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PubMed1990

Supersensitivity to catecholamines after inhibition of extraneuronal uptake (uptake2) or O-methylation.

The influence of inhibition of uptake2 and of O-methylation on beta-adrenoceptor-mediated responses of guinea-pig trachea and rat uterus to some catecholamines was compared. The responses were more markedly enhanced by inhibition of O-methylation (by U-0521) than by inhibition of uptake2 (by hydrocortisone). The ranking order for the degree of super-sensitivity caused by either U-0521 or hydrocortisone was different in the two tissues, suggesting differences between the O-methylating systems of those tissues. In experiments with 3H-isoprenaline metabolism, hydrocortisone had a weak inhibitory effect on O-methylation in both tissues.

Animals↗
PubMed1991

Extraneuronal inactivation of noradrenaline in tissue culture.

Corticosterone-sensitive extraneuronal transport (uptake2) and metabolism of noradrenaline was investigated in the clonal human Caki-1 cell line. Caki-1 cells are the first experimental system for uptake2 which is based on a tissue culture technique. Previous experiments with Caki-1 cells opened the possibility of a close relationship between uptake2 and the renal transport system for organic cations (RTOC). The finding that steroids potently inhibit both uptake2 and RTOC further supports this hypothesis. Noradrenaline which has been taken up into Caki-1 cells by uptake2 is metabolized by the intracellular enzymes catechol-O-methyltransferase (COMT) and to a lesser extend by monoamineoxidase (MAO).

Adenocarcinoma↗
PubMed1992

The extraneuronal transport mechanism for noradrenaline (uptake2) avidly transports 1-methyl-4-phenylpyridinium (MPP+).

The corticosterone-sensitive extraneuronal transport mechanism for noradrenaline (uptake2) removes the neurotransmitter from the extracellular space. Recently, an experimental model for uptake2 has been introduced which is based on tissue culture techniques (human Caki-1 cells). The present study describes some properties of uptake2 in Caki-1 cells and introduces a new substrate, i.e., 1-methyl-4-phenylpyridinium (MPP+). Experiments on Caki-1 cells disclosed disadvantages of tritiated noradrenaline as substrate for the investigation of uptake2. The initial rate of 3H-noradrenaline transport [kin = 0.58 microliter/(mg protein.min)] was low compared with other cellular transport systems and intracellular noradrenaline was subject to rapid metabolism (kO-methylation = 0.54 min-1). The neurotoxin MPP+ was found to be a good substrate of uptake2. Initial rates of specific 3H-MPP+ transport into Caki-1 cells were saturable, the Km being 24 micromol/l and the Vmax being 420 pmol/(mg protein.min). The rate constant of specific inward transport was 34 times higher [19.6 microliters/(mg protein.min)] than that of 3H-noradrenaline. The ratio specific over non-specific transport was considerably higher for 3H-MPP+ (12.6) than for 3H-noradrenaline (3.0). 3H-MPP+ transport into Caki-1 cells was inhibited by various inhibitors of uptake2. The highly significant positive correlation (p less than 0.001, r = 0.986, n = 7) between the IC50's for the inhibition of the transport of 3H-noradrenaline and 3H-MPP+, respectively, proves the hypothesis that MPP+ enters Caki-1 cells via uptake2. 3H-MPP+ is taken up via uptake2 not only by Caki-1 cells but also by the isolated perfused rat heart which is another established model of uptake2.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗
PubMed1987

The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: multifactorial induction of outward transport.

The mechanism of action of indirectly acting sympathomimetic amines was studied in the rat vas deferens, after inhibition of vesicular uptake (by reserpine), of MAO (by pargyline) and of COMT (by U-0521). 1. Km-values for the neuronal uptake of 12 substrates were determined as the IC50 of the unlabelled substrate inhibiting the initial rate of neuronal uptake of 0.2 mumol/l 3H-(-)-noradrenaline. The IC50 ranged from 0.35 mumol/l (for(+)-amphetamine) to 44.3 mumol/l (for 5-HT). The Vmax (determined for 8 substrates) was substrate-dependent. 2. Tissues were loaded with 0.2 mumol/l 3H-(-)-noradrenaline and then washed out with amine-free solution. All 12 substrates of uptake1 induced an outward transport of 3H-noradrenaline, and equieffective concentrations were positively correlated with Km. Moreover, the EC50 for release greatly exceeded Km. It is proposed that this discrepancy between EC50 and Km is indicative of the fact that at least four factors (each one in strict dependence on Km) contribute to the initiation of outward transport of 3H-noradreanline: a) the appearance of the carrier on the inside of the axonal membrane (facilitated exchange diffusion), b) the co-transport of Na+, c) the co-transport of Cl- (both lowering the Km for 3H-noradrenaline at the inside carrier), and d) inhibition of the re-uptake of released 3H-noradrenaline (through competition for the outside carrier). 3. At least for amezinium, Vmax appears to limit the maximum rate of outward transport. 4. For some substrates (especially for the highly lipophilic ones) bell-shaped concentration-release curves were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines.

In the present study the influence of oestradiol, catechol oestrogens, and O-methylated oestrogens was determined on the contractile responses of the isolated rabbit aorta to (-)-adrenaline. Oestradiol (40 mumol/l), 2-hydroxyoestradiol (2OHE2) (20 mumol/l), and 2-methoxyoestradiol (2MeOE2) (20 mumol/l) all sensitized the rabbit aorta to contractile responses to (-)-adrenaline. Similarly, the 2-hydroxy and 2-methoxy derivatives of oestrone and oestriol also sensitized the aorta to (-)-adrenaline-induced contractions. The largest degree of sensitization was seen in the presence of the 2-methoxysteroids. Oestradiol and 2OHE2 did not increase responses of the aorta to (-)-noradrenaline, while slight potentiation of contraction was seen in the presence of 2MeOE3. The potentiating effect of 2OHE2 on contractile responses to (-)-adrenaline was abolished by prior treatment of the tissue with a COMT inhibitor (U-0521, 55 mumol/l). Conversely, pretreatment of the tissue with 2OHE2 prevented the augmented aortic contraction to (-)-adrenaline usually seen after inhibition of COMT. The non-additive nature of the sensitization seen after combined treatment with 2OHE2 and U-0521 was qualitatively similar to that seen following combined exposure to maximally effective concentrations of U-0521 and an inhibitor of extraneuronal uptake (hydrocortisone 100 mumol/l). Oestradiol and 2MeOE2 reduced the formation of both the 3H-O-methylated, 3H-deaminated and the 3H-O-methylated deaminated metabolites of 3H-(-)-adrenaline (0.15 mumol/l) during exposure of the aorta to the tritiated catecholamine.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Methoxyestradiol↗
PubMed1993

Release and disposition of 3H-noradrenaline in the saphenous vein of neonate and adult dogs.

Release of 3H-noradrenaline and formation of 3H-metabolites were studied in the saphenous vein of newborn (mean age, 18 h) and adult dogs. Vein strips were incubated with 0.23 mumol/l of 3H-noradrenaline during 1 h and washed out for 110 min; thereafter, the perifusion fluid was collected in 5-min samples. Electrical stimulation was applied at 120 min (1 Hz, 2 ms, 100 V, for 5 min). In some experiments the tissues were preincubated with 1 mmol/l pargyline (to inhibit monoamine oxidase). In these experiments, 12 mumol/l cocaine (to inhibit uptake1), 41 mumol/l hydrocortisone (to reduce uptake2) and 50 mumol/l U-0521 (to inhibit COMT) were present during the perifusion. 3H-noradrenaline, 3H-DOPEG, 3H-NMN, 3H-DOMA and 3H-OMDA were separated by column chromatography. The noradrenaline content of the tissue was estimated by HPLC followed by electrochemical detection. A morphological study was also carried out by light and electron microscopy. The endogenous noradrenaline content of the saphenous vein was 4.3 times higher in adults than in neonates. The number of varicosities was similar in adults and newborns but the number of vesicles per varicosity profile was 5 times higher in adults. Hence, the endogenous noradrenaline content per vesicle was about the same in adults and newborns. The accumulation of 3H-noradrenaline per vesicle was about 5 times higher in newborns than in adults. On the other hand, the vein wall media of neonates was about 3 times thinner than that of adults. The evoked fractional release of tritium was about 10 times higher in neonates than in adults, whether the inactivation pathways were blocked or not.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1989

The uptake and metabolism of 3H-catecholamines in rat cerebral cortex slices.

The accumulation and metabolism of 3H-catecholamines were studied in cerebral cortex slices obtained from rats pretreated with reserpine, during 30 min of incubation with 50 nmol/l of the 3H-amines. In some experiments neuronal uptake (uptake1) was inhibited by the presence of 0.3 mumol/l desipramine, in others COMT was inhibited by 30 mumol/l U-0521. When both MAO and COMT were intact, most of the metabolism of 3H-noradrenaline was neuronal (i.e., desipramine-sensitive). For 3H-adrenaline rates of neuronal metabolism were much lower than for 3H-noradrenaline, non-neuronal O-methylation accounting for about 50% of total metabolism. Rates of metabolism of 3H-dopamine were similar to those of 3H-noradrenaline, but with a predominance of non-neuronal metabolism, which involved O-methylation and deamination. - Under these conditions, very little 3H-catecholamine was recovered from the tissues; moreover, desipramine tended to increase tissue levels. Hence, tissue content then appears to partly reflect extracellularly distributed 3H-amines. After block of MAO rates of metabolism of 3H-noradrenaline and 3H-dopamine were greatly reduced, and tissue levels were increased. Desipramine now antagonized the accumulation of 3H-amines in the tissue, while U-0521 increased it. Rates of O-methylation (in the presence of desipramine) increased in the order 3H-noradrenaline less than 3H-dopamine. It is concluded that neuronal uptake is associated with MAO only, and rates of neuronal deamination increased in the order: 3H-adrenaline less than 3H-dopamine much less than 3H-noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Antagonism of the behavioral effects of cocaine and d-amphetamine by prazosin.

Key pecking by pigeons was maintained under a 30-response fixed-ratio schedule of food delivery; lever pressing by squirrel monkeys was maintained under a 3-min fixed-interval schedule of food delivery. Administered alone, d-amphetamine (0.1-3.0 mg/kg), cocaine (1.0-3.0 mg/kg) and bupropion (1.0-30 mg/kg) either did not affect or decreased fixed-ratio responding of pigeons, whereas d-amphetamine (0.056-0.3 mg/kg) either increased or decreased (0.56 mg/kg) responding of monkeys maintained under the fixed-interval schedule. Prazosin, a selective centrally-active alpha 1 antagonist, produced a dose-dependent reversal of the rate-decreasing effects of d-amphetamine and cocaine but not of bupropion on fixed-ratio responding in pigeons. Prazosin also reversed both the rate-increasing and rate-decreasing effects of d-amphetamine on fixed-interval responding of squirrel monkeys. In contrast, the non-selective alpha-antagonist phentolamine enhanced d-amphetamine-induced decreases in fixed-ratio responding. These findings suggest that the behavioral effects of d-amphetamine and cocaine are produced at least in part by activation of central alpha 1 receptors. Prazosin may be a useful tool for better understanding the mechanisms through which cocaine, amphetamine, and other abused stimulant drugs exert their potent behavioral effects.

Animals↗
PubMed1986

Lithium and bupropion antagonise the phasic changes in locomotor activity caused by dopamine infused into the rat nucleus accumbens.

Dopamine infused persistently (25 micrograms/24 h for 13 days) into the nucleus accumbens of rat brain caused phasic increases in spontaneous locomotor activity during the period of infusion. This phasic responding was prevented by lithium administered throughout the infusion period in divided doses (3 X daily administrations of 2.5 mg/kg IP) or as a continuous IP infusion (7.5 mg/kg/24 h), and by bupropion treatment (5-20 mg/kg 3 X daily). In contrast, imipramine, amitriptyline and nomifensine failed to prevent the phasic locomotor response to dopamine at doses which did not by themselves cause marked motor changes. Locomotor activity was measured using individual photocell cages, and rats preselected to (-)NPA were those initially showing a modest locomotor activity. Fourteen to twenty-eight days after discontinuing the dopamine infusion rats showed increased responsiveness to (-)NPA which persisted throughout the remainder of the 70-day withdrawal period. This long-term change was prevented when lithium was given continuously throughout the period of dopamine infusion, but not when lithium was given in divided doses, showing the importance of the mode of drug delivery. The long-term change caused by the dopamine infusion could also be prevented by bupropion but not by imipramine, amitriptyline or nomifensine to show again that the actions of classical antidepressant drugs may be differentiated from those of lithium and bupropion. Therefore, it is suggested that the model of phasic hyperactivity described may provide a means for more closely analysing, both behaviourally and biochemically, the site and mechanism of action of lithium (and bupropion) in the control of the short- and long-term consequences of an enhanced mesolimbic dopamine activity.

Amitriptyline↗
PubMed1979

[Concentrations of cytostatic drugs in organs and tumors: comparison after intravenous and intratumoral injection (author's transl)].

The cytostatic drugs Chlorambucil and Bleomycin were labeled with 131I and with 57Co, respectively: Ruthenocenealdehyde-(N-methyl-N-beta-chlorethyl)-hydrazone and Ruthenocene-3-phenyl-prop.1-en-3-one were labeled with the gamma emitter 103Ru. In tumor-bearing mice the elimination and organ distribution of these radioactive substances were tested after intravenous (i.v.) and intratumoral (i.t.) injection of the drugs. The organ load showed lower values after i.t. than after i.v. application, while the radioactivity concentrations in the tumor were considerably increased after i.t. injection. The integrals of the concentration-time curves showed 10--80 times higher concentrations in the tumor after i.t. compared to i.v. injection of the drugs.

Animals↗
PubMed1985

Characterization of the bupropion cue in the rat: lack of evidence for a dopaminergic mechanism.

Using a two-lever operant task rats were trained to discriminate 40 mg/kg IP of bupropion from saline. Despite bupropion's established dopaminergic activity in vitro and in vivo, it was found that the bupropion cue was neither mimicked by the dopaminergic drugs L-DOPA and bromocriptine nor blocked by a variety of neuroleptics (haloperidol, thioridazine, and thiothixene). In addition, bupropion was active in attenuating the behavior-suppressing effects of haloperidol, unlike amphetamine and the atypical antidepressants, nomifensine and viloxazine. The bupropion cue was not mimicked or disrupted by adrenergic or serotonergic drugs, but it did generalize to some stimulants (amphetamine, cocaine and caffeine) as well as to nomifensine and viloxazine. The generalizations were blocked by neuroleptics. These data indicate that bupropion's cue properties may not be based on its ability to modulate dopaminergic receptor activity. The possible involvement of phenylethylamine in the bupropion cue is also discussed.

Animals↗
PubMed1985

Behavioral screen for antidepressants: the effects of drugs and electroconvulsive shock on performance under a differential-reinforcement-of-low-rate schedule.

Those antidepressant drugs that are in wide clinical use decrease response rate and increase reinforcement rate when administered to rats performing on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Drugs that are not antidepressants do not have this effect. In this experiment, the following were examined for their effects on a DRL 72-s schedule: trazodone, zimelidine, fluoxetine, and bupropion (atypical antidepressants); electroconvulsive shock (ECS, which is an effective treatment for depression); and haloperidol and clozapine (antipsychotic drugs). Trazodone (3.12-25.00 mg/kg), fluoxetine (10-20 mg/kg), and ECS decreased response rate and increased reinforcement rate. Zimelidine (20 mg/kg) increased reinforcement rate and nonsignificantly decreased response rate. At doses between 2.5 and 40 mg/kg, bupropion had no effect on reinforcement rate or response rate, but at 60 mg/kg response rate was increased and reinforcement rate was nonsignificantly decreased. At the higher dose, the effects of bupropion resemble those of a psychomotor stimulant. Haloperidol (0.04 mg/kg) and clozapine (2.5-10.0 mg/kg) decreased response rate and reinforcement rate. These results suggest that the DRL 72-s schedule may be useful for testing the antidepressant potential of new drugs.

Animals↗
PubMed1980

Stimulus properties of antidepressants in the rat.

Various doses of bupropion HCl (Wellbatrin) (5, 10, and 20 mg/kg), a new phenylaminoketone antidepressant, were employed as cues in a two-lever operant discrimination from saline control injections in rats on an FR10 schedule of food reinforcement. Subjects reached and maintained a high level of discrimination in the O vs 20 mg/kg bupropion stimulus condition but not at the lower doses. In generalization testing, the following compounds produced dose-related responding on the bupropion lever: viloxazine, nomifensine, caffeine, d-amphetamine, cocaine, methylphenidate, and benzylpiperazine. Drugs that failed to show dose-related generalization included phenethylamine, thyrotropin-releasing hormone, imipramine, nortriptyline, amitriptyline, desipramine, mianserin, chlordiazepoxide, diazepam, scopolamine, phenobarbital, and morphine. With the important exception of viloxazine, the generalization profile of bupropion seems to reflect its previously reported locomotor stimulant effects in the rat rather than its antidepressant activity and suggests that species differences exist between man and rat with regard to the pharmacologic activity of this new antidepressant.

Animals↗
PubMed1983

Comparative efficacy and safety of bupropion and placebo in the treatment of depression.

This was a 4-week, three-center, double-blind, randomized, parallel, placebo-controlled evaluation of the efficacy and safety of bupropion in hospitalized depressed patients. Results from 27 placebo and 48 bupropion-treated patients were analyzed for efficacy and safety. Assessments of efficacy and safety were made at baseline and weekly during the study. Preliminary and secondary measures of efficacy included the Clinical Global Impressions for severity (CGI-S) and improvement (CGI-I) of illness, Hamilton Depression and Hamilton Anxiety Scales, and the Zung Self-Rating Scales for depression and anxiety. Assessments of safety included vital signs, electrocardiogram, clinical laboratory tests, and adverse experiences. Dosages of bupropion were 300-600 mg/day. Results showed that bupropion was significantly (P less than 0.01) more effective than placebo at termination of study on the CGI-S, CGI-I, Hamilton Depression and Hamilton Anxiety Scales. On the Zung Self-Rating Depression and Anxiety Scales, statistical trends favored bupropion at termination of study over placebo (P less than 0.10). Adverse events in the bupropion and placebo groups were minimal with notable absence of sedation and anticholinergic- and cardiovascular-related side effects. We conclude that bupropion was significantly more effective than placebo in treating depression and accompanying anxiety in depressed inpatients.

Adult↗
PubMed1982

Effects of dopamine uptake inhibitors on schedule-controlled behavior in the squirrel monkey.

Squirrel monkeys responded under a multiple fixed-interval (FI) fixed-ratio (FR) schedule of stimulus-shock termination. Benztropine mesylate (0.03-1.7 mg/kg), bupropion HCl (0.3-5.6 mg/kg), mazindol (0.01-0.3 mg/kg), and nomifensine maleate (0.1-1.0 mg/kg) markedly increased responding under the FI schedule, but not under the FR schedule. Mazindol was about three-times more potent than nomifensine and ten-times more potent than bupropion. Benztropine and mazindol were about equal in potency. The order and relative magnitude of potency differences for mazindol, nomifensine, and bupropion are similar to those reported by others for in vitro inhibition of dopamine uptake in rat striatum, but the relative potency of benztropine was greater in these behavioral experiments than expected from its potency in inhibiting dopamine uptake.

Animals↗
PubMed1983

A comparison of bupropion, dextroamphetamine, and placebo in mixed-substance abusers.

The subjective, behavioral, and physiological effects of bupropion, a nontricyclic antidepressant, were compared with those of dextroamphetamine and placebo in a randomized double-blind crossover study. The volunteers who participated were multiple-drug abusers. Six acute drug treatments, three doses of bupropion (100, 200, 400 mg), two doses of dextroamphetamine (15, 30 mg), and placebo were administered orally at intervals of not less than 72 h. Results indicated that the subjective effects of amphetamine as measured by the Addiction Research Center Inventory (ARCI) differed markedly from bupropion and placebo. Bupropion, in contrast to amphetamine, had no peripheral sympathomimetic effects and did not reduce appetite or caloric intake.

Adult↗