RESUMO
Cortical tryptophan hydroxylase (TPH) activity was reduced 3 h after a 10 or 15 mg/kg i.p. dose of either amphetamine (AMP), methamphetamine (METH), or p-chloroamphetamine (PCA). These injections of METH or PCA also decreased cortical serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations; none of the four doses of AMP decreased indoleamine concentrations. The time course of the effects following a 15 mg/kg dose of each amine was also different. Cortical TPH activity was reduced by all three amines for periods up to 24 h, whereas only METH and PCA significantly decreased 5-HT and 5-HIAA concentrations for long periods. These data suggest that each of the amphetamines may inhibit TPH activity, whereas only METH and PCA produced long-lasting decreases in indoleamine concentrations, reflecting either varying degrees of toxicity or differential effects of AMP on enzyme activity and neurotransmitter concentrations.
Assuntos
Anfetamina/farmacologia , Anfetaminas/farmacologia , Córtex Cerebral/efeitos dos fármacos , Metanfetamina/farmacologia , Serotonina/fisiologia , p-Cloroanfetamina/farmacologia , Animais , Córtex Cerebral/enzimologia , Cromatografia Líquida de Alta Pressão , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Fatores de Tempo , Triptofano Hidroxilase/antagonistas & inibidoresRESUMO
Rats treated with iprindole (IPR) (10 mg/kg, i.p.) were given a single dose (15 mg/kg, i.p.) of amphetamine (AMP). Marked decreases in the activity of tryptophan hydroxylase (TPH) were observed in both the cerebral cortex and neostriatum after 6 hr, with maximum depression observed at 24 hr. Enzyme activity had returned to control levels in neostriatum after 3 days and in cerebral cortex after 7 days. Levels of serotonin (5-HT) in both the cerebral cortex and neostriatum were significantly lowered at 24 hr but had recovered by 72 hr. Levels of tryptophan (TRP) in the cortex were significantly elevated after 6 hr, recovering by 24 hr. In the neostriatum, the activity of tyrosine hydroxylase (TH) was significantly depressed by 24 hr and remained so for 7 days. Concentrations of dopamine (DA) were decreased at all times examined. This study clarifies the differences previously observed in the response of the serotonergic system to amphetamine or methamphetamine (METH) in iprindole-treated rats.
Assuntos
Encéfalo/efeitos dos fármacos , Dextroanfetamina/farmacologia , Indóis/farmacologia , Iprindol/farmacologia , Metanfetamina/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Animais , Encéfalo/enzimologia , Córtex Cerebral/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Serotonina/metabolismo , Triptofano/metabolismo , Triptofano Hidroxilase/antagonistas & inibidoresRESUMO
A single dose (17.5 mg/kg i.p.) of methamphetamine was administered to iprindole-treated (10 mg/kg i.p.) rats. Forebrain concentrations of methamphetamine and amphetamine were significantly increased in iprindole-treated rats 1 and 6 hr after injection; in contrast to rats pretreated with saline, both amines were also detected after 18 hr. Three and 7 days after injection, significant decreases were seen in tryptophan hydroxylase (TPH) activity and serotonin concentrations in the cerebral cortex, neostriatum and hypothalamus. Hypothalamic TPH activity had recovered by 14 days. Neostriatal tyrosine hydroxylase activity and dopamine concentrations were significantly depressed at all time points examined. Iprindole alone produced a significant increase in cortical TPH activity after 1 day. After 3 days, TPH activity was significantly decreased when compared with control, whereas serotonin and 5-hydroxyindoleacetic acid concentrations were significantly increased. This study demonstrates that persistence of methamphetamine and/or amphetamine at the site of action is important for neurotoxicity.
