Characterization of dopamine-dependent rewarding and locomotor stimulant effects of intravenously-administered methylphenidate in rats.
In general, psychostimulants are thought to exert rewarding and locomotor stimulating effects via increased dopamine transmission in the ventral striatum. However, little is known about the mechanisms underlying the effects of the stimulant drug methylphenidate. The present study examined the putative role of dopaminergic transmission in i.v. methylphenidate reward as measured by conditioned place preference. Rats were shown to exhibit conditioned place preference for i.v. methylphenidate (5 mg/kg, not 2 mg/kg). Administration of the dopamine receptor antagonist cis-flupenthixol (0.1-0.8 mg/kg i.p.), either during conditioning or on test day, dose-dependently attenuated the magnitude of the conditioned place preference. Finally, we examined the effects of bilateral 6-hydroxydopamine lesions of nucleus accumbens core, medial shell or anteromedial olfactory tubercle on the rewarding and locomotor stimulant effects of methylphenidate. Residual dopamine innervation, as assessed by radioligand binding to the dopamine transporter, revealed a significant association between core dopamine innervation and the locomotor stimulant effect of methylphenidate. However, neither core nor medial shell dopamine innervation was related to conditioned place preference magnitude. Instead, conditioned place preference magnitude was associated with dopamine innervation in the anteromedial olfactory tubercle. These results establish a role for dopaminergic transmission in both i.v. methylphenidate conditioned place preference and locomotor stimulation. As well, they suggest that different ventral striatal subregions mediate the rewarding (anteromedial olfactory tubercle) and locomotor stimulant (accumbens core) effects of methylphenidate.
Sellings
L H L
LH
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Room 1325, Montreal, Quebec, Canada H3G 1Y6.
McQuade
L E
LE
Clarke
P B S
PB
D018663:Adrenergic Agents / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000293:injuries / Q000503:physiopathology; D004298:Dopamine / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005475:Flupenthixol / Q000494:pharmacology; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D012201:Reward; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism
D018663:Adrenergic Agents; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D008774:Methylphenidate; D016627:Oxidopamine; D005475:Flupenthixol; D004298:Dopamine