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E Sanders-Bush

Publications and source records attributed to E Sanders-Bush.

At least 109 records · Page 6Linked to original sources
PubMed1978

Long-term reduction of brain serotonin by p-chloroamphetamine: effects of inducers and inhibitors of drug metabolism.

The present experiments were designed to test the hypothesis that the long-term effects of p-chloroamphetamine (PCA) on serotonergic neurons in rats are mediated by a neurotoxic metabolite. The effects of well-known inducers and an inhibitor of hepatic microsomal drug-metabolizing enzymes on the PCA-induced decreases in brain levels of 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase activity and the half-life of PCA in brain were examined. All of these modified the half-life of PCA in a predictable manner: 3-methylcholanthrene and, to a much lesser extent, phenobarbital decreased the half-life of PCA while piperonyl butoxide markedly increased it. Fluoxetine, an inhibitor of 5-HT uptake, also increased the half-life of PCA in brain. In addition, fluoxetine blocked the long-term effects of PCA on 5-HT levels and tryptophan hydroxylase activity. Of the classical metabolic tools, only 3-methylcholanthrene provided complete protection from the long-term, neurotoxic effects of PCA. Although the mechanism of this protection is unknown, it is not mediated by a blockade of 5-HT uptake since 3-methylcholanthrene did not decrease the synaptosomal uptake of 5-HT. Piperonyl butoxide pretreatment markedly increased the half-life of PCA in brain, but it failed to modify consistently the effects of PCA. The results indicate that the long-term, neurotoxic effects of PCA are not mediated by the major, hepatic metabolites of the drug, but leave open the possibility of a minor, neurotoxic metabolite.

Amphetamines↗
PubMed1977

Rapid tolerance to the motor effects of p-chloroamphetamine in rats.

Studies were designed to test the hypothesis that tolerance to the effect of p-chloroamphetamine (PCA) on motor activity in rats would develop with repeated injections. In related biochemical studies the effects of single or repeated doses of PCA on the in vitro synaptosomal uptake of 3H-NE and 3H-DA and on the in vivo metabolism of intraventricularly administered 3H-NE and 3H-DA were investigated. The administration of 10 mg/kg of PCA induced a complex behavioral syndrome, which was quantified by scoring specific symptoms after direct observation. In agreement with previous data, this syndrome appears to be mediated by a release of 5-HT since pretreatment with PCA prevented its development on subsequent injection of the drug. After the administration of lower doses of PCA, total motor activity as measured in activity cages increased, and tolerance to this effect also developed rapidly. For example, pretreatment with 5 mg/kg of PCA greatly attenuated the stimulant effect of a subsequent dose of 3 or 5 mg/kg of the drug. Moreover, the degree of tolerance was the same if the time between the 2 injections was 1 day or 2 weeks, suggesting that 5-HT release is also involved in the tolerance to the motor effects of lower doses of the drug. Moreover, biochemical studies of the response of catecholaminergic neurons to PCA suggest that tolerance does not develop to the effects on DA and NE neurons on repeated injection of PCA.

Amphetamines↗
PubMed1977

Temporal effects of p-chloroamphetamine on catecholamine synthesis.

Within 0.25 h after the administration of 5 mg/kg of p-chloroamphetamine (PCA), the conversion index of both norepinephrine (NE) and dopamine (DA) was increased. The effect on DA synthesis was similar, but of less magnitude after 1.25 h, while the effect on NE was reversed, i.e. the conversion index was decreased. This biphasic effect of PCA on NE synthesis is discussed the in the context of two opposing regulatory mechanisms for neuronal catecholamine synthesis.

Amphetamines↗
PubMed1975

An evaluation of the use of intraventricularly administered [3H]5-hydroxytryptamine as a marker for endogenous brain 5-hydroxytryptamine.

