Chronic morphine administration decreases 5-hydroxytryptamine and 2-hydroxyindoleacetic acid content in the brain of rats

To study the effects of chronic morphine treatment on cerebral 5-hydroxytryptamine (5HT) metabolism morphine was administered twice daily for 5 or 8 weeks to male Wistar rats. Control rats were treated with 0.9% NaCl solution for the same period. In rats treated chronically with morphine for 8 weeks the cerebral concentrations of 5HT and 5HIAA were reduced by 12--15% (P less than 0.05) at 26--28 h after the last morphine injection (50 mg/kg s.c.). No such decrease was found in the brain of rats treated with morphine for 5 weeks. A test dose of morphine (30 mg/kg s.c. 2h) increased the cerebral concentration and probenecid-induced accumulation of 5HIAA in the rats treated with morphine for 8 weeks almost as much as in the brain of the control rats. Naloxone (10 mg/kg s.c. 2h) did not cause clear changes in the cerebral 5HT or 5HIAA concentration. These experiments suggest that endogenous opioid mechanisms are concerned in the regulation of 5HT neurons and that prolonged morphine treatment weakens these mechanisms. This weakening of endogenous regulation of 5HT neurons, which, however, still respond to acute morphine administration, might be part of the mechanism of compulsive drug use in narcotic addiction. It is possible that these neurons in dependent individuals do not function optimally without exogenous morphine. A similar phenomenon--weakening of endogenous regulation combined with clear responsivity to exogenous opiates--occurs in the cerebral dopamine neurons of rats treated chronically with narcotic analgesics.     

Role of the sympathetic nervous system in cold-induced hypertension in rats

Hypertension develops in rats exposed chronically to cold [6 +/- 2 degrees C (SE)] and includes both an elevation of mean arterial pressure and cardiac hypertrophy. Previous studies suggest that cold-exposed animals, at least initially, have a large sustained increase in the activity of their sympathetic nervous system, suggesting a failure of the baroreceptor system to provide sufficient negative feedback to the central nervous system. The present study was designed to investigate whether alterations in the activity of the sympathetic nervous system, including the baroreceptor reflex, occur during exposure to cold and whether they contribute to cold-induced hypertension. Twenty male rats were prepared with indwelling catheters in the femoral artery and vein. Ten of the rats were exposed to cold (6 +/- 2 degrees C) chronically, while the remaining 10 were kept at 26 +/- 2 degrees C. Withdrawal of arterial blood samples (less than 5 ml/kg), measurement of direct arterial pressures, and measurement of baroreflex function were carried out at 0800 h at intervals throughout the experiment. Norepinephrine and epinephrine concentrations in plasma were also determined at intervals throughout the experiment. Systolic, diastolic, and mean blood pressures of cold-exposed rats were increased to levels significantly above those of controls. The sensitivity of the baroreflex (delta heart period/delta mean arterial pressure) was decreased in the cold-treated group. The concentration of norepinephrine in plasma increased after 24 h of exposure to cold and remained elevated throughout the experiment, whereas the concentration of epinephrine in plasma increased initially but returned to control levels after 19 days of exposure to cold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diazepam increases 5-hydroxyindole concentrations in rat brain and spinal cord

Diazepam elevates serotonin (5HT) and 5-hydroxyindoleacetic acid (5HIAA) concentrations in rat brain and spinal cord. The maximal effect occurs 1–2 hrs after drug injection and is dose related between 5–20 mg/kg (intraperitoneal). The action of diazepam on brain 5HT and 5HIAA concentrations is modified by previous food consumption: the ingestion of a diet that raises brain 5HT and 5HIAA one hour before drug injection enhances the diazepam-induced increase in brain indoles; consumption of a diet that lowers brain 5HT and 5HIAA partially blocks the elevation in brain indoles that follows diazepam injection.     

Mitochondrial respiration in muscle and liver from cold-acclimated hypothyroid rats.

