Review
σ Receptors: potential medications development target for anti-cocaine agents

https://doi.org/10.1016/S0014-2999(03)01723-0Get rights and content

Abstract

The ability of cocaine to interact with σ receptors suggests a viable target for medications development. Recently, numerous novel compounds and antisense oligodeoxynucleotides targeting σ receptors have been synthesized and shown to prevent the behavioral toxicity and psychomotor stimulant effects of cocaine in animals. Protective doses of σ receptor antagonists have also been shown to prevent changes in gene expression that are induced by cocaine. Together, the studies provide insight and promising future directions for the development of potential medications for the treatment of cocaine addiction and overdose.

Introduction

Cocaine abuse is a major public health problem and there are no effective treatments for it (Carroll et al., 1999). Of the many strategies that can be adopted to develop an effective anti-cocaine agent, the one that has been most avidly pursued is the development of antagonists that compete with cocaine for its target proteins.

Since cocaine is generally thought to act as a dopamine reuptake inhibitor to produce its reinforcing effects (Kuhar et al., 1991), much of the drug development effort in recent years has been aimed at making a compound that can interfere with cocaine's access to dopamine transporters, while allowing the reuptake of dopamine into the pre-synaptic nerve terminal. Unfortunately, of the hundreds of compounds that have been developed and tested, the vast majority of them exhibit neurochemical and behavioral profiles similar to cocaine (Carroll et al., 1999). Although several of these compounds have been reported to attenuate responding to cocaine in pre-clinical studies Nader et al., 1997, Villemagne et al., 1999, thus far, no medication for the treatment of cocaine addiction has emerged from these efforts Carroll et al., 1999, Newman, 2000. These disappointments, together with the fact that mice lacking dopamine transporters still respond to the rewarding properties of cocaine Rocha et al., 1998, Sora et al., 1998, suggest the need to explore other viable targets for the development of anti-cocaine agents.

In addition to blocking the reuptake of dopamine, cocaine also inhibits the reuptake of serotonin and norepinephrine and binds to a number of neurotransmitter receptors (Ritz and George, 1993). Of the myriad of sites with which cocaine interacts, the monoamine transporters, muscarinic receptors, and σ receptors are thought to be most relevant in mediating the psychological and physiological properties of the drug because the affinity of cocaine for these proteins fall within a concentration range that can be achieved in vivo (Ritz and George, 1993). Earlier investigations on serotonergic, noradrenergic, and muscarinic mechanisms have succeeded in confirming a role for these systems in the actions of cocaine, but suggest that they may be less optimal drug development targets because of limited efficacy and/or unfavorable side effect profiles. Therefore, current studies have targeted the most recently discovered of these sites, the σ receptor.

This review begins with an overview on σ receptors. Then, the ability of σ receptor antagonism to attenuate cocaine-induced behaviors is summarized, with an emphasis on the contribution of different σ receptor subtypes to the protective actions. Next, the ability of a σ receptor antagonist to prevent cocaine-induced changes in gene expression is presented. Finally, the potential mechanisms involved in these anti-cocaine effects are briefly described, along with future directions for research. Together, the data suggest that σ receptors are logical and promising medications development targets for the treatment of cocaine abuse.

Section snippets

Historical perspective

σ Receptors were first postulated by Martin et al. (1976) based on the actions of SKF 10,047 (N-allylnormetazocine) and related benzomorphans. The name “σ” originated from the first letter “S” in SKF 10,047, which was thought to be the prototypic ligand for these binding sites. Unfortunately, SKF 10,047 is now recognized as a non-selective ligand, which contributed to the turbulent early history surrounding σ receptors. The seminal studies of Martin et al. involved racemic SKF 10,047, which is

Comparison of antagonism using σ receptor antagonists and antisense oligos

Functional antagonism of σ receptors can be achieved using either pharmacological antagonists or antisense oligodeoxynucleotides. Pharmacological antagonists act by interfering with the access of cocaine to σ receptors (Fig. 2A). Antisense oligos, on the other hand, deplete the number of σ receptors that are available for cocaine binding by interfering with the synthesis of new receptor proteins (Fig. 2B). The end result in both cases is a reduction in the number of σ receptors that are

Antagonism of σ receptors attenuates cocaine-induced changes in gene expression

The ability of σ receptor antagonists to prevent the toxic and psychomotor effects of cocaine is now well documented. However, the mechanisms associated with the behavioral protective actions of σ receptor antagonists have yet to be fully characterized. In an effort to begin identifying candidate protection genes, a recent study combined behavioral pharmacological studies with microarray analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) confirmations (Liu et al., 2002).

