Cocaine occupancy of sigma<sub>1</sub>receptors and dopamine transporters in mice

Lever, John R.; Fergason-Cantrell, Emily A.; Watkinson, Lisa D.; Carmack, Terry; Lord, Sarah A.; Xu, Rong; Miller, Dennis K.; Lever, Susan Z.

doi:10.1002/syn.21877

Cited by 29 publications

(36 citation statements)

References 68 publications

(128 reference statements)

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“…HMGB1, for example, has been shown to be increased following methamphetamine administration (Frank et al, 2016a). There is also evidence that cocaine and methamphetamine bind intracellular sigma-1 receptors that typically associate with the endoplasmic reticulum, but can migrate between organelles upon ligand binding (Lever et al, 2016; Nguyen et al, 2005; Sharkey et al, 1988; Yao et al, 2011). In fact, HMGB1 has been shown to increase via sigma-1 receptors in cultured astrocytes treated with methamphetamine (Zhang et al, 2015).…”

Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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Background The plenary session at the 2016 Behavior, Biology and Chemistry: Translational Research in Addiction Conference focused on glia as potential players in the development, persistence and treatment of substance use disorders. Glia partake in various functions that are important for healthy brain activity. Drugs of abuse alter glial cell activity producing several perturbations in brain function that are thought to contribute to behavioral changes associated with substance use disorders. Consequently, drug-induced changes in glia-driven processes in the brain represent potential targets for pharmacotherapeutics treating substance use disorders. Methods Four speakers presented preclinical and clinical research illustrating the effects that glial modulators have on abuse-related behavioral effects of psychostimulants and opioids. This review highlights some of these findings and expands its focus to include other research focused on drug-induced glia abnormalities and glia-focused treatment approaches in substance use disorders. Results Preclinical findings show that drugs of abuse induce neuroinflammatory signals and disrupt glutamate homeostasis through their interaction with microglia and astrocytes. Preclinical and clinical studies testing the effects of glial modulators show general effectiveness in reducing behaviors associated with substance use disorders. Conclusions The contribution of drug-induced glial activity continues to emerge as an intriguing target for substance use disorder treatments. Clinical investigations of glial modulators have yielded promising results on substance use measures and indicate that they are generally safe and well-tolerated. However, results have not been entirely positive and more questions remain for continued exploration in the development and testing of glial-directed treatments for substance use disorders.

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Section: Drugs Of Abuse and Glial Cell Activitymentioning

confidence: 99%

Glial and neuroinflammatory targets for treating substance use disorders

Bachtell

Jones

Heinzerling

et al. 2017

Drug and Alcohol Dependence

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“…Our target ligand, [ 125 / 127 I]- E -IA-DM-PE-PIPZE (Fig. 1), did exhibit high affinity and selectivity for σ 1 receptors in vitro, labeled the sites in mouse brain and periphery in vivo, and proved sensitive to in vivo competition by strong ligands [55–57] and by weak ligands, such as cocaine [58]. Extension to imaging by SPECT using I-123 or by PET using I-124 (t ½ 4.2 d; 511 keV, β + ) [59] may be possible.…”

Section: Sigma Receptors and Ligand Designmentioning

confidence: 99%

“…The mice are readily available, and both primary sites of interest, the σ 1 and σ 2 receptor subtypes, are known to be present. Further, binding parameters for each subtype are defined in these membranes for “gold standard,” commercially available tritiated radioligands [58]. Finally, in vivo evaluations of [ 125 I]- E -IA-BF-PE-PIPZE were planned in the CD-1 ® mouse strain (Section 7), so the in vitro and in vivo findings would be unified.…”

Section: Competition Binding Assaysmentioning

confidence: 99%

“…Nonetheless, haloperidol has been routinely used in such assays for over 25 years [93–95]. The 1000 nM concentration is much greater than its K i of 1.3 nM for σ 1 sites in mouse brain membranes [58], so it fully inhibits [ 3 H]-PTZ binding. Ligands for definition of non-specific binding should always be used at > 100 times their K i to achieve > 99% inhibition of radioligand binding according to the law of mass-action.…”

Section: Competition Binding Assaysmentioning

confidence: 99%

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Tactics for preclinical validation of receptor-binding radiotracers

Lever

Fan

Lever

2017

Nuclear Medicine and Biology

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Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.

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“…Studies of several acute toxic effects of cocaine also show promise for differentiating agonist or antagonist effects of sR ligands (Matsumoto et al, 2014). Although the acute toxicity produced by cocaine may in part be mediated by sRs (Lever et al, 2016), the complex pharmacology of cocaine and the cocaine-antagonist effects of both s 1 R and s 2 R ligands renders these outcomes less than definitive. Thus, an in vivo procedure for definitively characterizing subtype-selective sR agonist and antagonist activity has not yet been widely accepted.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Cocaine or Receptor Agonist Self Administration by Subtype-Selective Receptor Antagonists

Katz

Hiranita

Kopajtic

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The identification of sigma receptor (sR) subtypes has been based on radioligand binding and, despite progress with s 1 R cellular function, less is known about sR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger sR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (1)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative sR antagonists. Radioligand binding studies determined in vitro sR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (1)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (1)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding s 1 Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding s 2 Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of sR agonist substitution for cocaine self administration as an assay capable of distinguishing sR subtype selectivity in vivo. These results further suggest that effectiveness of dual sR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for s 1 Rs and further support this dual targeting approach to development of cocaine antagonists.

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Cocaine occupancy of sigma₁receptors and dopamine transporters in mice

Cited by 29 publications

References 68 publications

Glial and neuroinflammatory targets for treating substance use disorders

Glial and neuroinflammatory targets for treating substance use disorders

Tactics for preclinical validation of receptor-binding radiotracers

Blockade of Cocaine or Receptor Agonist Self Administration by Subtype-Selective Receptor Antagonists

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Cocaine occupancy of sigma1receptors and dopamine transporters in mice

Cited by 29 publications

References 68 publications

Glial and neuroinflammatory targets for treating substance use disorders

Glial and neuroinflammatory targets for treating substance use disorders

Tactics for preclinical validation of receptor-binding radiotracers

Blockade of Cocaine or Receptor Agonist Self Administration by Subtype-Selective Receptor Antagonists

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Product

Resources

About

Cocaine occupancy of sigma₁receptors and dopamine transporters in mice