Down regulation of beta-receptors by bupropion and its major metabolite in mouse brain.

Mice were treated with bupropion Compound II (major metabolite of bupropion) or desmethylimpramine (DMI) twice a day intraperitoneally for either 1 or 3 weeks. The binding of dihydroalprenolol and spiroperidol in the frontal cortex and limbic forebrain areas were analyzed. There was a significant reduction in beta-receptors in the frontal cortex induced by DMI at both times examined. Bupropion showed a significant reduction of beta-receptor in the frontal cortex by 3 weeks. Though propiophenone did not have any significant effect on beta-receptors in the frontal cortex, it down-regulated beta-receptors in the limbic forebrain area significantly by 1 and 3 weeks. There was no significant effect of buropion or propiophenone on the binding of spiroperidol either in the cortex (S2 receptor) or in the limbic forebrain (dopaminergic). These results show that bupropion may exert part of its clinical effect through its metabolite propiophenone.

Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine.

The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.

Brain regional [3H]flunitrazepam binding in rats chronically treated with bupropion or B.W.306U.

After 21 days of twice daily i.p. injections of bupropion (10 mg/kg), B.W.306U (10 mg/kg) or saline, 5 rat brain regions were removed for [3H]flunitrazepam binding assay. Scatchard analysis of the binding data revealed no change in the Bmax in any brain regions in drug-treated rats compared to controls. There was, however, a significant change in the Kd value in the limbic forebrain of B.W.306U-treated rats.

Drug-induced differentiation of a rat glioma in vitro: II. the expression of S-100, a glial specific protein and steroid sulfatase.

Amethopterin and 5-bromodeoxyuridine (BUdR) were used to induce morphological changes in cloned rat glioma (C6). The expression of S-100 protein, an acidic protein localized in glial cells, and steroid sulfatase, an ubiquitously distributed enzyme found in high concentration in glial cells, were followed during cell growth, from subculture to well into the stationary phase of control and drug-treated cultures. Amethopterin and BUdR differed in their effects on glioma morphology and in the expression of the biochemical parameters. Amethopterin coordinately stimualted both the production of S-100 protein and steroid sulfatase activity when cell division was inhibited during early logarithmic growth phase. BUdR stimulated steroid sulfatase activity but repressed production of S-100 protein. The results are discussed with respect to the mechanism of regulation of the differentiated state of tumor cells.

Regional effects of 6-hydroxydopamine (6-OHDA) on free radical scavengers in rat brain.

Superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase (GSH-Px) were measured in the caudate-putamen (CPu), the hippocampus (HIP), and the brainstem (BS) of the brains of control animals and of rats treated with one intracerebroventricular infusion of 6-hydroxydopamine (6-OHDA). Injection of 6-OHDA resulted in significant decreases in the activity of SOD in the CPu, the BS, and in the HIP. There were decreases in catalase in the CPu and in the BS, but not in the HIP. GSH was reduced in the CPu and the BS but not changed in the HIP. There were small decreases in the activity of GSH-Px only in the BS. These changes may be secondary to the production of free radicals after the infusion of 6-OHDA in rat brain.

Modification of beta-adrenergic receptor binding in rat brain following thyroxine administration.

The effect of repeated administration of thyroxine on beta-adrenergic receptor binding was studied in several brain regions in the rat using [3H]dihydroalprenolol as a ligand. Thyroxine treatment resulted in an increased density of beta-adrenergic receptors in the cerebral cortex while a decreased binding was found in subcortical tissue representing the thalamus, striatum and parts of the limbic system. There was no change in binding in the cerebellum or in the brainstem. The results indicate that thyroxine may regulate beta-adrenergic receptors in certain brain areas.

Vitamin E attenuates the toxic effects of 6-hydroxydopamine on free radical scavenging systems in rat brain.

Rats were divided into the following four groups namely (a) sham-operated control, (b) 6-OHDA-treated, (c) sham-operated vitamin E-fed and (d) Vitamin E-fed treated with 6-OHDA. Total glutathione (GSH) and superoxide dismutase (SOD) were measured in brainstem (BS), striatum (ST), hippocampus, frontal cortex, and nucleus accumbens (N. Acc.). GSH and SOD levels were significantly decreased in all regions of 6-OHDA-treated rats compared to controls. Feeding of vitamin E resulted in a significant reduction of GSH in ST and N. Acc. but caused increases in SOD in BS, ST, and N. Acc. Pretreatment of rats with vitamin E caused significant attenuation of the effects of 6-OHDA on GSH and SOD in most of the brain regions. These results show that vitamin E can spare the scavenging systems from the injurious effects of 6-OHDA.

