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Mini-Review • DOI: 10.2478/s13380-012-0030-0 • Translational Neuroscience • 3(3) • 2012 • 294-299 Translational Neuroscience ROLES OF σ1 RECEPTORS Jun Toyohara*, IN THE MECHANISMS Muneyuki Sakata, Kiichi Ishiwata OF ACTION OF CNS DRUGS Positron Medical Center, Abstract Tokyo Metropolitan Institute of Gerontology, Accumulating evidence suggests that σ1 receptors play a role in the mechanisms of action of some therapeutic 1-1, Naka, Itabashi, Tokyo, 173-0022, Japan 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 for1 σ 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 1σ receptors may be involved in the mechanisms of action of some therapeutic drugs. Keywords • σ1 receptor • Fluvoxamine • Donepezil • Ifenprodil • SSRI • Neuronal plasticity • Positron emission tomography Received 13 July 2012 accepted 17 July 2012 © Versita Sp. z o.o. Abbreviations the effects of a prototypical opioid agonist, receptors, PGMRC1 sites were localised in the SKF10,047 (N-allylnormetazocine), were ER and mitochondria. AChE - acetylcholinesterase independent from those of other opioid Endogenous ligands for the σ1 and σ2 AD - Alzheimer’s disease receptor agonists [1]. It was later determined receptors have not been fully identified, CNS - central nervous system that σ receptors have unique binding sites and those for the σ1 receptor were first EBP - emopamil binding protein that are different from those of other opioid proposed to be neurosteroids, including ER - endoplasmic reticulum receptors, and at least two subtypes (σ1 and pregnenolone sulphate and progesterone [7]. ifenprodil - 4-[2-(4-benzylpiperidin-1-yl)-1- σ2) were classified based on pharmacological The endogenous hallucinogenic trace amine hydroxypropyl]phenol criteria [2]. In 1996, the σ1 receptor was N,N-dimethyltryptamine was recently found NE-100 - 4-methoxy-3-(2-phenylethoxy)- successfully cloned and characterised as to be a potent endogenous ligand for the σ1 N,N-dipropylbenzeneethanamine a protein of 233 amino acids with two receptor [8]. NGF - nerve growth factor transmembrane domains [3]. Although the σ1 The σ1 and σ2 receptors display different NMDA - N-methyl-D-aspartate receptor is not homologous to any mammalian tissue distributions and distinct physiological PCP - phencyclidine protein, it shows a 30% overlap with yeast D8- and pharmacological profiles in the central PET - positron emission tomography D7 sterol isomerase, also known as emopamil- and peripheral nervous systems [9]. The σ1 PGRMC1 - progesterone receptor membrane binding protein (EBP) [4]. The σ2 receptor has receptors are widely distributed in the central component 1 yet to be cloned. nervous system (CNS) and in peripheral SA4503 - 1-[2-(3,4-dimethoxyphenyl)ethyl]- The σ1 receptors have been shown to act as tissues [10]. Peripherally, both subtypes are 4-(3-phenylpropyl)piperazine ligand-regulated molecular chaperones in the overexpressed in rapidly proliferating cells, SSRI - selective serotonin reuptake inhibitor endoplasmic reticulum (ER) [5]. It is the first such as those in various types of cancer, and the VT - total distribution volume. molecular chaperone in which the activity was functional roles of the receptors, especially σ2, found to be regulated by synthetic compounds have been the focus of tumour imaging studies Introduction in a clear agonist-antagonist manner [5]. Very [11]. In the CNS, the σ1 receptor may function recently, the putative σ2 binding site was as a modulator of signal transduction through The σ receptors were initially categorised identified as progesterone receptor membrane glutamatergic transmitter systems mediated as a subtype of opioid receptors, because component 1 (PGRMC1) [6]. Similar to the σ1 by N-methyl-D-aspartate (NMDA) receptors. * E-mail: [email protected] 294 Translational Neuroscience The σ1 receptor has been implicated in cellular or paroxetine, significantly potentiated nerve administration of fluvoxamine (20 mg/kg/day), differentiation [12,13], neuroplasticity [14,15], growth factor (NGF)-induced neurite outgrowth but not sertraline (10 or 20mg/kg/day) [23]. The neuroprotection [16,17] and cognitive function in PC12 cells in a concentration-dependent effect of fluvoxamine on PCP-induced cognitive in the brain [18]. manner [22]. The potentiation by fluvoxamine