The effects of long-term cold exposure on muscle and liver mitochondrial oxygen consumption in hypothyroid and normal rats were examined. Thyroid ablation was performed after 8-wk acclimation to 4 degrees C. Hypothyroid and normal controls remained in the cold for an additional 8 wk. At the end of 16-wk cold exposure, all hypothyroid rats were alive and normothermic and had normal body weight. At ambient temperature (24 degrees C), thyroid ablation induced a 65% fall in muscle mitochondrial oxygen consumption, which was reversed by thyroxine but not by norepinephrine administration. After cold acclimation was reached, suppression of thyroid function reduced muscle mitochondrial respiration by 30%, but the hypothyroid values remained about threefold higher than those in hypothyroid muscle in the warm. Blockade of beta- and alpha1-adrenergic receptors in both hypothyroid and normal rats produced hypothermia in vivo and a fall in muscle, liver, and brown adipose tissue mitochondria respiration in vitro. In normal rats, cold acclimation enhanced muscle respiration by 35%, in liver 18%, and in brown adipose tissue 450% over values in the warm. The results demonstrate that thyroid hormones, in the presence of norepinephrine, are major determinants of thermogenic activity in muscle and liver of cold-acclimated rats. After thyroid ablation, cold-induced nonshivering thermogenesis replaced 3,5,3'-triiodothyronine-induced thermogenesis, and normal body temperature was maintained.     

Cold-induced increases in phenylethanolamine N-methyltransferase (PNMT) mRNA are mediated by non-cholinergic mechanisms in the rat adrenal gland

Previously, we reported that cold stress induces a rapid increase in adrenomedullary PNMT mRNA levels, followed by concomitant increases in PNMT immunoreactivity (10). In the present study, the extracellular signals mediating this adaptive response to stress were investigated using northern analysis and RNA slot-blot hybridization. Although adrenal denervation significantly diminished cold-induced increments in adrenomedullary PNMT mRNA levels, it did not completely abolish the cold stress response. In contrast to these results, splanchnectomy completely inhibited cold-induced increments in TH mRNAs in the same tissue samples. These findings indicate that the effects of cold exposure on PNMT mRNA levels are mediated by both neural and non-neural mechanisms, and that adrenal PNMT and TH are differentially regulated in response to cold stress. Surprisingly, the neural component of the PNMT stress response could not be attenuated by peripheral administration of chlorisondamine, a powerful nicotinic ganglionic blocking agent. In contrast, chlorisondamine was effective in inhibiting sympathetic neural activity, as judged by the drug's ability to completely block increases in blood pressure, heart rate, and plasma catecholamines resulting from spinal cord stimulation in pithed rats. The administration of atropine, a muscarinic receptor antagonist, also failed to inhibit cold-induced alterations in adrenal PNMT mRNA. These results suggest that the trans-synaptic induction of adrenal PNMT mRNA involves a non-cholinergic component, and that cold-induced increases in PNMT mRNA are not coupled to acetylcholine-mediated adrenal catecholamine release.     

Factors affecting cold-induced hypertension in rats

A 3- to 4-week exposure of rats to a cold environment (5 +/- 2 degrees C) induces hypertension, including elevation of systolic, diastolic, and mean blood pressures and cardiac (left ventricular) hypertrophy. The studies described here were designed to investigate some factors affecting both the magnitude and the time course for development of cold-induced hypertension. The objective of the first study was to determine whether there was an ambient temperature at which the cold-induced elevation of blood pressure did not occur. The objective of the second experiment was to determine whether body weight at the time of exposure to cold affected the magnitude and time course for development of hypertension. To assess the first objective, male rats were housed in a chamber whose temperature was maintained at 5 +/- 2 degrees C while others were housed in an identical chamber at 9 +/- 2 degrees C. After 7 days of exposure to cold, the rats exposed to the colder temperature had a significant elevation of blood pressure (140 +/- 2 mm Hg) compared with the group maintained at 9 degrees C (122 +/- 3 mm Hg). The rats exposed to 9 degrees C had no significant elevation of systolic blood pressure at either 27 or 40 days after initiation of exposure to cold. At the latter time, the temperature in the second chamber was reduced to 5 +/- 2 degrees C. By the 25th day of exposure to this ambient temperature, the rats had a significant increase in systolic blood pressure above their levels at 9 degrees C. Thus, there appears to be a threshold ambient temperature for elevation of blood pressure during exposure to cold. That temperature appears to lie somewhere between 5 and 9 degrees C. The second objective was assessed by placing rats varying in weight from approximately 250 to 430 g in air at 5 degrees C. There was a highly significant direct relationship (r = 0.96) between body weight at the time of introduction to cold and the number of days required to increase systolic blood pressure by 10 mm Hg above pre-cold exposure level. The third objective was to make an initial assessment of potential differences among strains of rats with respect to development of cold-induced hypertension. To this end, rats of the Fischer 344 strain were used. Systolic blood pressures of these rats also increased during chronic exposure to cold.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anatomical and functional recovery following spinal cord transection in the chick embryo

