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

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 [(3)H]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 [(3)H]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.

SA 4503 attenuates cocaine-induced hyperactivity and enhances methamphetamine substitution for a cocaine discriminative stimulus.

Cocaine exhibits preferential (~15-fold) affinity for σ1 over σ2 sigma receptors, and previous research has shown an interaction of σ1 receptor-selective ligands and cocaine's behavioral effects. The present study investigated the effect of the putative sigma receptor agonist SA 4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride) on cocaine's locomotor stimulatory and discriminative stimulus properties. At doses without intrinsic activity, SA 4503 dose-dependently attenuated cocaine-induced hyperactivity in mice. This inhibition was overcome by increasing the cocaine dose. In rats trained to use cocaine as a discriminative stimulus in a drug discrimination task, doses of SA 4503 that did not substitute for the cocaine stimulus did not alter the cocaine substitution curve. However, SA 4503 potentiated the effect of methamphetamine to substitute for the cocaine stimulus. These data support a role for sigma receptors in the locomotor-activating properties of cocaine and, importantly, indicate a role for these receptors in the discriminative stimulus effects of methamphetamine. The data also suggest sigma receptors mediate the activity of different dopamine pathways responsible for the behavioral effects of psychostimulants.