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Biomedical subjects

J F Contrera

Publications and source records attributed to J F Contrera.

12 recordsLinked to original sources
PubMed1991

Comparison of the effects of repeated oral versus subcutaneous fenfluramine administration on rat brain monoamine neurons: pharmacokinetic and dose-response data.

The importance of the route of drug administration (oral vs. subcutaneous) on the neurochemical effects and pharmacokinetics of repeated d,1-fenfluramine administration in rats (1-24 mg/kg b.i.d., i.e., 2-48 mg/kg/day for 4 days) was examined. Overall, comparable dose-dependent alterations in brain monoamine markers were observed following repeated oral (PO) and subcutaneous (SC) administration of fenfluramine. Doses of 1 and 2 mg/kg fenfluramine were without significant effects on the density of 3H-paroxetine-labeled serotonin (5-HT) uptake sites. Higher doses of fenfluramine (4, 12 and 24 mg/kg) produced dose-dependent decreases in 5-HT, 5-hydroxyindoleacetic acid and 5-HT uptake sites with maximal decreases (80-90%) occurring at the 12 mg/kg dose. Fenfluramine administration produced dose-dependent and biphasic effects on brain dopamine markers with increases in homovanillic acid (HVA) observed at 2 hours, whereas decreases in the levels of dopamine, HVA and dihydroxyphenylacetic acid were evident at 18 hours posttreatment. Norepinephrine levels were only decreased at the highest dose of fenfluramine. Significantly higher levels of brain fenfluramine were observed following SC than following PO administration of the drug. On the other hand, comparable levels of its active metabolite norfenfluramine were present in the brain following the two routes of fenfluramine administration. These data suggest the importance of norfenfluramine levels in the brain in determining the high-dose neurotoxic effects of fenfluramine on brain 5-HT neurons in rats.

Administration, Oral↗
PubMed1991

Role for brain corticotropin-releasing factor in the weight-reducing effects of chronic fenfluramine treatment in rats.

Fenfluramine is an amphetamine derivative which is used as a weight-reducing agent in the treatment of obesity. It has been postulated that fenfluramine affects brain serotonin (5HT) neurons resulting in decreased food intake and altered autonomic outflow which, in turn, increases metabolism. CRF decreases food intake and, in addition, has been demonstrated to reduce body weight in genetically obese rats through selective activation of sympathetic and inhibition of parasympathetic outflows. Because 5HT is a potent CRF secretagogue, we tested the hypothesis that the weight-reducing effects of fenfluramine administration may be mediated, in part, through altered CRF secretion. Chronic fenfluramine treatment (1-24 mg/kg sc, twice daily, 4 days) resulted in a dose-dependent decrease in hypothalamic CRF concentration at 30 min after the final drug injection and was accompanied by a significant reciprocal increase in plasma corticosterone concentration. These data suggest that the decrease in hypothalamic CRF was a consequence of increased CRF secretion. These changes in hypothalamic CRF and plasma corticosterone correlated with brain fenfluramine levels. In contrast, high dose fenfluramine treatment significantly increased hippocampus, midbrain, and spinal cord CRF concentrations whereas levels in cerebral cortex, caudate putamen, thalamus, pons/medulla, and cerebellum were unaffected. There was no effect of this fenfluramine treatment protocol on regional brain TRH or neurotensin concentrations. In keeping with the well known development of tolerance to the weight-reducing effects of fenfluramine, chronic fenfluramine treatment resulted in lesser increases in corticosterone secretion than after acute treatment. Whereas weight loss observed after chronic fenfluramine treatment was associated with stimulation of hypothalamic-pituitary-adrenocortical hormone secretion, the weight-recovery phase after cessation of drug treatment was associated with decreased levels of plasma corticosterone. These data, demonstrating fenfluramine-induced alterations in brain CRF and plasma corticosterone, suggest that CRF may represent an important endogenous transmitter which mediates the weight-reducing effects of the drug.

Adrenocorticotropic Hormone↗
PubMed1990

Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography.

Fenfluramine is an amphetamine derivative that in humans is used primarily as an anorectic agent in the treatment of obesity. In rats, subchronic high-dose d,l-fenfluramine treatment (24 mg/kg subcutaneously, twice daily for 4 days) causes long-lasting decreases in brain serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid, and high-affinity 5HT uptake sites. Moreover, this high-dose treatment regimen causes both selective long-lasting decreases in fine-caliber 5HT-immunoreactive axons and appearance of other 5HT-immunoreactive axons with morphology characteristic of degenerating axons. Determination of the potential neurotoxic effects of fenfluramine treatment using immunohistochemistry is limited from the perspectives that staining is difficult to quantify and that it relies on presence of the antigen (in this case 5HT), and the 5HT-depleting effects of fenfluramine are well known. In the present study, we used quantitative in vitro autoradiography to assess, in detail, the density and regional distribution of [3H]paroxetine-labeled 5HT and [3H]mazindol-labeled catecholamine uptake sites in response to the high-dose fenfluramine treatment described above. Because monoamine uptake sites are concentrated on monoamine-containing nerve terminals, decreases in uptake site density would provide a quantitative assessment of potential neurotoxicity resulting from this fenfluramine treatment regimen. Marked decreases in densities of [3H]paroxetine-labeled 5HT uptake sites occurred in brain regions in which fenfluramine treatment decreased the density of 5HT-like immunostaining when compared to saline-treated control rats. These included cerebral cortex, caudate putamen, hippocampus, thalamus, and medial hypothalamus. Smaller, but nonetheless significant, decreases in density of [3H]paroxetine-labeled 5HT uptake sites were noted in brain regions in which partial sparing of 5HT-like immunoreactive fibers had been reported following fenfluramine treatment, specifically septum, lateral hypothalamus, and amygdala. In contrast, [3H]mazindol autoradiography revealed that total catecholamine (i.e., dopamine and norepinephrine) uptake sites in cerebral cortex, caudate putamen, and locus coeruleus, areas in which [3H]paroxetine-labeled 5HT uptake sites were significantly decreased, were unaffected by this fenfluramine treatment. These data support the hypothesis that subchronic, high-dose fenfluramine treatment causes selective degeneration of 5HT axons in rat brain. Since pharmacokinetic studies show that the dosing regimen used in this study exposes rat brain to concentrations of fenfluramine that are approximately 600 times greater than those resulting from the therapeutic oral dose, caution must be exercised in extrapolating these data to humans.

Animals↗
PubMed1990

Effects of repeated fenfluramine administration on indices of monoamine function in rat brain: pharmacokinetic, dose response, regional specificity and time course data.

The pharmacokinetics and neurochemical effects of repeated fenfluramine administration in rats (1-24 mg/kg s.c., b.i.d. for 4 days) were examined with respect to dose dependence, regional specificity and time course of recovery. Fenfluramine administration resulted in parallel increases in plasma and brain concentrations of the drug and its metabolite, norfenfluramine, which were dose-related but nonlinear. Doses of 1 and 2 mg/kg fenfluramine increased brain serotonin (5-HT) and 5-hydroxyindoleacetic acid with no significant effects on 5-HT uptake sites. Higher doses of fenfluramine (4-24 mg/kg) reduced all three brain 5-HT markers with maximal decreases (80%-90%) occurring at 12 mg/kg. High-dose (24 mg/kg) fenfluramine administration led to larger decreases in 5-HT markers in neocortex, striatum and hippocampus than in hypothalamus, brain stem and spinal cord. Following 80% to 90% reductions of the 5-HT markers in neocortex and hippocampus at 18 hr after drug treatment, 5-HT and 5-hydroxyindoleacetic acid returned to control levels by 4 and 16 weeks, respectively, but 5-HT uptake sites initially recovered more slowly, with a 25% reduction still evident at 8 months. At this time 5-HT and 5-hydroxyindoleacetic acid were again reduced. Fenfluramine administration produced dose-dependent and biphasic effects on brain dopamine markers. Increases in homovanillic acid levels were apparent at 2 hr, whereas decreases in the levels of dopamine, homovanillic acid and dihydroxyphenylacetic acid were evident at 18 hr post-treatment. Norepinephrine levels were only decreased by doses of fenfluramine greater than or equal to 4 mg/kg. Fenfluramine administration did not cause long-term alterations in dopamine or norepinephrine uptake sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine.

Methylphenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.

Animals↗
PubMed1989

Fenfluramine selectively and differentially decreases the density of serotonergic nerve terminals in rat brain: evidence from immunocytochemical studies.

