5-HT(6) receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine.
The localization of serotonin 5-HT(6) receptors in limbic and motor brain regions, and the high affinity of these receptors for several antipsychotic agents, suggest that they may be involved in motor activity, reward-related behaviors, and psychotic disorders. The present study characterized the effects of a novel 5-HT(6) receptor antagonist, SB 258510A, on psychostimulant-induced motor activity, self-administration, and increases in extracellular dopamine in the nucleus accumbens and frontal cortex of male Wistar rats. The locomotor-activating effects of amphetamine (1mg/kg) were dose-dependently enhanced by pretreatment with SB 258510A (3, 10mg/kg). Similarly, amphetamine self-administration was dose-dependently altered by SB 258510A in a manner indicative of enhanced reinforcing effects of amphetamine on both fixed and progressive ratio schedules of reinforcement. SB 258510A treatment had no effect on either cocaine-induced locomotor activity or cocaine self-administration. Dual-probe in vivo microdialysis revealed that pretreatment with 3mg/kg SB 258510A potentiated an amphetamine-induced increase in extracellular dopamine more robustly in the frontal cortex than in the nucleus accumbens. These data indicate that activation of 5-HT(6) receptors may regulate behaviors related to amphetamine but not cocaine, and point to the frontal cortex as a possible site of action for these effects.
Frantz
K J
KJ
Department of Neuropharmacology CVN7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kfrantz@scripps.edu
Hansson
K J
KJ
Stouffer
D G
DG
Parsons
L H
LH
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012054:Reinforcement, Psychology; D012646:Self Administration; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000697:Central Nervous System Stimulants; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine