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Roles of σ1 receptors in the mechanisms of action of CNS drugs

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Translational Neuroscience

Abstract

Accumulating evidence suggests that σ1 receptors play a role in the mechanisms of action of some therapeutic drugs, such as the selective serotonin reuptake inhibitors (SSRIs), donepezil, and ifenprodil. Among the SSRIs, fluvoxamine, a potent σ1 receptor agonist, has the highest affinity for σ1 receptors, while donepezil and ifenprodil also show high affinity for σ1 receptors. These drugs affect neuronal plasticity indicated by potentiation of nerve-growth factor (NGF)-induced neurite outgrowth in PC12 cells. Furthermore, phencyclidine (PCP)-induced cognitive impairment, associated with animal models of schizophrenia, is significantly improved by sub-chronic administration of fluvoxamine and donepezil. These pharmacological actions are antagonised by treatment with the selective σ1 receptor antagonist NE-100. Positron emission tomography (PET) with the σ1 specific ligand carbon-11-labelled 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine ([11C]SA4503) indicated that fluvoxamine and donepezil can bind to σ1 receptors in the healthy human brain in a dose-dependent manner. These findings suggest that σ1 receptors may be involved in the mechanisms of action of some therapeutic drugs.

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Abbreviations

AChE:

acetylcholinesterase

AD:

Alzheimer’s disease

CNS:

central nervous system

EBP:

emopamil binding protein

ER:

endoplasmic reticulum

ifenprodil:

4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol

NE-100:

4-methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine

NGF:

nerve growth factor

NMDA:

N-methyl-D-aspartate

PCP:

phencyclidine

PET:

positron emission tomography

PGRMC1:

progesterone receptor membrane component 1

SA4503:

1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine

SSRI:

selective serotonin reuptake inhibitor

V T :

total distribution volume

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Authors and Affiliations

  1. Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, 1-1, Naka, Itabashi, Tokyo, 173-0022, Japan

    Jun Toyohara, Muneyuki Sakata & Kiichi Ishiwata

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  1. Jun Toyohara
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  2. Muneyuki Sakata
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  3. Kiichi Ishiwata
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Correspondence to Jun Toyohara.

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Toyohara, J., Sakata, M. & Ishiwata, K. Roles of σ1 receptors in the mechanisms of action of CNS drugs. Translat.Neurosci. 3, 294–299 (2012). https://doi.org/10.2478/s13380-012-0030-0

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