Progress in brain research
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Cholinergic lesion paradigms have been used to study the role of the cholinergic system in cortical arousal and cognitive function, and its implication in cognitive deficits that occur in Alzheimer's disease. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins (e.g. AF64A) by stereotaxic injection into the Nbm to produce reductions in cortical cholinergic activity. ⋯ NMDA receptor binding was markedly reduced and AMPA, kainate, and GABAA receptor binding has been significantly increased in cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to immunolesion of the basal forebrain cholinergic system. Equivalent changes in cortical glutamate and GABA receptor subtype levels have been observed 7 days after electrolytic or ibotenic acid lesion of the Nbm. The data suggest that cholinergic immunolesion by 192IgG-saporin exhibits a valuable tool to produce specific cholinergic deficits in rats, which can be used as a model to study the effect of treatment with various drugs for compensating the impaired cortical cholinergic input.
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Review
Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma.
Sympathetic post-ganglionic neurons may be involved in the generation of pain, hyperalgesia and inflammation under pathophysiological conditions. Two categories of influence of the sympathetic neuron on afferent neurons can be distinguished and this distinction seems to be related to whether the coupling between afferent and sympathetic neuron develops after nerve lesion or after tissue trauma with inflammation (Fig. 15): A. Peripheral nerve lesion generates plastic changes of the afferent and sympathetic postganglionic neurons, depending on the type of nerve lesion (e.g. complete, partial). ⋯ Sympathetically mediated (neurogenic) inflammation and neurogenic inflammation mediated by afferents may interact reciprocally and enhance the inflammatory process as well as the sensitization of nociceptive afferents. Norepinephrine may also lead to sensitization of nociceptive afferents under inflammatory conditions. This sensitization is presumably mediated by alpha 2-adrenoceptors in the sympathetic varicosities and by a prostaglandin (probably PGI2) which is synthesized and released by or in association with the sympathetic varicosities.
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At the neuromuscular junction and possibly also at the synaptic level in the brain, the main sequence of events (see Fig. 5) that involves purines in modulation of ACh release includes the following observations: (1) storage of ATP and its release either together with, or independently of acetylcholine. ATP is also released from the post-junctional component. Adenosine as such is released either from the motor nerve terminals or from the post-junctional component. (2) There is extracellular hydrolysis of ATP to adenosine, which is the active substance to modulate transmitter release. ⋯ This relative activation depends upon the intensity (frequency, pulse duration) of stimulation of the motor nerve terminals. (7) Adenosine released as such seems to preferentially activate A1 receptors, whereas the adenosine formed from metabolism of adenine nucleotides prefers to activate the A2a receptors. In conclusion, to find out precisely what occurs with ACh in transmitting its message at the synaptic level, one has to consider the subtle ways used by purines to modulate the ACh response. It therefore appears of interest that pharmacological and therapeutic strategies use this knowledge to approach cholinergic transmission deficiencies based upon reduction of ACh release.