RT Journal Article
SR Electronic
T1 Relationship Between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine's Motor Stimulatory Effects in Mice by PD144418
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.216671
DO 10.1124/jpet.114.216671
A1 John R. Lever
A1 Dennis K. Miller
A1 Emily A. Fergason-Cantrell
A1 Caroline L. Green
A1 Lisa D. Watkinson
A1 Terry L. Carmack
A1 Susan Z. Lever
YR 2014
UL http://jpet.aspetjournals.org/content/early/2014/08/06/jpet.114.216671.abstract
AB Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (σ1) receptors. Selective σ1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity σ1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated σ1 receptor and dopamine transporter (DAT) occupancy in vivo, and reexamined effects on locomotor activity. PD144418 displayed high affinity for σ1 sites (Ki 0.46 nM) and 3,596-fold selectivity over σ2 sites (Ki 1,654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (Ki > 100 μM), and the DAT interaction was weak (Ki 9.0 μM). In vivo, PD144418 bound to central and peripheral σ1 sites in mouse, with an ED50 of 0.22 μmol / kg in whole brain. No DAT occupancy by PD144418 (10.0 μmol / kg) or possible metabolites was observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16 and 10 μmol / kg) attenuated cocaine-induced hyperactivity in a dose-dependent manner in mice. There was good correlation (r2 = 0.88) of hyperactivity reduction with increasing cerebral σ1 receptor occupancy. The behavioral ED50 of 0.79 μmol / kg corresponded to 80% occupancy. Significant σ1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 h after a single 10.0 μmol / kg dose of PD144418.