Reviewσ Receptors: potential medications development target for anti-cocaine agents
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).
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