Farhat Batool

Regionally specific effects of diazepam on brain serotonin metabolism in rats: Sustained effects following repeated administration

The effects of single (1mg/kg) and repeated (1mg/kg 2* daily for 4 days) diazepam administration are investigated on brain regional 5-hydroxytryptamine (5-HT; serotonin) and 5-hydroxy indoleacetic acid (5-HIAA) concentration in rats. Daily treatment decreased food intakes but body weights did not decrease. Administration of diazepam (1mg/kg) to 4 day saline injected rats on the 5th day decreased 5-HT levels in the hippocampus and increased it in the hypothalamus. 5-HIAA levels were increased in the striatum and decreased in the hypothalamus 4 day diazepam injected rats injected with saline on the 5th day also exhibited similar changes of 5-HT and 5-HIAA. Cortical levels of 5-HIAA were also smaller in these rats. Administration of diazepam to 4 day diazepam injected rats again decreased 5-HT in the hippocampus and 5-HIAA in the hypothalamus. 5-HT and 5-HIAA were both decreased in the striatum. Regionally specific effects of diazepam on brain serotonin metabolism are discussed in relation to their possible functions.

Pre- and postsynaptic responses to 1-(1-naphthylpiperazine) following adaptation to stress in rats.

In view of a role of pre- and postsynaptic serotonin (5-hydroxytryptamine; 5-HT) receptors in adaptation to stress, effects of 1-(1-naphthylpiperazine) (1-NP) were compared in unrestrained and repeatedly restrained adapted rats. In the first part of the study, effects of various doses (1.0-15 mg/kg ip) of 1-NP were monitored on brain 5-HT metabolism (presynaptic response) and on the activity (postsynaptic response) of rats in an activity cage to which the rats were habituated before the drug administration. The drug injected at doses of 2.5-15.0 mg/kg increased motor activity and decreased brain 5-hydroxyindoleacetic acid (5-HIAA) concentration in a dose-dependent manner. In the second part of the study, rats were restrained on wire grids 2 h/day for 5 days. First-day episode of 2-h restraint decreased 24-h cumulative food intake, water intake and growth rate. The decreases attenuated following second-, third- and fourth-day episodes of 2-h restraint were not observed following fifth-day episode of 2-h restraint stress, suggesting adaptation to the stress schedule has occurred. Serotonergic and motor responses to 1-NP in unrestrained and repeatedly restrained adapted rats were compared by injecting the drug at a dose of 5 mg/kg, a dose that above results suggested would not produce maximal effects on 5-HT metabolism or motor activity. Administration of 1-NP at a dose of 5 mg/kg increased motor activity and decreased brain 5-HIAA concentration in unrestrained and repeatedly restrained adapted rats. Increases of motor activity were much greater in repeatedly restrained adapted than unrestrained rats. Decreases of 5-HIAA concentration were comparable in the two groups. The results are discussed in the context of an increase in the effectiveness of postsynaptic 5-HT-1A and 5-HT-1B receptors and a decrease in the effectiveness of presynaptic 5-HT-1A (somatodendritic) and 5-HT-1B (terminal) receptors following adaptation to stress. It is suggested that these changes of receptor responsiveness might help coping with stress demand to produce adaptation to stress.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats 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 kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) 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 kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased 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, significantly (p < 0.01) decreased 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 receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed. O dozi ovisni učinci klozapina i risperidona na metabolizam serotonina i dopamina u pojedinim područjima mozga i na ekstrapiramidalne nuspojave u štakora 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 kg-1) ili risperidon (1,0, 2,5 i 5,0 mg kg-1). 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 kg-1). 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.

Acute administration of clozapine and risperidone altered dopamine metabolism more in rat caudate than in nucleus accumbens: a dose-response relationship.

The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin1A receptors in the pathophysiology of schizophrenia is also discussed.