Cocaine occupancy of sigma1 receptors and dopamine transporters in mice

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

Research output: Contribution to journalArticle

Abstract

Activation of sigma11) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy σ1 receptors in vivo, using CD-1® mice and the novel radioligand [125I]E-N-1-(3'-iodoallyl)-N'-4-(3″,4″-dimethoxyphenethyl)-piperazine ([125I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 μmol/kg for (-)-cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [125I]3β-(4-iodophenyl)tropan-2β-carboxylic acid isopropyl ester ([125I]RTI-121) binding. A chief finding is the relatively small potency difference between (-)-cocaine occupancy of σ1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (-)-cocaine with σ1 receptors were assessed further using [125I]E-IA-DM-PE-PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (-)-Cocaine binding to cerebral σ1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E-IA-DM-PE-PIPZE gave an ED50 of 0.23 μmol/kg for occupancy of cerebral σ1 receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (-)-cocaine-induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E-IA-DM-PE-PIPZE is a probable σ1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ1 and σ2 receptors expressed in CD-1® mouse brain.

Original languageEnglish (US)
JournalSynapse
DOIs
StateAccepted/In press - 2015
Externally publishedYes

Fingerprint

Dopamine Plasma Membrane Transport Proteins
Cocaine
Brain
Corpus Striatum
Specific Gravity
Poisons
Carboxylic Acids
Autoradiography
Esters
Spleen
Pharmacology
Ligands
Lung

Keywords

  • Cocaine
  • Dopamine transporter
  • Locomotor activity
  • Mouse
  • Occupancy
  • Sigma receptor
  • Substance abuse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Lever, J. R., Fergason-Cantrell, E. A., Watkinson, L. D., Carmack, T. L., Lord, S. A., Xu, R., ... Lever, S. Z. (Accepted/In press). Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. Synapse. https://doi.org/10.1002/syn.21877

Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. / Lever, John R.; Fergason-Cantrell, Emily A.; Watkinson, Lisa D.; Carmack, Terry L.; Lord, Sarah A.; Xu, Rong; Miller, Dennis K.; Lever, Susan Z.

In: Synapse, 2015.

Research output: Contribution to journalArticle

Lever, JR, Fergason-Cantrell, EA, Watkinson, LD, Carmack, TL, Lord, SA, Xu, R, Miller, DK & Lever, SZ 2015, 'Cocaine occupancy of sigma1 receptors and dopamine transporters in mice', Synapse. https://doi.org/10.1002/syn.21877
Lever JR, Fergason-Cantrell EA, Watkinson LD, Carmack TL, Lord SA, Xu R et al. Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. Synapse. 2015. https://doi.org/10.1002/syn.21877
Lever, John R. ; Fergason-Cantrell, Emily A. ; Watkinson, Lisa D. ; Carmack, Terry L. ; Lord, Sarah A. ; Xu, Rong ; Miller, Dennis K. ; Lever, Susan Z. / Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. In: Synapse. 2015.
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AU - Fergason-Cantrell, Emily A.

AU - Watkinson, Lisa D.

AU - Carmack, Terry L.

AU - Lord, Sarah A.

AU - Xu, Rong

AU - Miller, Dennis K.

AU - Lever, Susan Z.

PY - 2015

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N2 - Activation of sigma1 (σ1) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy σ1 receptors in vivo, using CD-1® mice and the novel radioligand [125I]E-N-1-(3'-iodoallyl)-N'-4-(3″,4″-dimethoxyphenethyl)-piperazine ([125I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 μmol/kg for (-)-cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [125I]3β-(4-iodophenyl)tropan-2β-carboxylic acid isopropyl ester ([125I]RTI-121) binding. A chief finding is the relatively small potency difference between (-)-cocaine occupancy of σ1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (-)-cocaine with σ1 receptors were assessed further using [125I]E-IA-DM-PE-PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (-)-Cocaine binding to cerebral σ1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E-IA-DM-PE-PIPZE gave an ED50 of 0.23 μmol/kg for occupancy of cerebral σ1 receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (-)-cocaine-induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E-IA-DM-PE-PIPZE is a probable σ1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ1 and σ2 receptors expressed in CD-1® mouse brain.

AB - Activation of sigma1 (σ1) receptors contributes to the behavioral and toxic effects of (-)-cocaine. We studied a key step, the ability of (-)-cocaine to occupy σ1 receptors in vivo, using CD-1® mice and the novel radioligand [125I]E-N-1-(3'-iodoallyl)-N'-4-(3″,4″-dimethoxyphenethyl)-piperazine ([125I]E-IA-DM-PE-PIPZE). (-)-Cocaine displayed an ED50 of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED50 of 26 μmol/kg for (-)-cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [125I]3β-(4-iodophenyl)tropan-2β-carboxylic acid isopropyl ester ([125I]RTI-121) binding. A chief finding is the relatively small potency difference between (-)-cocaine occupancy of σ1 receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (-)-cocaine with σ1 receptors were assessed further using [125I]E-IA-DM-PE-PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (-)-Cocaine binding to cerebral σ1 receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E-IA-DM-PE-PIPZE gave an ED50 of 0.23 μmol/kg for occupancy of cerebral σ1 receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (-)-cocaine-induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E-IA-DM-PE-PIPZE is a probable σ1 receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ1 and σ2 receptors expressed in CD-1® mouse brain.

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