Brain acetylcholine receptors

Wada K, Ballivet M, Boulter J, ConnoUy J, Wada E, Deneris ES, Swanson LW, Heinemann S, Patrick J (1988) Eunctional expression of a new pharmacological subtype of brain acetylcholine receptor. Science 240 330-334... 

McLane, K. E., Wu, X., and Conti-Tronconi, B. M. (1990). Identification of a brain acetylcholine receptor a subunit able to bind a-bungarotoxin. J. Biol Chem. 265 9816-9824. 

Nicotinic receptors (nicotinic acetylcholine receptors, nACHR) exist not only in the membrane of vertebrate skeletal muscle at the synapse between nerve and muscle (muscle-type nAChR) but also at various synapses throughout the brain, mainly at presynaptic positions (neuronal-type nAChR). Whereas the muscle-type nAChR is precisely composed of two a 1-subunits, one (3 -subunit, one y -subunit and one y -subunit (adult)... 

Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors native subtypes and their relevance. Trends Pharmacol Sci 27 482-491... 

Levey, A, Kitt, CA, Simmonds, WF, Price, DL and Brann, MR (1991) Identification and localisation of muscarinic acetylcholine receptor proteins in brain with subtype specific antibodies. J. Neurosci. 11 3218-3226. 

The acetylcholine receptor (AChR) of Torpedo electric organ is also a PCP "receptor." However, this nicotinic AChR has about one-tenth the affinity for PCP than that of the rat brain PCP receptor [K0.5 = 0.3 pM, versus = 4-6 pM for Torpedo (Heidmann et al. 1983 flaring et al. 1984)]. Moreover, the nicotinic AChR has subunits of MR<66 kD, and these are the subunits that are specifically labelled with 3H-Az-PCP in the Torpedo electroplax membranes (Heidmann et al. 1983 Haring and Kloog 1984 Haring et al. 1984). These data indicate that the nicotinic AChR-PCP receptor differs from the rat brain PCP receptor. Furthermore, our findings are... 

Velazquez-Moctezuma, J., Shiromani, P. J. 8i Gillin, J. C. (1990b). Acetylcholine and acetylcholine receptor subtypes in REM sleep generation. Prog. Brain Res. 84,... 

Nicotine increased DA levels both in vivo11,193 and in vitro. 94 196 Nicotine197 and its metabolites198 were found to both release and inhibit the reuptake of DA in rat brain slices, with uptake inhibition occurring at a lower concentration than that required for DA release. In addition, the (-) isomer was more potent than the (+) isomer.197 However, the effects of nicotine upon DA release and uptake were only apparent when brain slices were utilized because nicotine was unable to affect DA when a synaptosomal preparation was utilized.197 These results indicate that nicotine exerts its effects upon the DAT indirectly, most likely via nicotine acetylcholine receptors. This finding was supported by the results of Yamashita et al.199 in which the effect of nicotine on DA uptake was examined in PC 12 and COS cells transfected with rat DAT cDNA. Nicotine inhibited DA uptake in PC 12 cells that possess a nicotine acetylcholine receptor. This effect was blocked by the nicotinic antagonists hexamethonium and mecamylamine. Additionally, nicotine did not influence DA uptake in COS cells, which lack nicotinic acetylcholine receptors. 

Parker, S.L., Fu, Y., McAllen, K. et al. Up-regulation of brain nicotinic acetylcholine receptors in the rat during long-term self-administration of nicotine disproportionate increase of the alpha6 subunit. Mol. Pharmacol. 65 611, 2004. 

Turek, J.W., Kang, C.H., Campbell, J.E., Americ, S.P., Sullivan, J.P. A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J. Neurosci. Methods. 61 113, 1995. 

Mitsis, E.M., van Dyck, C.H., Krantzler, E. et al. Prolonged occupancy of nicotinic acetylcholine receptors by nicotine in human brain a preliminary study. Paper presented at the Annual Meeting of the Society for Research on Nicotine and Tobacco, Orlando, FL, 2006. 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

Perhaps the largest gap in the evidence surrounds the primary site of action of nicotine in the brain - the acetylcholine receptor itself. Studies on links with tobacco dependence in humans will await closer definition of the complex interaction between nicotine and its receptor and the identification of the receptor sub-types that are important in addiction pathways (see Section 22.4). 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Histaminergic neurons can regulate and be regulated by other neurotransmitter systems. A number of other transmitter systems can interact with histaminergic neurons (Table 14-1). As mentioned, the H3 receptor is thought to function as an inhibitory heteroreceptor. Thus, activation of brain H3 receptors decreases the release of acetylcholine, dopamine, norepinephrine, serotonin and certain peptides. However, histamine may also increase the activity of some of these systems through H, and/or H2 receptors. Activation of NMDA, p opioid, dopamine D2 and some serotonin receptors can increase the release of neuronal histamine, whereas other transmitter receptors seem to decrease release. Different patterns of interactions may also be found in discrete brain regions. 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Using the knowledge that rabies virus can spread into the brain neurons, scientists mimic its delivery system. A short, 29 amino acid peptide chain is derived from the rabies virus glycoprotein (RVG). The RVG binds to the acetylcholine receptor on the neurons and the endothelium cells of the blood-brain barrier. Through this interaction, transvascular delivery is enabled. 

