Biomedical subjects

G Vosmer

Publications and source records attributed to G Vosmer.

At least 19 recordsLinked to original sources

PubMed2000

Rats selectively bred for responsiveness to 5-hydroxytryptamine(1A) receptor stimulation: differences in differential reinforcement of low rate 72-second performance and response to serotonergic drugs.

High (+/-)-8-hydroxy-dipropylaminotetralin HBr (8-OH-DPAT)-sensitive (HDS) rats and low 8-OH-DPAT-sensitive (LDS) rats were selectively bred for differences in sensitivity to the hypothermic effect of the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist 8-OH-DPAT in 30 to 35-day-old rat pups. These rats were trained on the differential reinforcement of low rate 72-s operant schedule. On this schedule, LDS rats had a higher response rate and a lower reinforcement rate than HDS rats. Drugs with primary action on the 5-HT system, 8-OH-DPAT, ketanserin, and fluoxetine, decreased response rate of HDS and LDS rats but increased the reinforcement rate of only the LDS rats. However, a drug with primary action on the norepinephrine system, desipramine, decreased response rate and increased reinforcement rate of HDS and LDS rats, suggesting that norepinephrine function was similar in the two lines of rats. The finding with desipramine indicates that increases in reinforcers on the differential reinforcement of low rate 72-s task are not simply dependent on baseline response or reinforcement rate. We also observed that 8-OH-DPAT engenders a greater hypothermic response in adult (90-day-old) HDS rats than in adult LDS rats. The 5-HT(1A) receptor antagonist WAY-100635 antagonized the hypothermic response. Tissue levels of 8-OH-DPAT from several brain regions in LDS and HDS rats did not differ from each other at either 15- or 30-min postinjection. Because the LDS and HDS rats have different responses to 5-HT-acting drugs, these rats may be useful for studying the role of the serotonergic system in depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1997

Combined phentermine/fenfluramine administration enhances depletion of serotonin from central terminal fields.

Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.

Animals↗

PubMed1990

The effects of monoamine uptake inhibitors and methamphetamine on neostriatal 6-hydroxydopamine (6-OHDA) formation, short-term monoamine depletions and locomotor activity in the rat.

Monoamine uptake inhibitors block the neurotoxic effects of methamphetamine (MA) upon dopaminergic and serotonergic neurons in the rat. The neurotoxic effects of MA upon dopaminergic neurons have previously been suggested to be mediated via formation of 6-hydroxydopamine (6-OHDA) from endogenous stores of dopamine (DA). In the present experiments, administration of the DA uptake inhibitor amfonelic acid (AFA, 10 mg/kg, i.p.) did not block the formation of 6-OHDA in rats treated with a single s.c. 100 mg/kg dose of MA. Consistent with the lack of effect by AFA on MA-induced 6-OHDA formation, neither AFA (10 mg/kg, i.p.) nor the DA and 5-hydroxytryptamine (5-HT) uptake inhibitor mazindol (40 mg/kg i.p., MAZ) blocked the depletion seen in neostriatal DA levels 1, 2 or 8 h following administration of a single 100 mg/kg dose of MA. In fact, AFA enhanced the DA depletions 2 and 8 h following MA administration. AFA also enhanced the MA-induced increase in locomotor activity in rats and this effect was blocked by lesions of dopaminergic neurons with i.v.t. (intraventricular) 6-OHDA in desipramine-pretreated rats. These results suggest that DA uptake inhibitors do not prevent the neurotoxic effect of MA on DA neurons by either preventing entry of MA into the cell or blocking the efflux of DA out of the cell. Instead, the DA uptake inhibitors appear to prevent the neurotoxic effect of MA upon dopaminergic neurons by blocking entry of 6-OHDA into the cell.

Animals↗

PubMed1990

alpha-Methyl-p-tyrosine pretreatment partially prevents methamphetamine-induced endogenous neurotoxin formation.

Depletion of brain dopamine (DA) by pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMT) has been shown to prevent the long-term neurotoxic effects of methamphetamine (MA). In addition, it has recently been reported that the neurotoxins 6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT) are formed endogenously in neostriatum and hippocampus, respectively, following a single neurotoxic dose of MA. We, therefore, have examined the ability of AMT pretreatment to prevent the MA-induced formation of 6-OHDA and 5,6-DHT. We report that AMT pretreatment significantly decreases the frequency with which 6-OHDA and 5,6-DHT are detected following MA administration. Neurotoxin formation is compared with brain levels of DA and 5-hydroxytryptamine (5-HT) 2 weeks after MA administration. It is concluded that the ability of AMT to attenuate both 6-OHDA formation and long-term depletions of DA is due to a decrease in the MA-releasable pool of DA. The effect of AMT on MA-induced depletions of 5-HT is less clear and may involve additional factors.

5,6-Dihydroxytryptamine↗

PubMed1990

Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons.

A single large dose (100 mg/kg, s.c.) of methamphetamine (MA) is known to exert neurotoxic effects on dopaminergic neurons. The potency at which a series of dopamine (DA) uptake inhibitors blocked MA-induced neostriatal depletions (amfonelic acid (AFA) much greater than mazindol (MAZ) greater than or equal to bupropion (BUP) greater than benztropine (BENZ)) was similar to their potency at blocking 6-hydroxydopamine (6-OHDA) neurotoxicity in rats. Amfonelic acid was able to block long-term neostriatal DA depletions when given 8 h, but not 16 h, after a single large MA dose. These results suggest that an intact and functional DA uptake site is necessary for the development of MA-induced long-term DA depletions.

Animals↗

PubMed1990

Pargyline increases 6-hydroxydopamine levels in the neostriatum of methamphetamine-treated rats.

Neostriatal 6-hydroxydopamine (6-OHDA) was detected in 6 of 13 rats pretreated 2 or 4 hr earlier with methamphetamine (MA; 100 mg/kg, SC) and pargyline (25 mg/kg, IP, 30 min before MA injection). Neostriatal 6-OHDA was detected in 2 of 16 rats treated 2 or 4 hr earlier with MA. These results suggest that pargyline pretreatment may enhance formation of 6-OHDA from endogenous stores of dopamine (DA) following MA administration. Alternatively, these results suggest that pargyline pretreatment may protect endogenously formed 6-OHDA from oxidative deamination by monoamine oxidase. Enhancement of MA-induced neostriatal 6-OHDA levels may be the mechanism by which pargyline enhances the long-term neurotoxic effects of MA upon dopaminergic nerve terminals. These observations support the hypothesis that MA toxicity to DA-containing fibers is caused by the conversion of released DA into 6-OHDA.

Animals↗

PubMed1989

Variability among brain regions in the specificity of 6-hydroxydopamine (6-OHDA)-induced lesions.

6-Hydroxydopamine (6-OHDA; 200 micrograms, 150 micrograms or 110 micrograms) or vehicle was infused stereotaxically into the lateral ventricles of rats, usually following pretreatment with desmethylimipramine (DMI). Various brain regions were then assayed for dopamine (DA), serotonin (5-HT) and norepinephrine (NE). As expected, 6-OHDA depleted DA in all brain regions examined. Unexpectedly, however, the two highest doses of 6-OHDA significantly decreased 5-HT levels in the hippocampus and increased 5-HT levels in the striatum. In addition, despite pretreatment with doses of DMI commonly considered adequate to block 6-OHDA-induced depletion of NE, all doses of 6-OHDA tested significantly reduced NE levels in the hippocampus, hypothalamus and septum. We interpret our data as suggesting that some brain regions are susceptible to nonspecific toxic effects of 6-OHDA at doses commonly employed. Furthermore, these nonspecific effects may or may not occur, depending on seemingly minor variations in experimental technique.

Animals↗

PubMed1989

Long-term central 5-HT depletions resulting from repeated administration of MDMA enhances the effects of single administration of MDMA on schedule-controlled behavior of rats.

The behavioral effect of single administration of +/- 3,4-methylene-dioxymethamphetamine (MDMA) on rats performing on the differential-reinforcement-of-low-rate 72-second schedule (DRL 72-sec) was compared before and after a period of repeated administration of MDMA known to deplete 5-hydroxytryptamine (5-HT) levels in the brain. Single administration of MDMA decreased reinforcement rate (1, 2, 4, 6 mg/kg) and increased response rate (4,6 mg/kg) of rats performing on the DRL 72-sec schedule. This effect is typical of amphetamines and other psychomotor stimulants. Four weeks after repeated administration of MDMA (6 mg/kg twice daily for 4 days) there was an increase in sensitivity to the effect of single administration of MDMA. Doses of 2, 4 and 6 mg/kg of MDMA resulted in increases in response rate that were significantly greater after repeated MDMA administration than before. Doses of 0.5, 2, and 6 mg/kg of MDMA resulted in decreases of reinforcement rate that were significantly greater after repeated MDMA administration than before. Repeated administration of MDMA resulted in long-term depletion of serotonin levels by 30-50% in the amygdala, neostriatum, hippocampus and the frontal cortex. Norepinephrine and dopamine (DA) levels were not significantly different from control in any of the brain regions analyzed. The behavioral and neurochemical results suggest that serotonergic neurons normally exert an inhibitory action upon the psychomotor stimulant effects of MDMA. Since the psychomotor stimulant effects of amphetamines appear to be mediated primarily by the dopamine system, these results provide evidence that 5-HT and DA may represent opposing systems in the DRL schedule-controlled behavior.

3,4-Methylenedioxyamphetamine↗

PubMed1988

Neurotoxicity in dopamine and 5-hydroxytryptamine terminal fields: a regional analysis in nigrostriatal and mesolimbic projections.

In summary, we have shown that MA is toxic to both 5-HT and DA cells and we have proposed a mechanism that would account for this response, namely, the conversion of the transmitters to neurotoxins. In addition, brain depletions of DA seem regionally specific with larger depletions occurring in some areas than in others. The depletions, however, do not seem to depend entirely on the nuclei of origin, that is, substantia nigra versus VTA. 5-HT was depleted by different amounts in the various regions examined and the 5-HT depletions, although proportional to the DA depletions, were consistently greater. The reasons for this differential sensitivity of the 5-HT and DA systems to the toxic effect of MA is speculative, but may be related to the differential formation of toxins due to the differing availability of oxygen and superoxides at serotonergic and dopaminergic synapses.

Amphetamine↗

PubMed1987

Endogenously produced 5,6-dihydroxytryptamine may mediate the neurotoxic effects of para-chloroamphetamine.

Para-chloroamphetamine (PCA) has been used to deplete brain serotonin (5-HT) in numerous studies of serotonergic involvement in various behaviors and physiological functions. PCA is believed to cause long-lasting depletions of 5-HT by causing the selective degeneration of serotonergic nerve terminals, but the mechanism by which it exerts this neurotoxic effect is not understood. In this experiment, 5,6-dihydroxytryptamine (5,6-DHT), a serotonergic neurotoxin, was detected by high performance liquid chromatography in the rat hippocampus 0.5-4 h after a single 15 mg/kg i.p. injection of PCA. 5,6-DHT was also detected in the somatosensory cortex following PCA administration, but much less frequently than in the hippocampus. Degenerating nerve terminals were observed in the striatum and somatosensory cortex in silver-stained brain sections from rats injected with PCA 1 or 2 days prior to sacrifice. Laminae III and IV of the somatosensory cortex also contained degenerating neuronal perikarya. The neurochemical and histological effects of PCA are very similar to those produced by a large dose of methylamphetamine (MA) in that both drugs are toxic to serotonergic nerve terminals and neuronal perikarya in the somatosensory cortex. We hypothesize that the formation of 5,6-DHT, perhaps from endogenous 5-HT, may mediate the toxic effects of PCA, MA and other amphetamine-related drugs on serotonergic neurons and on a subpopulation of cortical neurons.

5,6-Dihydroxytryptamine↗

PubMed1987

5,6-Dihydroxytryptamine, a serotonergic neurotoxin, is formed endogenously in the rat brain.

Methamphetamine (MA) in high doses produces long-term toxic effects on the serotonergic system in the rat brain, including depletions of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid and reductions in 5-HT reuptake and tryptophan hydroxylase activity. In this study, the formation of 5,6-dihydroxytryptamine (5,6-DHT), a serotonergic neurotoxin, was observed in the rat hippocampus after a single 100 mg/kg injection of MA. The 5,6-DHT was detected by reverse-phase high-performance liquid chromatography with electrochemical detection in tissue samples taken 0.5-4 h after MA administration; the highest levels of 5,6-DHT (0.032 ng/mg wet tissue) were detected at 1 h. Following administration of MA, 5-HT was also depleted in the neocortex, but 5,6-DHT was not detected as frequently in this brain region as in the hippocampus. Comparisons were made between the long-term hippocampal 5-HT depletions seen either after an injection of MA or after intraventricular 5,6-DHT infusions and the levels of 5,6-DHT measured in the hippocampus shortly after each treatment. The amount of 5,6-DHT produced after MA administration appears to be adequate to cause the observed long-term 5-HT depletions. We suggest that 5,6-DHT formed from 5-HT may mediate the neurotoxic effects of MA on serotonergic nerve terminals.

5,6-Dihydroxytryptamine↗

PubMed1987

Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain.

(+/-)-3,4-Methylenedioxymethylamphetamine (MDMA) was administered s.c. to rats (10, 20 or 40 mg/kg b. wt.) and guinea pigs (20 mg/kg) twice a day for 4 days, 2 weeks before decapitation. Norepinephrine, dopamine and serotonin (5-HT) levels were assayed in the hippocampus, hypothalamus, striatum and neocortex. In rats, MDMA produced dose-dependent reductions in 5-HT in all brain regions examined. The highest dose also reduced norepinephrine and/or dopamine in some regions. The 20-mg/kg dose of MDMA depleted 5-HT in all regions of the guinea pig brain assayed. In both species, repeated administration of 20 mg/kg of MDMA reduced the Vmax but not the Km of 5-HT uptake 2 weeks after administration. A single 40-mg/kg injection of MDMA depleted 5-HT 2 and 8 weeks after administration to rats in all regions of the brain examined except the hypothalamus. Administration of 80 mg/kg of MDMA twice a day for 2 days to rats depleted striatal 5-HT and dopamine. Brain sections from rats injected with MDMA according to this dosage regimen were stained by the Fink-Heimer method. Degenerating axon terminals and cell bodies were observed in the striatum and somatosensory cortex, respectively. These findings suggest that MDMA is toxic to serotonergic and, to a lesser extent, catecholaminergic neurons. Some neurons that do not contain these transmitters (neocortical neurons) are also affected.

3,4-Methylenedioxyamphetamine↗

PubMed1985

The effect of water-deprivation on locomotor activity in rats treated with 6-hydroxydopamine.

Male albino rats treated with 6-hydroxydopamine (6-OHDA) became more hyperactive than did vehicle-treated controls when both groups were water-deprived. Rats were treated with vehicle, 150 or 250 micrograms of 6-OHDA intraventricularly, after pretreatment with desmethylimpramine (25 mg/kg) and pargyline (50 mg/kg). Eleven days after these treatments, under ad libitum water conditions, the 6-OHDA-treated rats were slightly hypoactive. After several days of water-deprivation all three groups showed increased mean locomotor activity levels, but rats treated with 6-OHDA showed a much greater increase than did vehicle-treated rats. Under subsequent ad libitum and deprivation conditions, locomotor activity decreased and increased, respectively, in all 3 groups. Again, the changes in activity levels of the 6-OHDA-treated groups were greater than those of the vehicle-treated group. In addition, rats treated with 250 micrograms 6-OHDA seemed to become sensitized to the novel environment of the stabilimeter rather than habituating to it. Dopamine (DA) levels were decreased as a result of the injections of 6-OHDA, and significant correlations were found between DA levels in the caudate-putamen and nucleus accumbens, and locomotor activity levels. These results, as well as those obtained by others, suggest that there is an interaction among DA levels, deprivational states, and locomotor activity levels in rats.

Animals↗

PubMed1985

Determination of dopamine, norepinephrine, serotonin and their major metabolic products in rat brain by reverse-phase ion-pair high performance liquid chromatography with electrochemical detection.

