Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs

John Connolly, Jim Boulter, Stephen F. Heinemann

Research output: Contribution to journalArticle

54 Citations (Scopus)

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 alpha 4-2 beta 2, has not been previously described. The alpha 4-2 mRNA is a splicing variant transcribed from the alpha 4 gene. In the experiments reported here, the alpha 4-2 beta 2 subtype was functionally indistinguishable from the alpha 4-1 beta 2 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 microM Ach. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(alpha 1 beta 1 gamma delta) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: alpha 2 beta 2, 1.01:1; alpha 3 beta 2, 2.01:1; alpha 4 beta 2, 0.76:1 and alpha 4-2 beta 2, 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 microM 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.

LanguageEnglish
Pages657-666
Number of pages10
JournalBritish Journal of Pharmacology
Volume105
Issue number3
DOIs
Publication statusPublished - Mar 1992

Fingerprint

Psychotropic Drugs
Nicotine
Cholinergic Receptors
Promethazine
Mecamylamine
Trifluoperazine
Muscles
Antipsychotic Agents
Phencyclidine
Amitriptyline
Nicotinic Receptors
Xenopus
Acetylcholine
Oocytes
Electrodes
Binding Sites
nicotinic receptor beta2
Pharmacology
RNA
Messenger RNA

Keywords

  • acetylcholine
  • animals
  • cloning, molecular
  • DNA
  • neurons
  • nicotine
  • oocytes
  • promethazine
  • psychotropic drugs
  • RNA
  • receptors, nicotinic
  • substance-related disorders
  • trifluoperazine
  • xenopus

Cite this

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title = "Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs",
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 alpha 4-2 beta 2, has not been previously described. The alpha 4-2 mRNA is a splicing variant transcribed from the alpha 4 gene. In the experiments reported here, the alpha 4-2 beta 2 subtype was functionally indistinguishable from the alpha 4-1 beta 2 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 microM Ach. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(alpha 1 beta 1 gamma delta) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: alpha 2 beta 2, 1.01:1; alpha 3 beta 2, 2.01:1; alpha 4 beta 2, 0.76:1 and alpha 4-2 beta 2, 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 microM 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.",
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Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs. / Connolly, John; Boulter, Jim; Heinemann, Stephen F.

In: British Journal of Pharmacology, Vol. 105, No. 3, 03.1992, p. 657-666.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs

AU - Connolly, John

AU - Boulter, Jim

AU - Heinemann, Stephen F.

PY - 1992/3

Y1 - 1992/3

N2 - 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 alpha 4-2 beta 2, has not been previously described. The alpha 4-2 mRNA is a splicing variant transcribed from the alpha 4 gene. In the experiments reported here, the alpha 4-2 beta 2 subtype was functionally indistinguishable from the alpha 4-1 beta 2 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 microM Ach. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(alpha 1 beta 1 gamma delta) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: alpha 2 beta 2, 1.01:1; alpha 3 beta 2, 2.01:1; alpha 4 beta 2, 0.76:1 and alpha 4-2 beta 2, 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 microM 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.

AB - 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 alpha 4-2 beta 2, has not been previously described. The alpha 4-2 mRNA is a splicing variant transcribed from the alpha 4 gene. In the experiments reported here, the alpha 4-2 beta 2 subtype was functionally indistinguishable from the alpha 4-1 beta 2 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 microM Ach. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor-(alpha 1 beta 1 gamma delta) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: alpha 2 beta 2, 1.01:1; alpha 3 beta 2, 2.01:1; alpha 4 beta 2, 0.76:1 and alpha 4-2 beta 2, 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 microM 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.

KW - acetylcholine

KW - animals

KW - cloning, molecular

KW - DNA

KW - neurons

KW - nicotine

KW - oocytes

KW - promethazine

KW - psychotropic drugs

KW - RNA

KW - receptors, nicotinic

KW - substance-related disorders

KW - trifluoperazine

KW - xenopus

U2 - 10.1111/j.1476-5381.1992.tb09035.x

DO - 10.1111/j.1476-5381.1992.tb09035.x

M3 - Article

VL - 105

SP - 657

EP - 666

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 3

ER -