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

• Published in: Pharmacology, biochemistry and behavior Vol. 97; no. 4; pp. 676 - 682
• Main Authors: Rodvelt, Kelli R., Lever, Susan Z., Lever, John R., Blount, Lucas R., Fan, Kuo-Hsien, Miller, Dennis K.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Inc 01.02.2011; Elsevier
• Subjects: Animals; Biological and medical sciences; Chromatography, High Pressure Liquid; Cocaine; Cocaine - antagonists & inhibitors; Cocaine - pharmacology; Dose-Response Relationship, Drug; Drug discrimination; Locomotion - drug effects; Locomotor activity; Magnetic Resonance Spectroscopy; Male; Medical sciences; Methamphetamine - agonists; Mice; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, sigma - agonists; Sigma receptors; Drug discrimination; Cocaine; Sigma receptors; Locomotor activity; Amphetamine derivatives; Drug; CNS stimulant; Psychotropic; Hyperactivity; Metamfetamine; Sigma receptor; Sympathomimetic; Ester; Locomotion; Drug of abuse; Stimulus discrimination
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2010.11.016

Cocaine exhibits preferential (~ 15-fold) affinity for σ 1 over σ 2 sigma receptors, and previous research has shown an interaction of σ 1 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. ► The putative sigma receptor agonist SA 4053 attenuates cocaine-induced hyperactivity. ► SA 4503 does not alter cocaine’s discriminative stimulus properties. ► SA 4503 enhanced methamphetamine substitution for cocaine. ► Sigma receptors mediate pathways responsible for stimulant addiction.