In vivo effects of the putative cognitive enhancer KA-672.HCl in comparison with 8-hydroxy-2-(di-N-propylamino) tetralin and haloperidol on dopamine, 3,4-dihydroxyphenylacetic acid, serotonin and 5-hydroxyindoleacetic acid levels in striatal and cortical brain regions.
1. KA-672.HCl (7-methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-di methyl-2H-1-benzopyran-2-one hydrochloride), designed as a cognitive enhancer, has been investigated through behavioural and binding studies. However, little is known about its biochemical effects on the dopaminergic and serotoninergic system in vivo. 2. In the present study the authors investigated the effects of KA-672.HCl (0.1 mg/kg and 1 mg/kg), 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) (1 mg/kg), haloperidol (0.1 mg/kg) and a mixture of haloperidol and 8-OH-DPAT on dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, in striatum and cerebral cortex of rats. 3. Male Wistar rats received an intraperitoneal injection of the drugs or vehicle 1 hour before striatal and cortical brain tissues were dissected out for neurochemical analysis. 4. KA-672.HCl, 8-OH-DPAT and haloperidol significantly reduced striatal DA levels, whereas only KA-672.HCl significantly reduced cortical DA levels. 8-OH-DPAT and haloperidol induced a significant increase in cortical DOPAC levels but only haloperidol significantly elevated the striatal DOPAC content. In contrast, only the higher dose of KA-672.HCl elevated striatal DOPAC levels. Furthermore, KA-672.HCl significantly reduced striatal 5-HT levels and slightly elevated striatal 5-HIAA concentrations. 8-OH-DPAT significantly decreased striatal 5-HIAA levels. All substances were able to enhance the cortical and striatal DA turnover. 5. The cortical and striatal 5-HT turnover was significantly decreased following 8-OH-DPAT treatment and significantly increased in the striatum after haloperidol and KA-672.HCl treatment. 6. The data suggest that KA-672.HCl possesses D2 antagonistic as well as 5-HT1A agonistic properties. However, additional mechanisms of actions by interaction with other neurotransmitter systems such as acetylcholine, excitatory or inhibitory amino acids need to be determined.
Teismann
P
P
Institute of Pharmacology and Toxicology, University of Marburg, Germany.
Ferger
B
B
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis*; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D004298:Dopamine / Q000032:analysis; D018492:Dopamine Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000032:analysis
D001578:Benzopyrans; D018492:Dopamine Antagonists; D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C112452:Ensaculin; D006220:Haloperidol; D004298:Dopamine