O dozi ovisni učinci klozapina i risperidona na metabolizam serotonina i dopamina u pojedinim područjima mozga i na ekstrapiramidalne nuspojave u štakora

The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg1) or risperidone (1.0, 2.5 and 5.0 mg kg1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100 %) cataleptic potential was achieved at a high dose (5.0 mg kg1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, increased significantly (p < 0.01) the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, decreased significantly (p < 0.01) in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptor interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.Cilj rada bio je procjena ponašanja i neurokemijskog profila klozapina i risperidona u ovisnosti o dozi nakon primjene na štakorima. Pokusnim životinjama intraperitonealno je injiciran klozapin (2,5, 5,0 i 10,0 mg kg1) ili risperidon (1,0, 2,5 i 5,0 mg kg1). Nakon jednog sata životinje su žrtvovane i uzeti su uzorci mozga. Nakon primjene lijeka ili fiziološke otopine praćeni su hipolokomotorički učinci (aktivnost u kavezu i katalepsija). Oba lijeka su pri visokim dozama značajno smanjila (p < 0,01) lokomotoričku aktivnost, a smanjenje je ovisilo o dozi. Maksimalni (100 %) kataleptički učinak postignut je visokom dozom risperidona (5,0 mg kg1). Neurokemijske procjene provedene su pomoću HPLC s elektrokemijskom detekcijom. Oba lijeka su pri svim dozama značajno (p < 0,01) povećala koncentraciju homovanilinske kiseline (HVA), metabolita dopamina (DA), u striatumu. Koncentracija dihidroksifeniloctene kiseline (DOPAC) u striatumu bila je povećana, a u ostatku mozga smanjena, posebno nakon primjene klozapina. Koncentracija 5-hidroksiindol octene kiseline (5-HIAA), najvažnijeg metabolita serotonina, značajno (p < 0,01) se smanjila u striatumu. 5-Hidroksitriptamin (5-HT) značajno se povećao (p < 0,01) nakon risperidona, a smanjio nakon klozapina u ostalim dijelovima mozga. Risperidon je značajno smanjio triptofan (TRP) u striatumu (p < 0,01), a povećao njegovu koncentraciju u ostalim dijelovima mozga. Također je povećao omjer HVA/DA u striatumu, dok je metabolizam 5-HT ostao nepromijenjen u ostalim dijelovima mozga. Rezultati upućuju na to da je interakcija ispitivanih lijekova s D2/5-HT1A receptorima uključena u nisku incidenciju ekstrapiramidalnih nuspojava. Razmatrana je uloga 5-HT1A receptora u terapiji šizofrenije