Comparison of the effects of deramciclane, ritanserin and buspirone on extracellular dopamine and its metabolites in striatum and nucleus accumbens of freely moving rats.
In the present study, we assessed the effect of single graded doses of a putative anxiolytic compound, the 5-HT(2A/C )antagonist, deramciclane fumarate (EGIS-3886), on the dopamine efflux and metabolism in nucleus accumbens and striatum and thus evaluated the dose window for deramciclane to cause adverse effects related to the brain dopaminergic system. Dual probe in vivo microdialysis in freely moving rats was used to compare the effects of graded doses of deramciclane fumarate (3, 10 and 30 mg/kg), 5-HT(2A/C )antagonist ritanserin (1 mg/kg) and a partial 5-HT(1A) agonist buspirone hydrochloride (5 mg/kg) on the extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens and striatum assayed by high performance liquid chromatography with electrochemical detection. The indirect dopamine agonist, D-amphetamine sulfate (2 mg/kg), was used as a positive control. Ritanserin, buspirone and deramciclane 3 and 10 mg/kg had no significant effects on the extracellular dopamine levels in either brain area but deramciclane 30 mg/kg significantly increased accumbal dopamine as well as DOPAC and HVA in both brain areas. As expected, the positive control D-amphetamine significantly increased both striatal and accumbal dopamine levels. The effects of buspirone or the highest deramciclane dose and D-amphetamine on DOPAC and HVA levels were opposite; buspirone and deramciclane increased while D-amphetamine decreased the metabolite levels in both brain areas. The results indicate that a single high dose of deramciclane has the neuroleptic- or buspirone-like effect, particularly in mesolimbic regions. There is at least a 5-fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat.
Kääriäinen
Tiina M
TM
Department of Pharmacology and Toxicology, University of Kuopio, Kuopio, Finland. Tiina.Kaariainen@uku.fi
Lehtonen
Marko
M
Forsberg
Markus M
MM
Savolainen
Jouko
J
Käenmäki
Mikko
M
Männistö
Pekka T
PT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology*; D001892:Camphanes / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016713:Ritanserin / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D001892:Camphanes; D015102:3,4-Dihydroxyphenylacetic Acid; D016713:Ritanserin; C060555:deramciclane; D002065:Buspirone; D004298:Dopamine; D006719:Homovanillic Acid