The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine

Abstract

Background Methamphetamine’s behavioral effects have been attributed to its interaction with monoamine transporters; however, methamphetamine also has affinity for sigma receptors. Method The present study investigated the effect of the sigma receptor agonist SA 4503 and the sigma receptor antagonists BD-1047 and BD-1063 on methamphetamine-evoked [3H] dopamine release from preloaded rat striatal slices. The effect of SA 4503 on methamphetamine-induced hyperactivity and on the discriminative stimulus properties of methamphetamine also was determined. Results SA 4503 attenuated methamphetamine-evoked [3H]dopamine release in a concentration-dependent manner. BD-1047 and BD-1063 did not affect release. SA 4503 dose-dependently potentiated and attenuated methamphetamine-induced hyperactivity. SA 4503 pretreatment augmented the stimulus properties of methamphetamine. Conclusions Our findings indicate that SA 4503 both enhances and inhibits methamphetamine’s effects and that sigma receptors are involved in the neurochemical, locomotor stimulatory and discriminative stimulus properties of methamphetamine.

N -phenylpropyl- N ′-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice

“…Interestingly, a high YZ-185 dose (31.6 µmol/kg) inhibited cocaine-induced hyperactivity, while a lower YZ-185 dose (0.1 µmol/kg) enhanced cocaine-induced hyperactivity. A similar pattern on methamphetamine-induced hyperactivity in rats was observed with SA4503 (Rodvelt et al 2011). At a low dose (2.7 µmol/kg) SA4503 enhanced the hyperactivity observed for the first 30 min after methamphetamine (0.5 mg/kg) injection.…”

“…Sigma ligand doses that altered methamphetamine- and cocaine-induced hyperactivity (Rodvelt et al 2011; Sage et al 2013) were greater than their in vivo binding ED 50 values. Effects started, for the most part, near the range where maximal receptor occupancy was observed.…”

“…The 31.6 µmol/kg SA4503 dose decreased (61%) methamphetamine-induced hyperactivity across the entire period (i.e., the 10–60 min time points) after stimulant injection. Previously in rats, 27 and 81 µmol/kg SA4503 inhibited (47 and 81%, respectively) methamphetamine-induced hyperactivity for as long as 80 min after stimulant injection (Rodvelt et al 2011). Presently, there were no significant differences in activity between mice administered 31.6 µmol/kg SA4503 followed by saline and those administered only saline, suggesting that the inhibition of methamphetamine-induced hyperactivity was not due to a general suppression of locomotor activity by SA4503.…”

“…Acute cocaine or methamphetamine injection produces a transient increase in locomotor activity in mice and N -phenylpropyl- N ’-substituted piperazine ligands alter this stimulant-induced hyperactivity (Rodvelt et al 2011; Sage et al 2013). SA4503 (2.7 and 27 µmol/kg), YZ-067 (10 and 31.6 µmol/kg) and Nahas-3h (0.316 – 10 µmol/kg) all attenuated cocaine-induced hyperactivity at ligand doses that had minimal impact on basal locomotor activity.…”

Ether modifications to 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503): Effects on binding affinity and selectivity for sigma receptors and monoamine transporters

“…Interestingly, SA4503 shows mixed properties in recent behavioral studies, and can either potentiate or attenuate certain effects of cocaine and methamphetamine in mice as a function of dose. 23,24 By contrast, the YZ analogs profile as σ 1 receptor antagonists based upon their ability to block cocaine-induced convulsions in mice. 22 …”