Following complete transection of the thoracic spinal cord at various times during embryonic development, chick embryos and posthatched animals exhibited various degrees of anatomical and functional recovery depending upon the age of injury. Transection on embryonic day 2 (E2), when neurogenesis is still occurring and before descending or ascending fiber tracts have formed, produced no noticeable behavioral or anatomical deficits. Embryos hatched on their own and were behaviorally indistinguishable from control hatchlings. Similar results were found following transection on E5, an age when neurogenesis is complete and when ascending and descending fiber tracts have begun to project through the thoracic region. Within 48 h following injury on E5, large numbers of nerve fibers were observed growing across the site of transection. By E8, injections of horse-radish peroxidase (HRP) administered caudal to the lesion, retrogradely labelled rostral spinal and brainstem neurons. Embryos transected on E5 were able to hatch and could stand and locomote posthatching in a manner that was indistinguishable from controls. Following spinal cord transections on E10, anatomical recovery of the spinal cord at the site of injury was not quite as complete as after E5 transection. Nonetheless, anatomical continuity was restored at the site of injury, axons projected across this region, and rostral spinal and brainstem neurons could be retrogradely labelled following HRP injections administered caudal to the lesion. At least part of this anatomical recovery may be mediated by the regeneration or regrowth of lesioned axons. Although none of the embryos transected on E10 that survived to hatching were able to hatch on their own, because several sham-operated embryos were also unable to hatch, we do not attribute this deficit to the spinal transection. When E10-transected embryos were aided in escaping from the shell, they were able to support their own weight, could stand, and locomote, and were generally comparable, behaviorally, to control hatchlings. Repair of the spinal cord following transection on E15 was considerably less complete compared to embryos transected on E2, E5, or E10. However, in some cases, a degree of anatomical continuity was eventually restored and a few spinal neurons rostral to the lesion could be retrogradely labelled with HRP. By contrast, labelled brainstem neurons were never observed following E15 transection. E15 transected embryos were never able to hatch on their own, and when aided in escaping from the shell, the hatchlings were never able to stand, support their own weight or locomote.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anatomical and functional recovery folloing spinal cord transection in the chick embryo

Following complete transection of the thoracic spinal cord at various times during embryonic development, chick embryos and posthatched animals exhibited various degrees of anatomical and functional recovery depending upon the age of injury. Transection on embryonic day 2 (E2), when neurogenesis is still occurring and before descending or ascending fiber tracts have formed, produced no noticeable behavioral or anatomical deficits. Embryos hatched on their own and were behaviorally indistinguishable from control hatchlings. Similar results were found following transection on E5, an age when neurogenesis is complete and when ascending and descending fiber tracts have begun to project through the thoracic region. Within 48 h following injury on E5, large numbers of nerve fibers were observed growing across the site of transection. By E8, injections of horseradish peroxidase (HRP) administered caudal to the lesion, retrogradely labelled rostral spinal and brainstem neurons. Embryos transected on E5 were able to hatch and could stand and locomote posthatching in a manner that was indistinguishable from controls. Following spinal cord transections on E10, anatomical recovery of the spinal cord at the site of injury was not quite as complete as after E5 transection. Nonetheless, anatomical continuity was restored at the site of injury, axons projected across this region, and rostral spinal and brainstem neurons could be retogradely labelled following HRP injections administered caudal to the lesion. At least part of this anatomical recovery may be mediated by the regeneration or regrowth of lesioned axons. Although none of the embryos transected on E10 that survived to hatching were able to hatch on their own, because several shamoperated embryos were also unable to hatch, we do not attribute this deficit to the spinal transection. When E10-transected embryos were aided in escaping from the shell, they were able to support their own weight, could stand, and locomote, and were generally comparable, behaviorally, to control hatchlings. Repair of the spinal cord following transection on E15 was considerably less complete compared to embryos transected on E2, E5, or E10. However, in some cases, a degree of anatomical continuity was eventually restored and a few spinal neurons rostral to the lesion could be retrogradely labelled with HRP. By contrast, labelled brainstem neurons were never observed following E15 transection. E15 transected embryos were never able to hatch on their own, and when aided in escaping from the shell, the hatchlings were never able to stand, support their own weight or locomote. We conclude that successful anatomical and functional recovery occurs following a complete spinal cord transection in the chick embryo made any time between E2 and E10. By E15, however, there is an altered response to the transection such that anatomical continuity is not restored sufficiently to mediate behavioral or functional recovery. Although the altered response of the chick embryo spinal cord to injury between E10 and E15 could be due to a variety of factors, we favor the notion that cellular or molecular changes associated with axonal growth and guidance occur at this time that are responsible for the transition from successful to unsuccessful recovery.     