Fenfluramine is an amphetamine derivative which is used primarily as an anorectic agent in the treatment of obesity. High doses of fenfluramine have been reported to cause long-term decreases in brain serotonin (5-HT) levels and density of high-affinity 5-HT uptake sites, actions characteristic of a "neurotoxic" effect of the drug. In view of these neurochemical changes, we used immunocytochemistry to assess, in detail, the effects of fenfluramine treatment on the morphology and density of 5-HT-like immunoreactive neurons in rat brain. Twelve to 18 hr after high dose dl-fenfluramine HCl treatment (24 mg/kg s.c., twice daily for 4 days), there was a profound regional decrease in density of fine-caliber 5-HT-like immunoreactive fibers and terminals in brain. This effect was especially apparent in cerebral cortex, hippocampus, cerebellum and striatum and less striking decreases were noted in septum, locus ceruleus and hypothalamus. On the other hand, 5-HT-like immunoreactive somata in midbrain nuclei and fibers and terminals in spinal cord appeared unaffected after fenfluramine treatment. Remaining 5-HT-like immunoreactive fibers and terminals displayed morphology characteristic of degenerating axons (thickening, swollen varicosities and fragmentation). Two weeks after the 4-day treatment regimen, patterns of 5-HT-like immunostaining appeared similar to those noted immediately (i.e., 18 hr) after drug treatment; however, the presence of grossly deformed fibers and terminals seen shortly after drug treatment was lacking. Tyrosine hydroxylase-like immunoreactivity, used to assess changes in catecholamine-containing neurons, appeared unaffected by drug treatment. These data suggest that, in rats, high s.c. doses of fenfluramine may be neurotoxic to some 5-HT-like immunoreactive axons and terminals. The relevance of these observations to the continued therapeutic use in humans of smaller p.o. doses of fenfluramine remains to be determined.

Animals↗
PubMed1978

Altered state of cardiac sympathetic nerves during immunologically induced anemia.

Cardiac norepinephrine (NE) levels exhibit a marked reduction in rats suffering from hemolytic anemia induced with antibodies against rat red blood cells. Administration of antiserum via tail vein resulted in a highly reproducible 70% drop in hemoglobin levels by 72 h. At 96 h cardiac NE levels were decreased by 67%; NE levels in vas deferens and submaxillary gland were not decreased. Within 10 days, both hemoglobin and cardia NE returned to near control levels. Hearts from anemic rats showed a 68% decrease in their ability to accumulate 3H-NE administered in tracer doses at 72 h of anemia. Cardiac NE turnover rates were increased 88% in 72 h anemic animals. These results are consistent with an anemia-induced activation of cardiac sympathetic nerves. Cardiac monoamine oxidase and dopamine-beta-hydroxylase activities in whole heart homogenates were similar in control and anemic animals at 72 h. These results suggest that NE depletion is not the result of decreased synthetic capacity of the nerves or degeneration of existing terminals. The data suggest that cardiac NE depletion during anemic stress is associated with the combined effects of increased NE release and a decrease in the effective NE uptake or binding capacity of sympathetic nerves. Anemia-induced depletion may, therefore, be different from the depletion associated with other forms of cardiovascular stress.

Anemia↗
PubMed1976

Intraventricular 6-hydroxydopamine lowers isolation-induced fighting behavior in male mice.

Male mice with high isolation-induced fighting tendencies were administered 200 mug 6-OHDA or vehicle intraventricularly and tested for fighting tendency for up to 10 weeks until sacrifice, and assayed for brain NE levels. A strong correlation was found between NE depletion and reduced fighting tendency after 6-OHDA treatment. The depressed fighting by mice with less than 200 ng. NE/g persisted throughout a series of test fights, indicating no recovery in fighting behavior throughout the survival time.

Aggression↗
PubMed1976

Depletion of cardiac norepinephrine during two forms of hemolytic anemia in the rat.

Knowledge of the status of cardiac norepinephrine (NE) during anemia could lead to a better understanding of the role the sympathetic nervous system plays in cardiac function during anemia. Rats were made anemic by treatment with phenylhydrazine (PHZ). After the rapid onset of anemia, 60% of the stored NE in the heart was lost within 48 hours after treatment. Associated with the loss of cardiac NE was an increase in the wet weight of the heart, which reached a value 40% above control 48 hours after treatment. PHZ itself probably does not directly mediate this depletion of NE, since the vas deferens, brain and spleen had a normal store of NE at 48 hours. This contention was supported when rats, treated with PHZ, were transfused with normal rat red blood cells. This transfusion resulted in PHZ-treated rats which were not anemic. The hearts of these rats were not depleted of NE, but the hearts of the nontransfused, PHZ-treated controls were. Anemia also was induced by treating rats with anti-rat red blood cell serum. The hearts of these rats also were depleted of NE. These experiments show that during two forms of anemia there is a loss of NE from the sympathetic neurons innervating the heart. The effect of this on regulation of cardiac function remains to be determined.

Anemia, Hemolytic↗