deficits was antagonised by co-administration The σ1 agonists show anti-amnesic was significantly blocked by co-administration of the selective σ1 receptor antagonist NE-100. and neuroprotective effects [19], and are of 4-methoxy-3-(2-phenylethoxy)-N,N- These findings suggest that agonistic activity therefore attractive, novel targets for the dipropylbenzeneethanamine (NE-100), of fluvoxamine at 1σ receptors plays a role in treatment of neuropsychiatric diseases suggesting that the neuroplastic actions the active mechanisms of fluvoxamine on PCP- (schizophrenia, depression and cognition) of fluvoxamine are mediated through σ1 induced cognitive deficits in mice. In these and neurodegenerative diseases, such as receptors. Furthermore, Hashimoto et al. reports, sertraline, which also has high affinity ischemic stroke and Alzheimer’s disease (AD). reported that phencyclidine (PCP)-induced for σ1 receptors, did not show any enhancement Several CNS drugs show high to moderate mouse cognitive deficits, as measured in the of neurite outgrowth and cognition. One affinities for σ1 receptors, including selective novel object recognition test, were significantly possible explanation may be differences in serotonin reuptake inhibitors (SSRIs) improved by subsequent sub-chronic (2 weeks) pharmacology (agonist vs. antagonist) between (fluvoxamine), acetylcholinesterase (AChE) inhibitors (donepezil) and cerebral vasodilator Table 1. Affinities of selective serotonin reuptake inhibitors (SSRIs) at1 σ receptors in the rat brain (modified from reference [21]). (ifenprodil). These compounds can influence cognitive functions both via their primary Ki (nM) Ki ratio Compounds Chemical structure targets and by activating σ1 receptors in the σ1 σ2 σ2/σ1 CNS. Furthermore, these compounds affect neuronal plasticity, a process implicated in the O pathophysiology of disease of the CNS, such as F major depressive disorder, schizophrenia and Fluvoxamine 36 8439 234 F AD. This article presents a review and discussion NO F of the roles of σ1 receptors in the mechanisms of action of several therapeutic drugs. H2N σ1 receptors and SSRIs Sertraline 57 5279 93 Cl NH SSRIs have been used as therapeutic drugs for depression. Although the mechanisms of Cl action of all SSRIs share the function of blocking F serotonin transporters, their pharmacological F effects are quite heterogeneous [20]. Inhibition (±)Fluoxetine 240 16100 68 F of serotonin reuptake and the consequent N O increase in serotonin availability are responsible H for the relief of depressive symptoms. On F the other hand, trans-synaptic effects such as modulation of signalling cascades, gene expression processes, and neuroplasticity are Citalopram 292 5410 19 N also important in the mechanism of action of antidepressants. These secondary properties of O the SSRIs may contribute to the differences in N efficacy and tolerability between members of the class. O Narita et al. reported that some SSRIs possess O high to moderate affinity for σ1 receptors [21]. The HN O Paroxetine 1893 22870 12 rank order of potency of SSRIs for σ1 receptor is as follows: fluvoxamine > sertraline > fluoxetine > citalopram >> paroxetine (Table 1). Nishimura F et al. reported that fluvoxamine, but not sertraline 295 Translational Neuroscience these SSRIs at σ1 receptors. Another possibility countries, including Japan and France (Table 3). in PC12 cells in a concentration-dependent is that other pharmacological activities of Ifenprodil binds to NMDA receptors as well manner [33]. In contrast, the a1 adrenergic sertraline may mask the effects of σ1 receptor as a1 adrenergic receptors and σ receptors, receptor antagonist, prazosin, and the NMDA agonism. suggesting a possible role of σ receptors in receptor NR2B antagonist, (aR,bS)-a-(4- Although less well defined, the clinical the mechanism of the neuroprotective action hydroxyphenyl)-b-methyl-4-(phenylmethyl)- effect of fluvoxamine is also consistent with of ifenprodil [30-32]. Ishima and Hashimoto 1-piperidinepropanol (Ro 25-6981), did not σ1 receptor agonism. Iyo et al. reported a case reported that ifenprodil significantly alter NGF-induced neurite outgrowth [33]. The that demonstrated the efficacy of fluvoxamine potentiated NGF-induced neurite outgrowth potentiation by ifenprodil was significantly (50 mg/day), but not paroxetine (20 mg/day), on