Effect of the exposure to chronic-intermittent cold on the thyrotropin and thyroid hormones in the rat

Rats exposed to acute cold (4 degrees C for 2 h), chronic cold (4 degrees C), and chronic-intermittent cold (4 degrees C for 2 h daily) were killed after 1, 2, 3, 4, and 10 days of cold exposure. The control group was maintained at 25 degrees C. In each animal, the plasma concentration of thyrotropine (THS), triiodothyronine (T3), and thyroxine (T4) was determined by radioimmunoassay. At the initial time of exposure, elevations in TSH, T3, and T4 were observed in the rats in each experimental group. However, on the 10th day, in rats exposed to chronic-intermittent cold, TSH, T3, and T4 decreased to values lower than the control values. In animals exposed to acute cold as well as to chronic cold no differences were found, with respect to the controls, in TSH and T4. In rats exposed to acute cold for 10 days, the T3 value was lower than the control value; however, in animals exposed to chronic cold, T3 was same as that in the controls. The results indicate that, in the rat, exposure to chronic-intermittent cold produces an inhibition in the secretion of TSH and thyroid hormones.     

Norepinephrine release in brown adipose tissue remains robust in cold-exposed senescent Fischer 344 rats

Near the end of life, old F344 rats undergo a transition, marked by spontaneous and rapidly declining function. Food intake and body weight decrease, and these rats, which we call senescent, develop severe hypothermia in the cold due in part to blunted brown fat [brown adipose tissue (BAT)] thermogenesis. We tested the hypothesis that this attenuation may involve diminished sympathetic signaling by measuring cold-induced BAT norepinephrine release in freely moving rats using linear microdialysis probes surgically implanted into interscapular BAT 24 and 48 h previously. In response to 2 h at 15 degrees C, senescent rats increased BAT norepinephrine release 6- to 10-fold but did not maintain homeothermy. This increase was comparable to that of old presenescent (weight stable) rats that did maintain homeothermy during even greater cold exposure (2 h at 15 degrees C followed by 1.5 h at 8 degrees C). Tail temperatures, an index of vasoconstrictor responsiveness to cold, exhibited similar cooling curves in presenescent and senescent rats. Thus cold-induced sympathetic signaling to BAT and tail vasoconstrictor responsiveness remain robust in senescent rats and cannot explain their cold-induced hypothermia.     

Regional Variations of 5HT Concentrations in Rora sg (staggerer) Mutants

Ataxic Rora ^sg (staggerer) mouse mutants, containing a deletion of the Rora gene which encodes a retinoid-like nuclear receptor, were compared to non-ataxic controls for concentrations of 5-hydroxytryptamine (HT), its main metabolite (5-hydroxy-indole acetic acid, 5HIAA), and its precursor (tryptophan) in cerebellum, brainstem, and forebrain. In Rora ^sg cerebellum, 5HT concentrations increased relative to controls, while tryptophan concentrations decreased. 5HIAA concentrations increased in mutant cerebellum and brainstem, but the 5HIAA/5HT ratio declined only in cerebellum. These results indicate that 5HT turnover decreased in cerebellum of an ataxic mutant, perhaps indicative of presynaptic accumulation and compromised neurotransmission and susceptible to be modified by 5HT pharmacotherapy.     