Hypothesized mechanism of anti-cocaine actions

The ability of σ receptor antagonists to attenuate a number of cocaine-induced behaviors is thought to result from their ability to intervene in the actions of cocaine at many different levels: (1) direct interference at the receptors, which are localized in key organ systems that are involved in cocaine's actions, (2) modulation of downstream neurotransmitter systems that are involved in the actions of cocaine, and/or (3) alterations in gene expression that are associated with the long-term

Conclusions

In conclusion, the data indicate that σ receptors are viable targets for the development of anti-cocaine agents. σ Receptors are localized in key organ systems such as the brain and heart, which mediate the psychostimulant and toxic effects of cocaine. Cocaine interacts with these receptors at concentrations that can be achieved in vivo, further supporting the physiological relevance of these sites. Pharmacological studies demonstrate that antagonism of σ receptors, particularly the σ1 subtype,

Acknowledgements

Much of the work described herein was supported by the National Institute on Drug Abuse (DA11979, DA13978).

References (124)

  • B Garrone et al.

    Effects of trazodone on neurotransmitter release from rat mossy fibre cerebellar synaptosomes

    Eur. J. Pharmacol.

    (2000)
  • M Hascoet et al.

    Sigma ligand S14905 and locomotor activity in mice

    Eur. Neuropsychopharmacol.

    (1995)
  • S.B Hellewell et al.

    A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain

    Brain Res.

    (1990)
  • S.B Hellewell et al.

    Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling

    Eur. J. Pharmacol.

    (1994)
  • T Herdegen et al.

    Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins

    Brain Res. Rev.

    (1998)
  • S Iyengar et al.

    Sigma receptors modulate both A9 and A10 dopaminergic neurons in the rat brain: functional interaction with NMDA receptors

    Brain Res.

    (1990)
  • K.L.R Jansen et al.

    Autoradiographic distribution of sigma receptors in human neocortex, hippocampus, basal ganglia, cerebellum, pineal and pituitary glands

    Brain Res.

    (1991)
  • K Kawamura et al.

    Synthesis and in vivo evaluation of [11C]SA6298 as a PET sigma1 receptor ligand

    Nucl. Med. Biol.

    (1999)
  • K Kawamura et al.

    In vivo evaluation of [11C]SA4503 as a PET ligand for mapping CNS sigma1 receptors

    Nucl. Med. Biol.

    (2000)
  • R Kekuda et al.

    Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1)

    Biochem. Biophys. Res. Commun.

    (1996)
  • M.J Kuhar et al.

    The dopamine hypothesis of the reinforcing properties of cocaine

    Trends Neurosci.

    (1991)
  • R.H Mach et al.

    The analgesic tropane analogue (±)-SM 21 has a high affinity for σ2 receptors

    Life Sci.

    (1999)
  • J Maj et al.

    Neuropharmacological profile of EMD 57445, a σ ligand with potential antipsychotic activity

    Eur. J. Pharmacol.

    (1996)
  • T Mamiya et al.

    Effects of sigma receptor agonists on the impairment of spontaneous alternation behavior and decrease of cyclic GMP level induced by nitric oxide synthase inhibitors in mice

    Neuropharmacology

    (2000)
  • R.R Matsumoto et al.

    Characterization of two novel σ receptor ligands: antidystonic effects in rats suggest σ receptor antagonism

    Eur. J. Pharmacol.

    (1995)
  • R.R Matsumoto et al.

    Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters

    Neuropharmacology

    (2001)
  • R.R Matsumoto et al.

    Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotides targeting σ1 receptors produce anti-cocaine effects in mice

    Eur. J. Pharmacol.

    (2001)
  • R.R Matsumoto et al.

    N-alkyl substituted analogs of the σ receptor ligand BD1008 and traditional σ receptor ligands affect cocaine-induced convulsions and lethality in mice

    Eur. J. Pharmacol.

    (2001)
  • R.R Matsumoto et al.

    Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides

    Neuropharmacology

    (2002)
  • K.A McCracken et al.

    Two novel σ receptor ligands, BD1047 and LR172, attenuate cocaine-induced toxicity and locomotor activity

    Eur. J. Pharmacol.

    (1999)
  • K.A McCracken et al.

    Novel σ receptor ligands attenuate the locomotor stimulatory effects of cocaine

    Eur. J. Pharmacol.

    (1999)
  • S McLean et al.

    Autoradiographic visualization of haloperidol-sensitive sigma receptors in guinea-pig brain

    Neuroscience

    (1988)
  • J Mei et al.

    Molecular cloning and pharmacological characterization of the rat sigma1 receptor

    Biochem. Pharmacol.

    (2001)
  • M Menkel et al.

    Selective σ ligands block stimulant effects of cocaine

    Eur. J. Pharmacol.

    (1991)
  • D.A Meyer et al.

    Neurosteroids enhance spontaneous glutamate release in hippocampal neurons. Possible role of metabotropic σ1-like receptors

    J. Biol. Chem.

    (2002)
  • J.F Neumaier et al.

    Calcium-dependent displacement of haloperidol-sensitive σ receptor binding in rat hippocampal slices following tissue depolarization

    Brain Res.

    (1989)
  • M Novakova et al.

    Ionotropic action of sigma receptor ligands in isolated cardiac myocytes from adult rats

    Eur. J. Pharmacol.

    (1995)
  • M Novakova et al.

    Highly selective sigma receptor ligands elevate inositol 1,4,5-triphosphate production in rat cardiac myocytes

    Eur. J. Pharmacol.

    (1998)
  • S.L Patrick et al.

    Increases in rat striatal extracellular dopamine and vacuous chewing produced by two σ receptor ligands

    Eur. J. Pharmacol.

    (1993)
  • R Quirion et al.

    A proposal for the classification of sigma binding sites

    Trends Pharmacol. Sci.

    (1992)
  • T.S Rao et al.

    Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation of N-methyl-d-asparate (NMDA) receptor complex-mediated event by sigma ligands

    Brain Res.

    (1991)
  • S Rawls et al.

    Sigma sites mediate DTG-evoked hypothermia in rats

    Pharmacol. Biochem. Behav.

    (2002)
  • P Romieu et al.

    Involvement of the sigma1 receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade

    Neuropsychopharmacology

    (2002)
  • P Seth et al.

    Cloning and structural analysis of the cDNA and the gene encoding the muring type 1 sigma receptor

    Biochem. Biophys. Res. Commun.

    (1997)
  • P Seth et al.

    Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor

    Biochim. Biophys. Acta

    (2001)
  • J Sharkey et al.

    Cocaine binding at σ receptors

    Eur. J. Pharmacol.

    (1988)
  • L.M Aanonsen et al.

    Phencyclidine and sigma receptors in rat spinal cord: binding characterization and quantitative autoradiography

    Synapse

    (1989)
  • W.D Bowen et al.

    [3H]-(+)-Pentazocine: a potent and highly selective benzomorphans-based probe for sigma-1 receptors

    Mol. Neuropharmacol.

    (1993)
  • P.J Brent et al.

    Protein phosphorylation and calcium uptake into rat forebrain synaptosomes: modulation by the sigma ligand, 1,3-diotolylguanidine

    J. Neurochem.

    (1997)
  • B.G Campbell et al.

    Sigma receptors inhibit contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation elicited by both electrical stimulation and exogenous serotonin

    J. Neurosci.

    (1989)
  • Cited by (0)

    View full text