Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity.
Major depressive disorder is a prevalent disease, and current pharmacotherapy is considered to be inadequate. It has been hypothesized that a triple reuptake inhibitor (TRI) that activates dopamine (DA) neurotransmission in addition to serotonin and norepinephrine (NE) circuitries may result in enhanced antidepressant effects. Here, we investigated the pharmacological effects of a serotonin-preferring TRI-amitifadine (EB-1010, formerly DOV 21947). The effects of amitifadine (10 mg/kg ip.) on extracellular concentrations of monoamines and their metabolites in rat brain regions were investigated using the in vivo microdialysis technique. The effects of amitifadine on locomotor activity and stereotyped behavior were also evaluated. A major metabolite of amitifadine, the 2-lactam compound, was investigated for inhibition of monoamine uptake processes. Amitifadine markedly and persistently increased extracellular concentrations of serotonin, NE, and DA in prefrontal cortex. The extracellular concentrations of DA were also increased in the DA-rich areas striatum and nucleus accumbens. The extracellular concentrations of the metabolites of serotonin, 5-hydroxyindoleacetic acid, and DA, 3,4-dihydroxyphenylacetic and homovanillic acid, were also markedly decreased in brain regions. Amitifadine did not increase locomotor activity or stereotypical behaviors over a broad dose range. The lactam metabolite of amitifadine weakly inhibited monoamine uptake. Thus, amitifadine increased extracellular concentrations of serotonin, NE, and DA, consistent with TRI. Although amitifadine significantly increased DA in the nucleus accumbens, it did not induce locomotor hyperactivity or stereotypical behaviors. The enhancement of serotonin, NE, and DA in rat brain regions associated with depression suggest that amitifadine may have novel antidepressant activity.
Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, 31-343 Krakow, Poland.
Krystyna
K
Golembiowska
Magdalena
M
Kowalska
Frank P
FP
Bymaster
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006719:Homovanillic Acid / Q000032:analysis; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
D015102:3,4-Dihydroxyphenylacetic Acid; D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D006719:Homovanillic Acid; D006897:Hydroxyindoleacetic Acid; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride