Effects Of Cholinergic Lesions Research Articles

Effects of Cholinergic Lesions and Cholinesterase Inhibitors on Aromatase and Estrogen Receptor Expression in Different Regions of the Rat Brain

Cholinergic projections have been shown to interact with estrogens in ways that influence synaptic plasticity and cognitive performance. The mechanisms are not well understood. The goal of this study was to investigate whether cholinergic projections influence brain estrogen production by affecting aromatase (ARO), or influence estrogen signaling by affecting estrogen receptor expression. In the first experiment, ovariectomized rats received intraseptal injection of the selective immunotoxin 192IgG-saporin to destroy cholinergic inputs to the hippocampus. In the second experiment ovariectomized rats received daily intraperitoneal injections of the cholinesterase inhibitors donepezil or galantamine for 1 week. ARO activity and relative levels of ARO, ERα, ERß, and GPR30 mRNAs were quantified in the hippocampus, frontal cortex, amygdala and preoptic area. Results show that the cholinergic lesions effectively removed cholinergic inputs to the hippocampus, but had no significant effect on ARO or on relative levels of ER mRNAs. Likewise, injections of the cholinesterase inhibitors had no effect on ARO or ER expression in most regions of the brain. This suggests that effects of cholinergic inputs on synaptic plasticity and neuronal function are not mediated by effects on local estrogen production or ER expression. One exception was the amygdala where treating with galantamine was associated with a significant increase in ARO activity. The amygdala is a key structure involved in registering fear and anxiety. Hence this finding may be clinically relevant to elderly patients who are treated for memory impairment and who also struggle with fear and anxiety disorders.

3H]vesamicol binding in brain: autoradiographic distribution, pharmacology, and effects of cholinergic lesions.

An autoradiographic analysis of high-affinity binding sites for the vesicular acetylcholine transport blocker [3H]vesamicol (2-(4-phenylpiperidino) cyclohexanol; AH 5183) was conducted in rat brain. [3H]Vesamicol binding was displaced 52-99% by DPPN [( 2,3,4,8]-decahydro-3-(4-phenyl-1-piperidinyl)-2-napthalenol) (IC50 = 14 nM) and by ketanserin (500 nM), haloperidol (43 nM), and vesamicol analogs, but not by drugs selective for adenosine, adrenergic, amino acid, calcium channel, monoaminergic, opioid, PCP, sigma, or several other receptor classes. [3H]Vesamicol binding was most concentrated in the interpeduncular nucleus and fifth and seventh cranial nerve nuclei. Moderate binding was found in the lateral caudate-putamen, medial nucleus accumbens, olfactory tubercle, vertical and horizontal diagonal bands of Broca, and basolateral amygdala. The distribution of [3H]vesamicol binding was similar to distributions of acetylcholine (r = 0.88), acetylcholine esterase (r = 0.97), choline acetyltransferase (ChAT) (r = 0.97), and [3H]hemicholinium-3 binding sites (r = 0.95-0.99). Lower correlations were obtained between [3H]vesamicol and muscarinic receptor densities (r = 0.50-0.70). Few exceptions to the match between binding and cholinergic neuronal markers were found, e.g., the molecular layer of the cerebellum and the thalamus. Lesions of cholinergic neuronal projections to the neocortex or hippocampus reduced [3H]vesamicol binding in each of these regions, but to a lesser extent than reductions in ChAT. [3H]Vesamicol binding sites appear to be anatomically associated with brain cholinergic neurons, a locus that is consistent with the control by this site of vesicular acetylcholine uptake.