Caffeine injection raises brain tryptophan level,but does not stimulate the rate of serotonin synthesis in rat brain

Acute caffeine injection (100 mg/kg) elevates brain levels of tryptophan (TRP), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA). Experiments were performed to determine if the increases in 5HT and 5HIAA result from a stimulation of the rate of 5HT synthesis. Both the rate of 5-hydroxytryptophan (5HTP) accumulation following NSD-1015 injection, and the rate of ³H-5-hydroxyindole synthesis from ³H-tryptophan were measured $\text{in vivo}$ following caffeine administration and found to be normal. Tryptophan hydroxylase activity, as measured $\text{in vitro}$ in brain homogenates, was also unaffected by caffeine. The results suggest that the elevations in brain 5HT and 5HIAA levels produced by caffeine do $\text{not}$ reflect enhanced 5HT synthesis, despite significant elevations in brain TRP level. Some other mechanism(s) must therefore be responsible for these elevations in brain 5-hydroxyindole levels.     

Attenuated response to cold of brown adipose tissue of mice made obese with gold thioglucose

In a first study, mice made obese with gold thioglucose became hypothermic when exposed to 4 degrees C. In a second study, lean mice and mice made obese with gold thioglucose (dynamic phase) were acclimated to 14 degrees C for up to 2 weeks and their brown adipose tissue was studied. The cold-induced increase in thyroxine 5'-deiodinase activity was initially slightly smaller in obese mice, but by 24 h and 2 weeks in the cold the activity of thyroxine 5'-deiodinase was the same in lean and obese mice. Unexpectedly, the elevated activity of 5'-deiodinase returned to the low level seen in warm-acclimated mice in both lean and obese mice after 2 weeks of cold acclimation. In gold thioglucose obese mice, a progressive cold-induced increase in the binding of guanosine diphosphate to isolated mitochondria, an index of both acute thermogenic activation and a long-term increase in uncoupling protein concentration, paralleled that seen in normal lean mice and remained at a high level after 2 weeks in the cold, although still remaining slightly lower than normal. It is not clear how a high level of mitochondrial GDP binding is maintained in cold-acclimated mice at the same time as a low level of thyroxine 5'-deiodinase activity when both are believed to be controlled by the sympathetic nervous system. We conclude that the gold thioglucose obese mouse can activate its brown adipose tissue fairly normally when it is exposed to cold, but that some attenuation of this process may contribute to the impaired survival of this mouse at low temperatures.     

The predominant role of brain angiotensinogen and angiotensin in environmentally induced hypertension

Rats exposed chronically to a cold environment (5 degrees C/4 degrees F) develop hypertension. This cold-induced hypertension (CIH) is a non-genetic, non-pharmacological, non-surgical model of environmentally induced hypertension in rats. The renin-angiotensin system (RAS) appears to play a role in both initiating and/or maintaining the high blood pressure in CIH. The goal of the present study was to evaluate the role of central and peripheral circulating RAS components, angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, in CIH. Seventy-two Sprague-Dawley adult male rats were used. Thirty-six rats were kept in cold room at 5 degrees C while the other 36 were at 24 degrees C as controls for 5 weeks. Systolic blood pressure (SBP) was recorded by tail cuff. The SBP was increased in rats exposed to cold within 1 week, and this increase was significant for the next 2-5 weeks of the cold exposure (p<0.01). Three subgroups of the cold-treated and control rats (n=12) were sacrificed at 1, 3 and 5 weeks. The brain and liver were removed and plasma was saved. The AGT mRNA significantly increased in the hypothalamus and liver in cold-treated rats from the first week of exposure to cold, and was maintained throughout the time of exposure to cold (n=4, p<0.01). The AGT protein levels in the brain, liver and plasma did not differ significantly between cold-treated and control rats (p>0.05, n=4). The hypothalamic Ang II levels were significantly increased, whereas plasma Ang II levels significantly decreased, in the rats of 5 weeks of cold exposure (n=8, p<0.05). Plasma ACE significantly increased in the rats of 1 week of cold exposure (p<0.05, n=12). The results show differential regulation of RAS components, AGT, ACE and Ang II, between brain and periphery in cold-exposed rats. We conclude that the exposure to low temperature initially increases plasma RAS but with continuous exposure to cold, the brain RAS maintains the hypertension, probably by sustained sympathetic activation, which would provide increased metabolism but also vasoconstriction leading to hypertension.     

