Abstract

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 re-examined effects on locomotor activity. PD144418 displayed high affinity for σ₁ sites (K_i 0.46 nM) and 3596-fold selectivity over σ₂ sites (K_i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (K_i >100 μM), and the DAT interaction was weak (K_i 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 were 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 hours after a single 10.0 μmol/kg dose of PD144418.