| Popis: |
Although the psychopharmacological effects of nicotine have been known since the last century, it was not until the end of the 1980s that neuronal nicotinic acetylcholine receptors (nAChRs) were found to be functional in the central nervous system (CNS). Initially, based on the binding of [3H]nicotine and [125I]a-bungarotoxin (α-Bgt) to various brain regions, it was suggested that two populations of neuronal nAChRs existed in the CNS. One population consisted of neuronal nAChRs that could bind [3H]nicotine with high affinity and the other consisted of nAChRs that would bind [125I]α-Bgt with high affinity (CLARKE et al. 1985; SORENSON and CHIAPINELLI 1985; SWANSON et al. 1987; WONNACOTT et al. 1988). Based on these assays, it was not clear whether nAChRs with a high affinity for nicotine represented a homogeneous population of receptors or a population of various receptor subtypes that had similar affinities to nicotine. In addition, although a-Bgt binding sites were found in various areas of the brain (CLARKE et al. 1985; LORING and ZIGMOND 1988; LUKAS and BENNETT 1980; SORENSON and CHIAPPINELLI 1992; SWANSON et al. 1987), no α-Bgt-sensitive nicotinic responses could be recorded from these areas, raising the possibility that α-Bgt binding sites in the brain did not represent functional nAChRs (reviewed in CLARKE 1992). Molecular biological studies came to demonstrate that there are at least eight neuronal nAChR “agonist-binding” α subunits (α2-α9; the mammalian counterpart of the avian α8 nAChR subunit is yet to be found) and three neuronal nAChR “structural” β subunits (βl-β4), and that various combinations of α and β subunits could result in ectopic expression in Xenopus oocytes of heteromeric, functional nAChRs with distinct pharmacological and kinetic properties. Furthermore, evidence was provided that functional, homomeric nAChRs sensitive to blockade by α-Bgt could be formed by α7, α8, or α9 subunit (reviewed in COLQUHOUN and PATRICK 1997; LINDSTROM 1995; ROLE and BERG 1996; SARGENT 1993). Thus, characterization of functional native neuronal nAChRs was going to be complex due to the existence of multiple receptor subtypes. |