Acute cold exposure,leptin, and somatostatin analog (octreotide) modulate thyroid 5'-deiodinase activity

We investigated the effect of acute cold exposure, leptin, and the somatostatin analog octreotide (OCT) on thyroid type I (D1) and II (D2) deiodinase activities. Microsomal D1 and D2 activities were measured by the release of (125)I from (125)I-reverse triiodothyronine (rT(3)) under different assay conditions. Rats exposed to 4 degrees C (15, 30, 60, and 120 min) showed progressive reduction in thyroidal D1 and D2, reaching approximately 40% at 2 h (P < 0.05) despite increased circulating TSH (P < 0,05) associated with the higher thyroid D1 and D2 in hypothyroid rats. A single injection of leptin (8 microg/100 g body wt sc) induced increased thyroid and liver D1 (P < 0.05), but not thyroid D2, activities at 30 and 120 min, independently of the serum TSH rise shown only at 2 h. OCT (1 microg/kg body wt sc) increased D1 and D2 activity significantly 24 h after a single injection, with no changes in serum TSH. Therefore, leptin and somatostatin are potential physiological upregulators of thyroid deiodinases, and their low secretion during acute cold exposure may be a potential mechanism contributing to cold-induced reduction in thyroid deiodinase activity.     

Influence of cold exposure and thyroid hormones on regulation of adrenal catecholamines.

Since thyroid hormones influence urinary excretion of catecholamines after exposure to cold, the effects of hyper- and hypo-thyroidism on adrenal tyrosine hydroxylase (TH) (EC 1.14.16.2), phenylethanolamine-N-methyl transferase (PNMT) (EC 2.1.1.28), and serum dopamine-beta-hydroxylase (DbetaH) (EC 1.14.17.1) of rats of 23 and 4 degrees C were studied. TH changes resembled the urinary excretion pattern at 4 degrees C in being higher after 8 days than after 1 day of exposure, and in declining as acclimation occurred. At 23 degrees C, TH activity of hypothyroid rats was significantly higher than in euthyroid or hyperthyroid animals, and after 1 day at 4 degrees C the value increased even more. While in the hypothyroid animals at 4 degrees C the concentration of adrenal catecholamines was less, the epinephrine to norepinephrine ratio was higher than at 23 degrees C. Very high TH activity with a decline in catecholamine concentration suggests that the capacity of TH had been exceeded. PNMT activity was significantly elevated in this group. TH activity was not decreased in the hyperthyroid group at 23 degrees C, and was increased after 8 days at 4 degrees C, suggesting that circulating thyroid hormones have no direct inhibitory effect on TH. Serum DbetaH was elevated after exposure to 4 degrees C, regardless of thyroid hormonal status. The activation of adrenal TH in hypothyroid rats at 23 degrees C and of TH, PNMT, and serum DbetaH at 4 degrees C is probably the result of increased activity of the sympathetic nervous system.     

Ascorbate-Stimulated Lipid Peroxidation in Human Brain Is Dependent on Iron but Not on Hydroxyl Radical