Following the intraventricular injection of a small amount of [3H]5-hydroxytryptamine ([3H]5-HT), the amount of radioactivity in telencephalic structures on the injected side was 6--7 times larger than that in corresponding areas on the opposite side. Moreover, a multiphasic disappearance of [3H]5-HT from whole brain or midbrain was found after the intraventricular injection of the labeled amine. However, after the intraventricular injection of [3H]tryptophan, the levels of [3H]5-HT in midbrain declined in a monophasic manner. A significant portion of the labeled amine derived from intraventricularly administered [3H]5-HT was resistant to the depleting effect of Ro4-1284 or to that elicited by destruction of the midbrain raphe nuclei, both of which caused an almost complete loss of endogenous 5-HT and labeled 5-HT formed from tryptophan. It thus appears that the intraventricular injection of [3H]5-HT leads to the formation of artifactual pools which are not present if the amine is synthesized in vivo. Studies with 6-hydroxydopamine suggested, however, that uptake of [3H]5-HT into adrenergic neurons did not occur to any great extent.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1975

Long-term effects of p-chloroamphetamine and related drugs on central serotonergic mechanisms.

Earlier studies from our laboratory have demonstrated a marked reduction in the brain level of 5-hydroxytryptamine (5-HT) and in the activity of tryptophan hydroxylase which persists for several weeks after a single dose of 10 mg/kg of p-chloroamphetamine (PCA). In the present study, equally long-lasting decreases were found after the administration of 5 mg/kg of PCA. p-Chloromethamphetamine also caused long-lasting reductions in the level of 5-HT and the activity of tryptophan hydroxylase in brain, whereas the effects of fenfluramine had disappeared 2 weeks after injection. The ability of brain synaptosomes to take up 5-HT was markedly reduced following doses of 2, 5 and 10 mg/kg of PCA. The in vitro addition of PCA to synaptosomal fractions markedly reduced the uptake of dopamine and norepinephrine; however, only a 30% reduction in the uptake of these amines was found in synaptosomes prepared from brains of rats treated with PCA. The effects on catecholamine uptake disappeared within 1 day after injection. In contrast, the time course of recovery of the synaptosomal uptake capacity for 5-HT followed a pattern similar to that found for the recovery of the level of 5-HT and the activity of tryptophan hydroxylase, with a 50% reduction still present 3 months after the injection of 10 mg/kg of PCA. The greatest reductions of 5-HT, tryptophan hydroxylase activity and synaptosomal uptake were found in the midbrain, hippocampus and striatum with less pronounced effects in the hypothalamus, medulla-pons and spinal cord. At both 1 and 14 days after injection of 5 and 7.5 mg/kg of PCA, tryptophan hydroxylase activity in whole brain was reduced by 50% or more; however, 4 days after treatment the activity of the enzyme was reduced only slightly or not at all. The results indicate that different independent mechanisms are responsible for the initial, reversible and the prolonged, irreversible effects of PCA on serotonergic neurons.

Amphetamine↗
PubMed1975

Correlation between brain levels and biochemical effects of the optical isomers of p-chloroamphetamine.

The biochemical effects of d- and l-p-chloroamphetamine (PCA) were compared with the brain levels of the unchanged drug at various times after a single injection. Initially both isomers produced rapid and pronounced decreases in the whole brain levels of serotonin and 5-hydroxyindoleacetic acid, tryptophan hydroxylase activity and the synaptosomal uptake of 3-H-serotonin. At later times (e.g., 2 weeks), the effects of the d-isomer were much more pronounced than were those of the l-isomer. At intermediate times (2-4 days), a variable and dose-dependent recovery of synaptsomal uptake activity and tryptophan hydroxylase activity occurred after d-PCA. In both whole brain and forebrain, long-term reductions in these activities were found. However, in the midbrain, an area containing the cell bodies of serotonergic neurons, only a slight initial decrease in tryptophan hydroxylase activity occurred. The whole brain levels of the two isomers were equal from 4 to 96 hours after injection and declined exponentially in a single monophasic manner monophasic decine of the levels of PCA was found in forebrain and midbrain samples. Thus, the initial and long-term effects of PCA are apparently mediated by different mechanisms. The former is correlated with the brain levels of the unchanged drug; the latter is not. The lack of any indication of a biphasic decay curve after 10 half-lives and the intermediate recovery of serotonergic function do not support a reserpine-like mechanism for the long-term effects of PCA. Instead, a mechanism related to neurotoxicity is proposed.

Amphetamines↗