The putative antidepressant DOV 216,303, a triple reuptake inhibitor, increases monoamine release in the prefrontal cortex of olfactory bulbectomized rats.
The first line of antidepressant treatment nowadays are selective serotonin reuptake inhibitors. Although they are relatively safe to use, selective serotonin reuptake inhibitors (SSRIs) can induce severe side effects. New promising antidepressants may be the triple monoamine reuptake inhibitors, which not only enhance serotonin and norepinephrine neurotransmission, but also increase brain dopamine levels. Recently it has been shown that one of the triple reuptake inhibitors, DOV 216,303 has antidepressant-like effects in the olfactory bulbectomy (OBX) model of depression, but the alterations in monoaminergic neurotransmission in these animals are still unknown. In the present study we investigated not only the effect of acute, but also chronic treatment of DOV 216,303 in OBX rats on monoamine and metabolite levels. The main results are decreased baseline dopamine levels in the prefrontal cortex one day after OBX, while 38days after OBX no difference could be observed in monoamine levels after vehicle treatment. Treatment with DOV 216,303 leads to increased extracellular levels of serotonin and norepinephrine neurotransmission, but also increased dopamine levels in OBX animals as well as their controls. This increase could be observed after one single administration, but also after chronic treatment. However, a DOV 216,303 challenge in chronically treated animals resulted in lower monoamine concentrations than the same challenge in untreated animals. More research is needed to investigate this seemingly hyporesponsivity to chronic DOV 216,303 treatment.
Utrecht Institute for Pharmaceutical Sciences (UIPS) and Rudolf Magnus Institute of Neuroscience (RMI), Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. j.prins1@uu.nl
Jolanda
J
Prins
Damiaan A
DA
Denys
Koen G
KG
Westphal
Gerdien A
GA
Korte-Bouws
Maria S
MS
Quinton
Rudy
R
Schreiber
Lucianne
L
Groenink
Berend
B
Olivier
S Mechiel
SM
Korte
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001372:Aza Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004334:Drug Administration Schedule; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D009830:Olfactory Bulb / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors*
C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine