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J D Fernstrom

Publications and source records attributed to J D Fernstrom.

At least 19 recordsLinked to original sources
PubMed1992

Effects of cysteamine administration on somatostatin biosynthesis and levels in rat hypothalamus.

A single injection of cysteamine (CSH; 2-aminoethanethiol; 300 mg/kg, sc) into male rats produced a rapid decline in immunoreactive somatostatin (IR-SRIF) levels in the hypothalamus (to 20% of preinjection values within 12 h) which persisted for several days. The levels of both somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28) were reduced. In contrast, the levels of somatostatin-28(1-12) were unaffected. Most (80-90%) of the lost SRIF molecules (both SRIF-14 and SRIF-28) could be recovered from CSH-injected rats by subjecting hypothalamic samples to denaturing, reducing, and reoxidizing conditions. These results suggest that CSH does not deplete the hypothalamus of SRIF molecules, but, instead, alters their chemical structures, rendering them undetectable using a SRIF-14-directed RIA. CSH injection also caused a rapid and complete suppression (within 1 h) of [35S]cysteine incorporation into SRIF-14 and SRIF-28. This reduction, however, was short-lived; normal incorporation rates returned within 10 h of drug administration. CSH did not influence [35S] cysteine incorporation into acid-precipitable protein or [35S]cysteine specific activity in the hypothalamus. In addition, [35S]SRIF molecules were not recovered from hypothalami of CSH-treated rats by subjecting samples to denaturing, reducing, and then reoxidizing conditions. These findings indicate that CSH injection causes a true, but short-lived (1- to 10-h), suppression of hypothalamic SRIF-14 and SRIF-28 formation. Finally, biosynthesis studies of longer duration revealed no prolonged effects of CSH. The drug produced no changes 4, 24, or 72 h postinjection in hypothalamic levels of the prepro-SRIF mRNA. Moreover, two injections of CSH, separated by 3 days, which continuously suppressed IR-SRIF levels for almost 1 week, caused only a transient suppression of [35S]SRIF-14 and [35S]SRIF-28 synthesis after each injection. These results indicate that the SRIF biosynthetic pathway is not activated by the prolonged CSH-induced depletion of IR-SRIF stores.

Animals↗
PubMed1991

A comparative analysis of the distribution of prosomatostatin-derived peptides in human and monkey neocortex.

Comparative analyses were made of the immunohistochemical and biochemical distributions of three prosomatostatin-derived peptides (PSDP) in human, perfused monkey, and unperfused monkey neocortex. The PSDP we examined were the tetradecapeptide somatostatin 14 (SS14); the N-terminal extension of this peptide, somatostatin 28 (SS28); and somatostatin 28(1-12) (SS28(1-12)). In immunohistochemical experiments, numerous SS28-immunoreactive perikarya were located in both superficial and deep layers of perfused monkey cortex, but none were present in the cerebral cortex from unperfused monkey or autopsied human brains. In contrast, the number of SS28(1-12)-immunoreactive neurons was five times greater in the superficial cortical layers of unperfused monkey than of perfused monkey brain. Moreover, unperfused monkey and human cortex contained notably more SS14-immunoreactive processes than perfused monkey cortex. These data suggested that SS28 may have been converted into SS14 and SS28(1-12) in unperfused tissue during the post-mortem interval. This hypothesis was examined biochemically by measuring the levels of immunoreactivity of SS14, SS28, and SS28(1-12) in samples of unperfused monkey cortex frozen at different time intervals after removal from the brain. Samples frozen 10 minutes or longer after removal contained only 10-20% the level of SS28 immunoreactivity measured in samples frozen immediately or 1 minute after removal. The levels of SS14 and SS28(1-12) immunoreactivity did not demonstrate such reductions, and may instead have increased at early time points. To further characterize post-mortem effects on PSDP and to explore for species differences, we performed a detailed comparison of the regional, laminar, and cellular distribution of SS28(1-12) immunoreactivity under the three conditions. A progressive loss of immunoreactivity, particularly in radial fibers, was found at increasing post-mortem intervals in unperfused monkey neocortex, indicating that differences in density and distribution of immunoreactive fibers between human and perfused monkey may result from post-mortem peptide degradation in unperfused tissue. In contrast, the larger size of SS28(1-12)-immunoreactive white matter neurons in humans as compared to monkeys appeared partially due to a post-mortem effect but also reflected a species difference. In addition, the density of white matter neurons was found to be significantly greater in human than in perfused or unperfused monkey. These data indicate that any study of human autopsy material must be assessed in light of possible post-mortem effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Colchicine-induced increases in immunoreactive neuropeptide levels in hypothalamus: use as an index of biosynthesis.

The colchicine-induced accumulation of vasopressin (AVP) and oxytocin (OXT) has recently been applied to estimate the synthesis and turnover rates for these neuropeptides in whole rat hypothalamus. In the present studies, this pharmacologic procedure has been examined as a potential method for estimating hypothalamic somatostatin (SRIF) synthesis rate, and evaluated further for its utility in estimating nonapeptide synthesis in individual hypothalamic nuclei. Adult male rats received a single injection of colchicine (8 micrograms) into the third ventricle under pentobarbital anesthesia. Twenty-four hr later, immunoreactive (IR) levels of AVP and OXT increased considerably, as previously noted. Hypothalamic IR-SRIF levels, however, were unaffected. The absolute increases in IR-AVP and IR-OXT were greatest in the supraoptic nucleus (SON), with smaller increments in the para/periventricular hypothalamus (PVH) and the median eminence (ME). IR-SRIF levels showed no changes in the PVH or the ME. As a test, the method was applied to the detection of changes in AVP synthesis in diabetic rats. The colchicine procedure reported increases in AVP synthesis in both the SON and PVH in diabetic animals, a result compatible with that obtained previously for whole hypothalamus using radiolabeled procedures. Together, the results indicate that the colchicine procedure is useful in detecting changes in the syntheses of some (AVP and OXT) but not all (SRIF) neuropeptides, and that when applicable, the method is sufficiently sensitive to detect changes in small hypothalamic regions. The method may prove useful in estimating changes in peptide synthesis analogous to that used for serotonin and dopamine; e.g., 5-hydroxytryptophan and dopa accumulation following inhibition of aromatic L-amino acid decarboxylase.

Animals↗
PubMed1991

In vivo tyrosine hydroxylation in rat retina: effect of aspartame ingestion in rats pretreated with p-chlorophenylalanine.

Rats were pretreated with p-chlorophenylalanine (PCPA) to inhibit hepatic phenylalanine hydroxylase. Two days later, oral aspartame (APM; aspartylphenylalanine methylester) administration substantially increased serum phenylalanine (Phe) concentrations and the ratio, in serum, of Phe to the sum of its competitors for transport into brain and retina (the other large neutral amino acids). Smaller changes occurred in serum tyrosine (Tyr) concentrations and in the ratio, in serum, of Tyr to the sum of its competitors. P-chlorophenylalanine-pretreated rats showed normal increases in retinal Tyr hydroxylation rate after Tyr injection, indicating that the enzyme was functionally normal. APM (0, 500, 1000, 1500 mg/kg body wt) intubation of PCPA-pretreated rats produced a dose-related increment in retinal Phe concentrations (up to six times normal values), no changes in retinal Tyr concentration, and no changes in retinal Tyr hydroxylation rate. The results thus indicate that very large increments in retinal Phe concentrations produced by enormous doses of APM do not modify Tyr hydroxylation in vivo.

Animals↗
PubMed1991

The hypothalamus is not the origin of vasopressin and oxytocin in the rat pineal gland.

Immunoreactive levels of vasopressin (VP) and oxytocin (OT) were quantitated in the rat pineal gland in the middle of August, when nonapeptide levels have been reported to peak annually. The pineal levels of both VP and OT were found to be substantially elevated when sampled in August, compared to sampling in July and September. mRNA levels for OT and VP in hypothalamic nuclei (supraoptic, paraventricular, and suprachiasmatic nuclei) showed no such increases during August. A lesioning of the paraventricular nuclei did not suppress pineal VP and OT levels. Finally, the injection of colchicine into the third ventricle caused pineal VP and OT levels to increase substantially. Together, these results affirm the occurrence of a summertime rise in pineal VP and OT levels and suggest that such increases do not derive from sites of VP and OT cell bodies in the hypothalamus. Rather, they indicate that the source of these pineal nonapeptides may be the pineal itself.

Animals↗
PubMed1990

Effects of L-tryptophan and other amino acids on electroencephalographic sleep in the rat.

Electroencephalographic sleep was quantitated in adult male Sprague-Dawley rats following single injections of the methylesters of tryptophan, valine or alanine. The amino acids were administered at the onset of the daily light period (09.00 h); electrographic data were collected for the succeeding 6-h period. Saline served as the injection control, and fluoxetine, a serotonin-reuptake blocker, as a positive control. The injection of tryptophan methylester (125 mg/kg) caused a delay in rapid eye movement (REM) sleep onset, and significantly reduced the amount of REM sleep during the first 2 h postinjection. Tryptophan produced no effect on sleep onset, nor did it influence total sleep time. Fluoxetine (2.5 mg/kg) produced similar effects, as previously observed. The methylesters of valine and alanine were without effect on REM sleep, when injected at a molar dose equivalent to that for tryptophan. No consistent effects of any of the test substances were noted on non-REM (NREM) sleep or waking time, or on any of the other sleep indices quantitated. Together, the data indicate that tryptophan selectively reduces REM sleep; the effect is not due to a non-specific action of amino acids or their methylesters. The effect on REM sleep may be the consequence of a tryptophan-induced stimulation of 5-HT synthesis and release, since it is like that produced by fluoxetine, a drug that enhances transmission across serotonin synapses.

Alanine↗
PubMed1990

Effect of an oral tryptophan/carbohydrate load on tryptophan, large neutral amino acid, and serotonin and 5-hydroxyindoleacetic acid levels in monkey brain.

Plasma and brain levels of tryptophan and other large neutral amino acids, and brain levels of serotonin and 5-hydroxyindoleacetic acid (5 HIAA) were measured in groups of adult cynomolgus monkeys 1 hr after they ingested one of four doses of a tryptophan-carbohydrate mixture. The doses had been administered once daily for 13 weeks. Dose-related increments occurred in plasma tryptophan, the plasma ratio of tryptophan to the sum of other large neutral amino acids, and in brain tryptophan levels. In contrast, the plasma ratios and brain levels of the other neutral amino acids each declined. Serotonin and 5 HIAA levels increased significantly, and in a dose-related manner in the brainstem and striatum, but not in cortex or hypothalamus. The results suggest that while tryptophan administration can stimulate serotonin production in primate brain, the effect may be restricted to certain brain regions. They also suggest that the transport of the large neutral amino acids into brain occurs via a competitive mechanism similar to that for other mammals.

Administration, Oral↗
PubMed1990

Effect of 8-hydroxy-2-(di-n-propylamino)-tetralin on the tryptophan-induced increase in 5-hydroxytryptophan accumulation in rat brain.

The injection of 8-hydroxy-2-(di-n-propylamino)-tetralin [8-OH-DPAT]reduced 5-hydroxytryptophan accumulation in vivo in rat cerebral cortex, hypothalamus and brainstem. Brain tryptophan levels were unaffected. Dose-related increases in 5-hydroxytryptophan accumulation produced by single injections of L-tryptophan (0, 25, 75 mg/kg ip) were substantially diminished by pretreatment with 8-OH-DPAT. The drug did not affect the tryptophan-induced increments in brain tryptophan level. Since 8-OH-DPAT is known to reduce the activity of serotonin neurons in vivo, these results suggest that when serotonin neurons are relatively inactive, the ability of an injection of tryptophan to stimulate serotonin synthesis is greatly attenuated.

5-Hydroxytryptophan↗
PubMed1990

In vivo somatostatin, vasopressin, and oxytocin synthesis in diabetic rat hypothalamus.

The in vivo labeling of somatostatin-14, somatostatin-28, arginine vasopressin, and oxytocin was studied in rat hypothalamus after third ventricular administration of [35S]cysteine to streptozotocin-diabetic and normal rats. Immunoreactive somatostatin levels in hypothalamus were unaffected by diabetes, as was the incorporation of [35S]cysteine into hypothalamic somatostatin-14 and somatostatin-28. In contrast, immunoreactive vasopressin levels in hypothalamus and posterior pituitary (and oxytocin levels in posterior pituitary) were below normal in diabetic rats. Moreover, [35S]cysteine incorporation into hypothalamic vasopressin and oxytocin (probably mainly in the paraventricular nucleus because of its proximity to the third ventricular site of label injection) was significantly above normal. The increments in vasopressin and oxytocin labeling were reversed by insulin administration. In vivo cysteine specific activity and the labeling of acid-precipitable protein did not differ between normal and diabetic animals; effects of diabetes on vasopressin and oxytocin labeling were therefore not caused by simple differences in cysteine specific activity. These results suggest that diabetes 1) does not influence the production of somatostatin peptides in hypothalamus but 2) stimulates the synthesis of vasopressin and oxytocin. For vasopressin at least, the increase in synthesis may be a compensatory response to the known increase in its secretion that occurs in uncontrolled diabetes.

Animals↗
PubMed1990

A defect in sodium-dependent amino acid uptake in diabetic rabbit peripheral nerve. Correction by an aldose reductase inhibitor or myo-inositol administration.

A myo-inositol-related defect in nerve sodium-potassium ATPase activity in experimental diabetes has been suggested as a possible pathogenetic factor in diabetic neuropathy. Because the sodium-potassium ATPase is essential for other sodium-cotransport systems, and because myo-inositol-derived phosphoinositide metabolites regulate multiple membrane transport processes, sodium gradient-dependent amino acid uptake was examined in vitro in endoneurial preparations derived from nondiabetic and 14-d alloxan diabetic rabbits. Untreated alloxan diabetes reduced endoneurial sodium-gradient dependent uptake of the nonmetabolized amino acid 2-aminoisobutyric acid by greater than 50%. Administration of an aldose reductase inhibitor prevented reductions in both nerve myo-inositol content and endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Myo-inositol supplementation that produced a transient pharmacological elevation in plasma myo-inositol concentration, but did not raise nerve myo-inositol content, reproduced the effect of the aldose reductase inhibitor on endoneurial sodium-dependent 2-aminoisobutyric acid uptake. Phorbol myristate acetate, which acutely normalizes sodium-potassium ATPase activity in diabetic nerve, did not acutely correct 2-aminoisobutyric uptake when added in vitro. These data suggest that depletion of a small myo-inositol pool may be implicated in the pathogenesis of defects in amino acid uptake in diabetic nerve and that rapid correction of sodium-potassium ATPase activity with protein kinase C agonists in vitro does not acutely normalize sodium-dependent 2-aminoisobutyric acid uptake.

Amino Acids↗
PubMed1989

In vivo tyrosine hydroxylation rate in retina: effects of phenylalanine and tyrosine administration in rats pretreated with p-chlorophenylalanine.

p-Chlorophenylalanine was administered to rats to inhibit hepatic phenylalanine hydroxylase activity. Two days later, phenylalanine injection was noted to produce substantial increases in serum phenylalanine levels, and relatively modest increments in serum tyrosine levels. Rats injected with p-chlorophenylalanine 2 days earlier showed a normal light-induced activation of retinal tyrosine hydroxylase activity in vivo, measured as dihydroxyphenylalanine accumulation following pharmacologic inhibition in vivo of aromatic L-amino acid decarboxylase activity. In addition, tyrosine injection into p-chlorophenylalanine-treated rats in the light produced anticipated increments in retinal tyrosine hydroxylation rate, showing the enzyme to be functionally normal. The acute administration of phenylalanine (62.5-500 mg/kg i.p.) to p-chlorophenylalanine-treated rats produced dose-related increments in retinal phenylalanine. In vivo tyrosine hydroxylation rate in retina was normal at all doses below 300 mg/kg. However, at the highest dose (500 mg/kg), when retinal phenylalanine levels were almost 5-times normal tyrosine hydroxylation rate consistently fell (to about half-normal values). These results demonstrate that very large elevations in tissue phenylalanine levels do not stimulate tyrosine hydroxylation in vivo, and that at extremely high levels phenylalanine inhibits tyrosine hydroxylation rate.

Animals↗
PubMed1989

Oral aspartame and plasma phenylalanine: pharmacokinetic difference between rodents and man, and relevance to CNS effects of phenylalanine. Short note.