Regional effects of iminodipropionitrile (IDPN) on free radical scavengers in rat brain.

Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were measured in different regions of the brains of control and IDPN-treated rats. IDPN treatment resulted in significant increase of SOD activity in the cerebellum. Other regions, except frontal cortex, exhibited a slight decrease. While there was no significant difference in GSH-Px activity in all regions compared to controls, CAT activity was slightly increased in the cerebellum. These results give credence to the notion that free radical damage to certain areas of the brain such as isodendric core of the brainstem may play a role in the development of movement disorders.

Nuclear protein kinase of brain: effect of S-100 protein.

The non-histone chromosomal protein fraction isolated from purified brain nuclei possesses protein kinase activity. 93% of this activity is lost by heating at 80 degrees C for 5 min. cAMP does not affect the reaction, but cGMP is inhibitory. In the presence of S-100, an acidic brain-specific protein, phosphate incorporation is enhanced 3 to 4 fold. Bovine serum albumin has no effect whereas histone inhibits activity.

Beta-adrenergic receptor binding in different regions of rat brain after various intensities of electroshock: relationship to postictal EEG.

Relationships among different intensities of electroshock treatment (EST), EEG-recordable primary after discharge (PAD), and beta-adrenergic binding in various brain regions were investigated in adult rats. Different intensities of EST (1-2, 6-8, 20-30 mamp) were applied through ear-clip electrodes for 7 consecutive days. A sigmoidal relationship was observed between the PAD and the applied current-intensity. 3H-dihydroalprenolol (DHA) was used as a ligand to evaluate beta-adrenergic receptor binding in membrane preparation of the following brain regions: Cerebral cortex, cerebellum, pons-medulla, and "midregion"-which consisted of the remainder tissue including thalamus, striatum, and midbrain. A significant decrease (28%) in binding was observed in cortex tissue after EST of 6-8 mamp but no changes were observed after either 1-2 mamp or 20-30 mamp. In "midregion," a significant increase (40%) in binding was observed after EST with the subconvulsive intensity (1-2 mamp) whereas no changes were seen at higher intensities. The results suggest that in cortex, the function relating beta-adrenergic binding to current intensities may not be monotonic. The increase in binding seen in the "midregion" after subconvulsive EST may not be associated with changes related to the clinical efficacy of EST.

Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs.

Recent reports indicate that bupropion, a novel non-tricyclic antidepressant, is metabolized differently in certain species of animals. To further define the disposition of bupropion, a study was done involving three species, the rat, mouse, and guinea pig, as animal models to evaluate bupropion metabolism. The pharmacokinetic profiles of bupropion and its major basic metabolites, BW 306U and BW A494U, were determined following the ip administration of 40 mg/kg bupropion to these animals. Pharmacokinetic profiles of the parent drug and metabolites from plasma and brain samples were obtained using a liquid chromatographic procedure. Further investigation of the reduced bupropion metabolite BW A494U was carried out by the ip administration of this metabolite to these animals and assaying the plasma and brain samples 90 min after dosing. Analysis of the pharmacokinetic data revealed that the rat quickly metabolized bupropion, but no basic metabolites accumulated. The mouse metabolized bupropion predominantly to BW 306U, whereas the guinea pig converted bupropion to reduced bupropion (BW A494U) as well as BW 306U. Brain/plasma ratios of bupropion among these animals did not vary significantly. However, both metabolites showed dramatic differences in their brain/plasma ratios among these species. When reduced bupropion (BW A494U) was injected, almost 3% of the plasma concentration of BW A494U was determined to be bupropion in the rat. Lesser amounts were converted in the mouse and guinea pig. Therefore, we have demonstrated that distinct differences exist in the metabolism of bupropion in various species of animals. The guinea pig, when compared to the rat or mouse, appears to constitute a model that most closely resembles that of human bupropion metabolism.