Chronic treatment with fluoxetine decreases cerebral metabolic responses to the 5-HT1A agonist 8-hydroxy-2(di-N-propylamino)tetralin and increases those to the 5-HT2A2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and to the dopaminergic agonist apomorphine.
Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor that, when given chronically, alters different neurotransmitter systems. To assess functional changes occurring in the 5-HT and dopaminergic systems, we investigated the effects of 5-HT(1A) agonist 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT), of the 5-HT(2A2C) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and of the dopamine D(12) agonist apomorphine (APO) on behavior and on regional cerebral metabolic rates for glucose (rCMRglc) in rats pretreated for 3weeks with saline or fluoxetine (8mgkgday). Behavioral effects were assessed for 8-OH-DPAT by scoring the 5-HT syndrome, for DOI by counting head shakes and for APO with an activity monitor. rCMRglc were measured with quantitative autoradiographic (14)C2-deoxyglucose technique in 60 brain regions at 10min after acute administration of 8-OH-DPAT 1mgkg, at 30min after DOI 5mgkg or at 10min after APO 1mgkg. Chronic fluoxetine did not alter the 5-HT syndrome by 8-OH-DPAT, decreased head shakes by DOI and enhanced hyperlocomotion by APO. 8-OH-DPAT produced rCMRglc increases in sensorimotor regions that were unaffected by fluoxetine pretreatment and diffuse metabolic decrements that were attenuated by fluoxetine in limbic and raphe areas (17% and 4% mean decreases, respectively, in saline control and fluoxetine-pretreated rats). DOI produced widespread rCMRglc declines that were intensified by fluoxetine (14% and 20% decreases, in control and fluoxetine rats). APO caused rCMRglc increases in 22 brain regions that were potentiated by fluoxetine in dopaminergic motor areas (10% and 25% increases, in control and fluoxetine rats). In conclusion, fluoxetine enhances 5-HT neurotransmission by blunting responsivity of 5-HT(1A) autoreceptors and increasing that of 5-HT(2A2C) postsynaptic receptors and enhances dopaminergic D(12) receptor neurotransmission.