A method is described for the separation and quantitation of catecholamines, serotonin, and their major metabolites with use of reverse-phase, ion-pair liquid chromatography with electrochemical detection. This method employs columns packed with a microparticulate C-18 resin, octyl sodium sulfate as the ion-pairing agent, and isocratic elution with a citrate-phosphate buffer containing methanol. Conditions are described for the separation of norepinephrine, normetanephrine, 3-methoxy-4-hydroxyphenylglycol, epinephrine, metanephrine, dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindole-3-acetic acid and for their quantitation in extracts of rat brain tissue.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Increased transport of 3,4-dihydroxyphenylacetic acid from brain during performance of operant behavior in the rat.

Although the performance of positively reinforced operant behavior is accompanied by increased turnover of brain dopamine in the rat, the accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC), the major metabolic product of dopamine in brain, is not increased during operant performance. The hypothesis that the lack of increased DOPAC accumulation stems from an increase in the rate at which DOPAC is eliminated from the brain was tested by measuring the relative rate of DOPAC transport from brain in rats performing operant behavior and in control rats. The transport of DOPAC was estimated following inhibition of monoamine oxidase with pargyline. The pargyline-induced depletions of DOPAC in the caudate putamen and amygdala were significantly greater in rats that performed operant behavior than in control rats. In the caudate putamen, the concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were also depleted by pargyline to a greater extent in operant performing rats than in controls. These results suggest that in addition to the increased turnover of dopamine in central neurons during operant behavior, the rate of elimination of acidic amine metabolites from brain is also accelerated.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Time-dependent changes in hypothalamic dopamine metabolism during feeding in the rat.

The accumulation of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), but not the serotonin metabolite 5-hydroxyindoleacetic acid, in the hypothalamus is increased in rats during the second, third and fourth hours of a four hour period of access to food following a 20 hour period of food deprivation. This metabolic change does not correlate with duration of access to food or with amount of food consumed. These results suggest that increased hypothalamic dopamine metabolism during feeding is not related in any simple way to either the onset or termination of feeding.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Formation of 6-hydroxydopamine in caudate nucleus of the rat brain after a single large dose of methylamphetamine.

We now report that 6-hydroxydopamine (0.39 +/- 0.31 nanograms/mg of tissue at 2 hr) is formed in the rat caudate nucleus after a single injection of methylamphetamine (100 mg/kg). The same dose of methylamphetamine causes approximately 50% depletion of caudate dopamine 2 weeks after the injection. We suggest that the formation of 6-hydroxydopamine from endogenous dopamine is responsible for the neurotoxicity to dopamine terminals seen after methylamphetamine administration.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1981

Noncompetitive amine uptake inhibition by the new antidepressant pridefine.

Pridefine (AHR-1118) is a pyrrolidine derivative with clinically established antidepressant efficacy. Previous work from this laboratory indicates that pridefine is a reuptake blocker of catecholamines and serotonin with weak releasing activity. This study characterized the mode of amine uptake inhibition by pridefine as noncompetitive. The uptake experiments were performed utilizing ouabain instead of zero-degree controls to differentiate between the passive and active components of uptake. Furthermore, the passive component was resolved into diffusion and binding of substrate. Correction was made for the effects of ouabain on binding. Kinetic constants determined from Lineweaver-Burk plots were: Km = 3 X 10(-7) M for NE, Km = 9 X 10(-8) M for DA, and Km = 3 X 10(-8) M for 5-HT. Dixon analyses of uptake at various pridefine concentrations indicated noncompetitive inhibition with Ki = 2.5 X 10(-6) M for NE uptake, Ki = 2.0 X 10(-6) M for DA uptake, and Ki = 1 X 10(-5) M for 5-HT uptake. These constants compare well IC50 values for the same transmitters: NE, IC50 = 2.4 X 10(-6) M; DA, IC50 = 2.8 X 10(-6) M; 5-HT, IC50 = 1.0 X 10(-5) M. The in vitro results indicate that pridefine is relatively specific as a catecholamine uptake blocker. It differs from tricyclic antidepressants which are reportedly competitive inhibitors of monoamine uptake. The possible mechanisms by which pridefine acts as a noncompetitive inhibitor are discussed.

Animals↗