RESUMEN
Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.
Asunto(s)
Clozapina/farmacología , Cuerpo Estriado/efectos de los fármacos , Genes fos , Haloperidol/farmacología , Neurotensina/genética , ARN Mensajero/análisis , Animales , Cuerpo Estriado/metabolismo , Haloperidol/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismoRESUMEN
Parenteral administration of phosphonoformic acid (PFA) results in phosphaturia, but the effects of oral PFA on Pi handling are not known. To assess this effect, PFA was administered in drinking water for 5 days to rats stabilized on normal (NPD) or low (LPD) phosphorus diets. In renal brush-border membrane vesicles (BBMV), kinetic studies showed a higher apparent Vmax for Pi in rats on LPD compared with rats on NPD (1,840 +/- 274 vs. 1,111 +/- 192 pmol.mg-1.5 s-1, respectively, P < 0.05, n = 5). In LPD rats, PFA reduced the apparent Vmax for Pi to 1,047 +/- 191 pmol.mg-1.5 s-1 (P < 0.05, n = 5) with no change in the apparent Km. Similarly, there was a higher apparent Vmax for Pi in intestinal BBMV from rats on LPD compared with rats on NPD. In LPD rats, PFA reduced the apparent Vmax for Pi with no change in the apparent Km. Oral PFA had no effect on the kinetics of Pi transport in renal or intestinal BBMV from rats on NPD. Pi-protectable [14C]PFA binding was lower in renal BBMV from PFA-treated LPD rats, but membrane fluidity was not different. Orally administered PFA can blunt the adaptive response of the renal and intestinal BBM to an LPD. The downregulation of Na(+)-Pi cotransport is mediated through a reduction in the number of Na(+)-Pi cotransporters.