Nicotine, the principal psychoactive alkaloid in tobacco, has cognitive-enhancing effects. It directly activates nicotinic acetylcholine receptors in brain areas critical for cognition, creating both acute and chronic effects. 

Reitstetter R, Lukas RJ, Gruener R. (1999). Dependence of nicotinic acetylcholine receptor recovery from desensitization on the duration of agonist exposure. J Pharmacol Exp Ther. 289(2) 656-60. Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ. (1993). Effects of systemic nicotine on serotonin release in rat brain. Brain Res. 621(2) 311-18. 

Tani Y, Saito K, Tsuneyoshi A, Imoto M, Ohno T. (1997). Nicotinic acetylcholine receptor (nACh-R) agonist-induced changes in brain monoamine turnover in mice. Psychopharmacology (Berlin). 129(3) 225-32. 

Chen DN, Patrick JW (1997) The a-bungarotoxin-binding nicotinic acetylcholine receptor from rat brain contains only the a7 subunit, J Biol Chem 272 24024-24029 Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain autoradiographic comparison of [ H]acetylcholine, [ H]nicotine, and [ I]-alpha-bungarotoxin, J Neurosci 5 1307-1315... 

Combi R, Dalpra L, Tenchini ML, Ferini-Strambi L (2004) Autosomal dominant nocturnal frontal lobe epilepsy A critical overview, J Neurol 251 923-934 Connolly J, Boulter J, Heinemann SF (1992) Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs, Br J Pharmacol 105 657-666 Conti-Tronconi BM, Dunn SM, Barnard EA, DoUy JO, Lai FA, Ray N, Raftery MA (1985) Brain and muscle nicotinic acetylcholine receptors are different but homologous proteins, Proc Natl Acad Sci U S A 82 5208-5212... 

Deneris ES, Boulter J, SwansonLW, Patrick , Heinemann S (1989) P3 A new member of nicotinic acetylcholine receptor gene family is expressed in brain, J Biol Chem 264 6268-6272 Drisdel RC, Green WN (2000) Neuronal a-bungarotoxin receptors are a7 homomers, J Neurosci 20 133-139... 

Goldman D, Simmons D, Swanson LW, Patrick J, Heinemann S (1986) Mapping of brain areas expressing RNA homologous to two different acetylcholine receptor a-subunits. Proc Nad Acad Sci 83 4076 080... 

Gotti C, Moretti M, Clementi F, Riganti L, McIntosh JM, Collins AC (2005) Expression of ni-grostriatal alpha 6-containing nicotinic acetylchohne receptors is selectively reduced, but not eliminated, by beta 3 subunit gene deletion. Mol Pharmacol 67 2007-2015 Gotti C, Zoli M, Clementi F (2006a) Brain nicotinic acetylcholine receptors native subtypes and their relevance. TIPS 27 482 91... 

Keyser KT, Britto ERG, Schoepfer R, Whiting P Cooper J, Conroy W, Brozozowska-Prechtl A, Karten HJ, Lindstrom J (1993) Three subtypes of a-bungarotoxin-sensitive nicotinic acetylcholine receptors are expressed in chick brain. J Neurosci 13 442-452 Khiroug S, Harkness PC, Lamb PW, Sudweeks S, Khiroug L, Millar NS, Yakel JL (2002) Rat nicotinic ACh receptor al and fil subunits co-assemble to form functional heteromeric nicotinic receptor channels. J Physiol 540 425 34... 

Paton WDM, Zaimis EJ (1949) The pharmacological actions of polymethylene bistrimethylammo-nium salts. Br J Pharmacol Chemother 4 381 00 Patrick J, Stallcup WB (1977) a-Bungarotoxin binding and cholinergic receptor function on a rat sympathetic nerve line. J Biol Chem 252 8629-8633 Patrick J, Boulter J, Deneris E, Wada K, Wada E, Connolly J, Swanson L, Heinemann S (1989) Structure and function of neuronal nicotinic acetylcholine receptors deduced from cDNA clones. Prog Brain Res 79 27-33... 

Rodriguez-Pinguet NO, Pinguet TJ, Figl A, Lester HA, Cohen BN (2005) Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca + activation of the a4 32 nicotinic acetylcholine receptor. Mol Pharmacol 68 487-501 Romano C, Goldstein A (1980) Stereospecific nicotine receptors on rat brain membranes. Science 210 647-650... 

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