PubMed · 12166167
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Yasusuke Kimoto. 2002. [Acetylcholine].. https://pubmed.ncbi.nlm.nih.gov/12166167/
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Disturbed vasomotor function in coronary arteries has clinical importance in early stages of coronary artery disease (CAD), as it may contribute to the potential risk for an ischaemic coronary event. In the present study, we have investigated the relationship between coronary vasomotor function and the extent of CAD. The response to acetylcholine and nitrate infusion was assessed by quantitative coronary angiography. The extent of CAD was categorized into two groups: minor CAD (normal coronary arteries and vessel wall irregularities) and significant CAD (one-, two- and three-vessel disease). A total of 277 patients with stable angina pectoris, referred for a first diagnostic coronary angiography, were eligible for analysis (mean age 57 years, 61% male). The response to nitrate was significantly impaired in patients with significant CAD ( P <0.001). On the other hand, the response to acetylcholine was not different between the two groups ( P =0.12); however, a trend between the response to acetylcholine and the extent of CAD was observed in patients without a previous infarction ( P =0.07), which was a significant interaction variable. Furthermore, a significant relationship between coronary vasomotor response and the number of cardiovascular risk factors was observed ( P <0.05). In conclusion, in a heterogeneous group of patients, coronary vasomotor function measured by nitrate infusion was more strongly associated with the extent of CAD and the number of risk factors than the response to acetylcholine. These data suggest that, in patients with advanced atherosclerosis or multiple risk factors, the vasomotor dysfunction is not solely restricted to the endothelium.
Striatal cholinergic interneurons located in the dorsal striatum and nucleus accumbens are amenable to influences of the dopaminergic mesolimbic pathway, which is a pathway involved in reward and reinforcement and targeted by several drugs of abuse. Dopamine and acetylcholine neurotransmission and their interactions are essential to striatal function, and disruptions to these systems lead to a variety of clinical disorders. Dopamine regulates acetylcholine release through dopamine receptors that are localized directly on striatal cholinergic interneurons. The dopamine D2 receptor, which attenuates acetylcholine release, has been implicated in drug relapse and is targeted by therapeutic drugs that are used to treat a variety of neurological disorders including Tourette Syndrome, Parkinson's disease and schizophrenia. The present study provides the first direct evidence for the localization of dopamine D2 receptors on striatal cholinergic interneurons of the rat brain using dual labeling immunocytochemistry procedures. Using light microscopy, dopamine D2 receptors were localized on the cell somata and dendritic and axonal processes of striatal cholinergic interneurons in the dorsal striatum and nucleus accumbens of the rat brain. These findings provide a foundation for understanding the specific roles that cholinergic neuronal network systems and interacting dopaminergic signaling pathways play in striatal function and in a variety of clinical disorders including drug abuse and addiction.
SIB-1553A ((+/-)-4-[2-(1-methyl-2-pyrrolidinyl)ethyl]thiophenol HCl) is a neuronal nicotinic acetylcholine receptor (nAChR) ligand which is active in rodent and primate models of cognition. In functional assays, SIB-1553A exhibits marked subtype selectivity for nAChRs as compared to nicotine. In addition SIB-1553A also exhibits affinities to histaminergic (H3) and serotonergic (5-HT1 and 5HT2) receptors and sigma binding sites. In the present investigation, we characterized SIB-1553A-induced neurotransmitter release in vivo. Following subcutaneous injection (s.c., 10 mg/kg), SIB-1553A rapidly entered the brain achieving concentration of approximately 20 microM 15 min post-injection and was eliminated from plasma with a terminal half-life of approximately 32 min. In freely moving rats, SIB-1553A (1-40 mg/kg, s.c.), markedly increased ACh release in the hippocampus and prefrontal cortex. In both regions, the magnitude of SIB-1553A-induced ACh release was greater than that seen with the prototypical nAChR agonist, nicotine (0.4 mg/kg, s.c.). Both isomers of SIB-1553A induced similar levels of increase in hippocampal ACh release. Increased hippocampal ACh release was also observed following oral administration of SIB-1553A (40 mg/kg) or after local perfusion into the hippocampus (1 mM). SIB-1553A-induced hippocampal ACh release was significantly attenuated by two nAChR antagonists, mecamylamine (MEC) and dihydro-beta-erythroidine (DHbetaE), and by the dopamine (DA) (D1) antagonist, SCH-23390, arguing that ACh release, in part, involves activation of nAChRs and a permissive DA synapse. In contrast to its robust effects on ACh release, SIB-1553A (40 mg/kg, s.c.) modestly increased striatal DA release (approximately 180% of baseline). Due to the proposed role of cholinergic pathways in learning and memory, the neurochemical profile of SIB-1553A suggests a potential for it to treat cognitive dysfunction.