroconvulsive therapy. Convulsive Therapy 5 227-243, 1989... 

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