Abstract: The time dependence of N -acetyl-aspartate (NAA) concentrations relative to lactate and pyruvate in the injured rat spinal cord was investigated. Segments of spinal cord from regions rostral, caudal, and at the epicenter of the injury were analyzed. NAA concentrations were determined by gas chromatography-mass spectrometry and lactate and pyruvate concentrations were determined by UV spectroscopy at 20 min, 60 min, 2 h, 8 h, 24 h, 3 days, and 1 week after injury. NAA levels fell most significantly at the epicenter of the injury, reaching 30% of basal levels within 24 h. In all segments, lactate levels increased significantly shortly after injury, peaking at two to five times normal basal levels between 20 and 60 min after injury. Rostral and caudal to the injury site, lactate elevations and NAA reductions were less dramatic. Pyruvate concentrations were not significantly altered in any of the sections after injury. The temporal and spatial relationships of NAA and lactate changes indicated that ischemic conditions due to injury in the upper thoracic rat spinal cord were distributed asymmetrically. Acute ischemia was more severe caudal to the injury site, and NAA concentrations were more severely impaired in the rostral direction. The results suggest that the extent of neuronal degeneration due to spinal cord injury does not correlate directly with acute ischemic severity as measured by the lactate/pyruvate ratio, and may be more closely related to secondary changes in the neuronal environment.     

Twenty-four hour rhythms in serum and brain indoleamine concentrations: tryptophan-5-hydroxylase and monoamine oxidase activity in the rat.

The relationship between the 24 h rhythm in 5-hydroxy-tryptamine (5HT) levels in rat brain, the availability of precursors of 5HT and the concentration of its major metabolite, 5-hydroxyindole acetic acid (5HIAA) has been investigated. Serum total and "free" tryptophan (TRY) levels and brain TRY levels all show a 24 h rhythm with highest concentrations in the middle of the dark phase i.e. 12 h displaced from that of the 5HT rhythm. No 24 h variation in either tryptophan-5-hydroxylase or monoamine oxidase activity was detected, nor did brain 5-hydroxytryptophan (5HTP) levels vary with clock hour. Changes in 5HIAA concentration paralleled those of 5Ht. The uptake of 14C-5HTP, 14C-TRY and 14C-5HT into homogenates of the septal region of rat brain did not display a circadian rhythm, although there was evidence that uptake of 14C-TRY in an isolated synaptosomal preparation from the same region was greater during the light phase, indicating the possibility that uptake of the precursor into the nerve ending may be, in part, responsible for the 24 h rhythm in brain 5HT. It is concluded that brain 5HT levels are independent of the serum or brain TRY concentrations measured. Since changes in 5HT with clock hour are paralleled by changes in 5HIAA, it also seems unlikely that the increase in brain 5HT during the light phase is caused by a decreased release of 5HT from nerve endings.     

Dietary serotonin and alcohol combined may provoke adverse physiological symptoms due to 5-hydroxytryptophol

The urinary excretion products of serotonin (5-hydroxytryptamine, 5HT) are 5-hydroxyindole-3-acetic acid (5HIAA) and 5-hydroxytryptophol (5HTOL), and the ratio of 5HTOL to 5HIAA is normally very low (< 0.01 ) in man. Intake of foods rich in 5HT (high amounts in banana, pineapple, and walnuts) induces a general increase in the output of 5HT metabolites, without affecting the 5HTOL/5HIAA ratio. In contrast, during metabolism of ethanol there is a shift in the catabolic pattern of 5HT, and the formation of 5HTOL increases appreciably at the expense of 5HIAA. Accordingly, the urinary 5HTOL/ 5HIAA ratio increases and does not recover to baseline levels until several hours after ethanol has been cleared from the body. When 10 healthy subjects ingested a moderate dose of ethanol (0.5 g/kg), the urinary 5HTOL/SHIAA ratio was increased approximately 70-fold on average at 4 h after intake. When the same amount of ethanol was ingested together with 3 bananas (approximately 10 mg 5HT), this ratio was increased approximately 100-fold at 4 h and still significantly higher than baseline levels at 24 h. Starting at 3-4 h after the combined intake of ethanol and banana, 7 subjects experienced one or more unpleasant symptoms (diarrhea, headache, and fatigue) which are associated with the 5HT system. The events were transient but typically lasted for several hours, and the duration correlated with the time period during which 5HTOL levels were raised. Intake of ethanol and banana separately produced much lower increases in 5HTOL output and caused no corresponding effects. This observation indicate that dietary 5HT intake together with even a moderate dose of ethanol can provoke unpleasant physiological symptoms. The symptoms may be attributed to the high concentration of 5HTOL.