α4‐β2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs

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Abstract
1 Xenopus oocytes were injected with various muscle and neuronal nicotinic acetylcholine receptor (ACh receptor, cholinoceptor) subunit RNA combinations and their pharmacological properties studied using two-electrode voltage clamp. The functional expression of one of these combinations, rat α4–2β2, has not been previously described. The α4–2 mRNA is a splicing variant transcribed from the α4 gene. In the experiments reported here, the α4–2β2 subtype was functionally indistinguishable from the α4–1β2 subtype. 2 For each subtype, the relative potency of nicotine compared with acetylcholine was obtained by estimating the relative concentration of nicotine which would elicit the same current response as 0.1 μm ACh. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(α1β1γδ) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: α2β2, 1.01:1; α3β2, 2.01:1; α4β2, 0.76:1 and α4–2β2, 0.76:1. The much greater relative nicotine sensitivity of the neuronal subtypes as compared with muscle receptors illustrates their potential to mediate the psychoactive and addictive effects of nicotine. However, it does not appear that the differences in relative nicotinic sensitivity among the neuronal receptors themselves can be used as a simple discriminative tool in neuronal tissue. 3 The slopes of the log dose-log response curves at low ACh concentrations were all greater than 1 but less than 2, suggesting that at least two agonist binding sites mediate the functional response of each hetero-oligomer. 4 The response of all the neuronal subtypes to ACh could be inhibited by the psychoactive drugs mecamylamine, amitriptyline, phencyclidine, trifluoperazine and promethazine. With the exception of the very potent antagonist, mecamylamine, the degree of block of the peak current to ACh produced by 10 μm concentrations of these drugs was remarkably similar (around 50%). 5 The degree of inhibition produced when the antipsychotic drug, trifluoperazine, was co-applied with ACh increased as the duration of application increased. Such an effect was not observed with promethazine, a related phenothiazine derivative which does not have antipsychotic actions.