Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat.
In view of a postulated role of the vigilance-promoting drug modafinil in depression, the interaction of modafinil and two classical antidepressant drugs, fluoxetine and imipramine, were studied in 5-HT levels in the dorsal raphe-cortical system using dual-probe microdialysis. Fluoxetine (1-10 mg/kg) dose-dependently increased dorsal raphe-cortical 5-HT levels. Modafinil at a very low dose (3 mg/kg), by itself ineffective, enhanced the fluoxetine (5 mg/kg)-induced increases of 5-HT levels in both brain areas. A synergistic interaction was observed in the prefrontal cortex with fluoxetine (1 mg/kg) in terms of 5-HT release, but not in the dorsal raphe. Imipramine (1.3 mg/kg) increased 5-HT levels in the dorsal raphe, but not in the prefrontal cortex, while the higher doses (10.9-21.8 mg/kg) caused substantial increases in both brain areas. Modafinil (3 mg/kg), injected before imipramine (1.3 mg/kg), which by itself was ineffective on cortical 5-HT levels, increased cortical 5-HT levels. On other hand, modafinil failed to affect the high-dose imipramine (10.9 mg/kg)-induced increase of 5-HT levels in the prefrontal cortex and the imipramine (1.3; 10.9 mg/kg)-induced increase of 5-HT levels in the dorsal raphe nucleus. These results demonstrate that modafinil in low doses enhances the acute effects of fluoxetine and imipramine on 5-HT levels in the dorsal raphe nucleus (fluoxetine only) and especially in the prefrontal cortex of the awake rat. These findings suggest a therapeutic potential of low doses of modafinil in the treatment of depression when combined with low doses of classical antidepressants, especially by increasing 5-HT transmission in cortical regions.
Ferraro
Luca
L
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Italy.
Fuxe
Kjell
K
Agnati
Luigi
L
Tanganelli
Sergio
S
Tomasini
Maria Cristina
MC
Antonelli
Tiziana
T
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003866:Depressive Disorder / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D000077408:Modafinil; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D005473:Fluoxetine; D007099:Imipramine; D000077408:Modafinil; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors