σ Receptors and Drug Abuse

Liu, Yun; Yu, Yongxin; Shaikh, Jamaluddin; Pouw, Buddy; Daniels, AnTawan; Chen, Guang-Di; Matsumoto, Rae R.

doi:10.1007/978-0-387-36514-5_15

Cited by 3 publications

(3 citation statements)

References 96 publications

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“…For example, the σR antagonists, rimcazole and BMY 14802 blocked cocaine-induced locomotor stimulation (Menkel et al, 1991). Other studies showed that sensitized locomotor responses to cocaine or methamphetamine were blocked by σR antagonists (Ujike et al, 1992; Witkin et al, 1993), and still other studies have found that the convulsive effects and lethality induced by cocaine are blocked by σR antagonists, and that σ1R antisense injected via indwelling cannulae to the lateral ventricles attenuated the convulsive and locomotor stimulant effects of cocaine, whereas a mismatch sequence was relatively less active (Liu et al, 2007). …”

Section: σ1r Regulation Of Plasma Membrane Proteinsmentioning

confidence: 99%

A role for sigma receptors in stimulant self-administration and addiction

Katz

Hong²,

Hiranita³

et al. 2016

Behavioural Pharmacology

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Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other sub-cellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces reinforcing effects of σR agonists, due to dopamine transporter actions. Once established the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical in the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for reinforcing effects of abused drugs. However, the self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including reinforcing effects assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant, and once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

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Section: σ1r Regulation Of Plasma Membrane Proteinsmentioning

confidence: 99%

A role for sigma receptors in stimulant self-administration and addiction

Katz

Hong²,

Hiranita³

et al. 2016

Behavioural Pharmacology

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“…However, 71 does not bind at 5-HT 7 receptors, and this latter population is unlikely to account for the potentiating effect that was described above. 18 16. σ RECEPTOR LIGANDS σ receptor research got off to an arduous beginning, but even early efforts hinted at a relationship between σ receptors and stimulant abuse (reviewed 96,97 ). One of the first agents found to bind at σ receptors was N-allylnormetazocine (NANM; 83) (Figure 17) (reviewed 98 ).…”

Section: "Candy Flipping"mentioning

confidence: 99%

“…σ receptor research got off to an arduous beginning, but even early efforts hinted at a relationship between σ receptors and stimulant abuse (reviewed , ). One of the first agents found to bind at σ receptors was N -allylnormetazocine (NANM; 83 ) (Figure ) (reviewed).…”

Section: σ Receptor Ligandsmentioning

confidence: 99%

The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The “Phenylalkylaminome” with a Focus on Selected Drugs of Abuse

Glennon

2017

J. Med. Chem.

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The phenylalkylamine, particularly phenylethylamine, moiety is a common structural feature found embedded in many clinically-approved agents. Greater still is its occurrence in drugs of abuse or substances with abuse potential. The simplest phenylethylamine, 2-phenylethylamine itself, is without significant central action when administered systemically at moderate doses, but simple structural modifications profoundly impact its pharmacology and result in a large number of useful pharmacological tools, agents with therapeutic potential, and in drugs of abuse (e.g. hallucinogens, central stimulants, empathogens). In vivo drug discrimination techniques and in vitro receptor/transporter methods have been applied to understand the actions of these phenylalkylamines and their mechanisms of action. Thus far, depending upon pendant substituents, certain receptors (e.g. serotonin receptors) and monoamine transporters (i.e., serotonin, dopamine, and norepinephrine transporters: SERT, DAT, and NET, respectively) have been implicated as playing major roles in the actions of these agents in a complex and, at times, interwoven manner.

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A Role for Sigma Receptors in Stimulant Self-Administration and Addiction

Katz

Hiranita

Hong

et al. 2016

Sigma Proteins: Evolution of the Concept of Sigma Receptors

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Sigma 1 receptors (σ 1 Rs) represent a structurally unique class of intracellular proteins that function as chaperones. σ 1 Rs translocate from the mitochondria-associated membrane to the cell nucleus or cell membrane, and through protein-protein interactions influence several targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Several studies have demonstrated that σR antagonists block stimulant-induced behavioral effects, including ambulatory activity, sensitization, and acute toxicities. Curiously, the effects of stimulants have been blocked by σR antagonists tested under place-conditioning but not self-administration procedures, indicating fundamental differences in the mechanisms underlying these two effects. The self administration of σR agonists has been found in subjects previously trained to self administer cocaine. The reinforcing effects of the σR agonists were blocked by σR antagonists. Additionally, σR agonists were found to increase dopamine concentrations in the nucleus accumbens shell, a brain region considered important for the reinforcing effects of abused drugs. Although the effects of the σR agonist, DTG, on dopamine were obtained at doses that approximated those that maintained self administration behavior those of another agonist, PRE-084 required higher doses. The effects of DTG were antagonized by non-selective or a preferential σ 2 R antagonist but not by a preferential σ 1 R antagonist. The effects of PRE-084 on dopamine were insensitive to σR antagonists. The data suggest that the self administration of σR agonists is independent of dopamine and the findings are discussed in light of a hypothesis that cocaine has both intracellular actions mediated by σRs, as well as extracellular actions mediated through conventionally studied mechanisms. OPEN ACCESSPharmaceuticals 2011, 4 881The co-activation and potential interactions among these mechanisms, in particular those involving the intracellular chaperone σRs, may lead to the pernicious addictive effects of stimulant drugs.

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σ Receptors and Drug Abuse

Cited by 3 publications

References 96 publications

A role for sigma receptors in stimulant self-administration and addiction

A role for sigma receptors in stimulant self-administration and addiction

The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The “Phenylalkylaminome” with a Focus on Selected Drugs of Abuse

A Role for Sigma Receptors in Stimulant Self-Administration and Addiction

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