A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice

John R. Lever, Dennis K. Miller, Caroline L. Green, Emily A. Fergason-cantrell, Lisa D. Watkinson, Terry L. Carmack, Kuo hsien Fan, Susan Z. Lever

Research output: Contribution to journalArticle

Abstract

Cocaine functions, in part, through agonist actions at sigma-1 (σ1) receptors, while roles played by sigma-2 (σ2) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 μmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 μmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 μmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

Original languageEnglish (US)
Pages (from-to)73-84
Number of pages12
JournalSynapse
Volume68
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Fingerprint

Cocaine
Ligands
Locomotion
Benzamides
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Opioid Receptors
Dopamine
sigma-2 receptor

Keywords

  • Behavior
  • Motor activity
  • Psychostimulant
  • Substance abuse

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Lever, J. R., Miller, D. K., Green, C. L., Fergason-cantrell, E. A., Watkinson, L. D., Carmack, T. L., ... Lever, S. Z. (2014). A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice. Synapse, 68(2), 73-84. https://doi.org/10.1002/syn.21717

A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice. / Lever, John R.; Miller, Dennis K.; Green, Caroline L.; Fergason-cantrell, Emily A.; Watkinson, Lisa D.; Carmack, Terry L.; Fan, Kuo hsien; Lever, Susan Z.

In: Synapse, Vol. 68, No. 2, 02.2014, p. 73-84.

Research output: Contribution to journalArticle

Lever, JR, Miller, DK, Green, CL, Fergason-cantrell, EA, Watkinson, LD, Carmack, TL, Fan, KH & Lever, SZ 2014, 'A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice', Synapse, vol. 68, no. 2, pp. 73-84. https://doi.org/10.1002/syn.21717
Lever JR, Miller DK, Green CL, Fergason-cantrell EA, Watkinson LD, Carmack TL et al. A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice. Synapse. 2014 Feb;68(2):73-84. https://doi.org/10.1002/syn.21717
Lever, John R. ; Miller, Dennis K. ; Green, Caroline L. ; Fergason-cantrell, Emily A. ; Watkinson, Lisa D. ; Carmack, Terry L. ; Fan, Kuo hsien ; Lever, Susan Z. / A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice. In: Synapse. 2014 ; Vol. 68, No. 2. pp. 73-84.
@article{32649c67bc4a45eea34931b9675030dd,
title = "A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice",
abstract = "Cocaine functions, in part, through agonist actions at sigma-1 (σ1) receptors, while roles played by sigma-2 (σ2) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1{\circledR} mice, and saw no alteration of basal activity at doses up to 31.6 μmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66{\%} upon pretreatment of mice with 1 at 31.6 μmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 μmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.",
keywords = "Behavior, Motor activity, Psychostimulant, Substance abuse",
author = "Lever, {John R.} and Miller, {Dennis K.} and Green, {Caroline L.} and Fergason-cantrell, {Emily A.} and Watkinson, {Lisa D.} and Carmack, {Terry L.} and Fan, {Kuo hsien} and Lever, {Susan Z.}",
year = "2014",
month = "2",
doi = "10.1002/syn.21717",
language = "English (US)",
volume = "68",
pages = "73--84",
journal = "Synapse",
issn = "0887-4476",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice

AU - Lever, John R.

AU - Miller, Dennis K.

AU - Green, Caroline L.

AU - Fergason-cantrell, Emily A.

AU - Watkinson, Lisa D.

AU - Carmack, Terry L.

AU - Fan, Kuo hsien

AU - Lever, Susan Z.

PY - 2014/2

Y1 - 2014/2

N2 - Cocaine functions, in part, through agonist actions at sigma-1 (σ1) receptors, while roles played by sigma-2 (σ2) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 μmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 μmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 μmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

AB - Cocaine functions, in part, through agonist actions at sigma-1 (σ1) receptors, while roles played by sigma-2 (σ2) receptors are less established. Attempts to discriminate σ2 receptor-mediated effects of cocaine in locomotor hyperactivity assays have been hampered by the lack of potent and selective antagonists. Certain tetrahydroisoquinolinyl benzamides display high σ2 receptor affinity, and excellent selectivity for binding to σ2 over σ1 receptors. The behavioral properties of this structural class of σ ligands have not yet been investigated. The present study evaluated 5-bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide, 1, a ligand shown by others to bind preferentially to σ2 over σ1 receptors, as well as dopamine D2 and D3 sites. First, we determined binding to monoamine transporters and opioid receptors, and noted 57-fold selectivity for σ2 receptors over the serotonin transporter, and >800-fold selectivity for σ2 receptors over the other sites tested. We then examined 1 in locomotor activity studies using male CD-1® mice, and saw no alteration of basal activity at doses up to 31.6 μmol/kg. Cocaine produced a fivefold increase in locomotor activity, which was attenuated by 66% upon pretreatment of mice with 1 at 31.6 μmol/kg. In vivo radioligand binding studies also were performed, and showed no occupancy of σ1 receptors or the dopamine transporter by 1, or its possible metabolites, at the 31.6 μmol/kg dose. Thus, ligand 1 profiles behaviorally as a σ2 receptor-selective antagonist that is able to counteract cocaine's motor stimulatory effects.

KW - Behavior

KW - Motor activity

KW - Psychostimulant

KW - Substance abuse

UR - http://www.scopus.com/inward/record.url?scp=84890185958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890185958&partnerID=8YFLogxK

U2 - 10.1002/syn.21717

DO - 10.1002/syn.21717

M3 - Article

C2 - 24123353

AN - SCOPUS:84890185958

VL - 68

SP - 73

EP - 84

JO - Synapse

JF - Synapse

SN - 0887-4476

IS - 2

ER -