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.
Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA.
Kelli R
KR
Rodvelt
Susan Z
SZ
Lever
John R
JR
Lever
Lucas R
LR
Blount
Kuo-Hsien
KH
Fan
Dennis K
DK
Miller
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008694:Methamphetamine / Q000819:agonists*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists*
D010879:Piperazines; D017480:Receptors, sigma; D008694:Methamphetamine; C101789:SA 4503; D003042:Cocaine