The ingestion of aspartame, a phenylalanine-containing dipeptide, raises plasma phenylalanine levels. These increments are much greater in humans than rats, because the rat hydroxylates phenylalanine five times faster than man. Accordingly, dose comparisons of aspartame (or phenylalanine) between humans and rats have usually been corrected by a factor of five. Recently, a correction factor of sixty has been proposed (Wurtman and Maher, 1987); the rationale is based on a novel calculation of competitive phenylalanine transport into brain. An analysis of the logic behind this postulation reveals there to be no basis for accepting the higher dose conversion of 60 between rat and man.

Administration, Oral↗
PubMed1988

A microcomputer-based sleep system: data acquisition and system calibration programs.

A data acquisition program is described for the Apple II series of microcomputers that allows for continuous, direct monitoring of electrographic elements from cortical, hippocampal and muscle leads from rats. The program detects cortical delta waves and sigma activity, hippocampal theta activity and electromyographic activity. The detected elements are counted and stored in memory at 15 second intervals (bins). Every three hours, the data are transferred to disks for permanent storage and off-line analysis.

Animals↗
PubMed1988

Carbohydrate ingestion and brain serotonin synthesis: relevance to a putative control loop for regulating carbohydrate ingestion, and effects of aspartame consumption.

The ingestion of a meal of carbohydrates by fasting rats rapidly increases brain tryptophan level and serotonin (5-HT) synthesis. The rise in brain tryptophan level follows from an increase in tryptophan transport into brain, the consequence of an insulin-induced reduction in the blood levels of several amino acids that compete with tryptophan for brain uptake. In contrast, ingesting protein with carbohydrate does not stimulate brain tryptophan uptake or 5-HT synthesis, because the blood levels of tryptophan's transport competitors are increased, not reduced. These observations form the biochemical basis of a current proposal for a regulatory loop governing meal-to-meal appetite for carbohydrates. This review briefly analyzes the experimental basis for the carbohydrate appetite regulatory loop, and finds it wanting. It also considers the proposal that the ingestion of the artificial sweetener aspartame might disrupt the putative regulatory loop for carbohydrate intake regulation, and thus promote rather than help to limit carbohydrate appetite, and finds this hypothesis unrealistic as well. In general, the conclusion is that while single meals do readily influence brain tryptophan uptake and 5-HT synthesis, it is presently unclear what role such neurochemical effects of food ingestion have in the control of specific appetites.

Amino Acids↗
PubMed1987

Short-term effects of fluoxetine and trifluoromethylphenylpiperazine on electroencephalographic sleep in the rat.

Fluoxetine and trifluoromethylphenylpiperazine (TFMPP) were studied for their short-term effects on electroencephalographic sleep in male rats. Following single injection, each drug produced a sizeable, dose-related suppression of rapid-eye-movement (REM) sleep that persisted for 4-5 h (fluoxetine, 0.625-5 mg/kg; TFMPP, 0.10-1.25 mg/kg). TFMPP also consistently increased non-REM (NREM) sleep during the second hour after drug injection, though this effect was not dose-related (it was seen at all doses tested). Fluoxetine produced small effects on NREM sleep that varied non-systematically with dose and time after drug injection. TFMPP, but not fluoxetine, also increased at all doses the number of delta waves per minute of NREM sleep in the second hour. A structural analog of TFMPP that is inactive at serotonin (5-HT) receptors [4-(m-trifluoromethylphenyl)piperadine; LY97117] was also tested, and found to be devoid of effects on NREM and REM sleep. Both fluoxetine (a 5-HT reuptake blocker) and TFMPP (a 5-HT agonist) enhance transmission across 5-HT synapses, though by different mechanisms. Because they have the common effect of suppressing REM sleep, and in a dose-related manner, the data support the notion that 5-HT neurons in the brain, when active, can suppress REM sleep.

Animals↗
PubMed1987

Protein consumption increases tyrosine concentration and in vivo tyrosine hydroxylation rate in the light-adapted rat retina.

The ingestion of a single, 40% protein meal increased serum and retinal tyrosine levels and stimulated retinal tyrosine hydroxylation rate in light-adapted rats. Consumption of a similar, protein-free meal elicited none of these effects. The results thus indicate for retinal dopamine neurons that physiologically induced increases in tyrosine level can readily stimulate in vivo tyrosine hydroxylation rate.

Amino Acids↗