Leptin,NPY, Melatonin and Zinc Levels in Experimental Hypothyroidism and Hyperthyroidism: The Relation to Zinc

Since zinc mediates the effects of many hormones or is found in the structure of numerous hormone receptors, zinc deficiency leads to various functional impairments in the hormone balance. And also thyroid hormones have important activity on metabolism and feeding. NPY and leptin are affective on food intake and regulation of appetite. The present study is conducted to determine how zinc supplementation and deficiency affect thyroid hormones (free and total T3 and T4), melatonin, leptin, and NPY levels in thyroid dysfunction in rats. The experiment groups in the study were formed as follows: Control (C); Hypothyroidism (PTU); Hypothyroidism+Zinc (PTU+Zn); Hypothyroidism+Zinc deficient; Hyperthyroidism (H); Hyperthyroidism+Zinc (H+Zn); and Hyperthyroidism+Zinc deficient. Thyroid hormone parameters (FT₃, FT₄, TT₃, and TT₄) were found to be reduced in hypothyroidism groups and elevated in the hyperthyroidism groups. Melatonin values increased in hyperthyroidism and decreased in hypothyroidism. Leptin and NPY levels both increased in hypo- and hyperthyroidism. Zinc levels, on the other hand, decreased in hypothyroidism and increased in hyperthyroidism. Zinc supplementation, particularly when thyroid function is impaired, has been demonstrated to markedly prevent these changes.     

Hypothyroidism during treatment with tyrosine kinase inhibitors

Tyrosine kinase inhibitors are relatively new targeted therapy drugs used for the treatment of metastatic clear cell kidney carcinoma, gastrointestinal stromal tumours, thyroid carcinoma and pancreatic neuroendocrine tumours during the progression of the disease. Hypothyroidism or thyroid dysfunction is often a side effect of this treatment. Therefore, monitoring of thyroid hormone levels before the beginning and during the treatment of tyrosine kinase inhibitors is a necessity. Hypothyroidism correlates with objective response to the treatment. Sunitinib. This is the most described tyrosine kinase inhibitor which causes hypothyroidism. The mechanism of hypothyroidism is still unclear. Sorafenib. Symptoms of hypothyroidism occur in 18% of patients treated with sorafenib due to metastatic renal cell carcinoma. Imatinib. Hypothyroidism is one of the most frequent side effects of the treatment. Emergent tracheotomy was necessary due to larynx swelling during marked hypothyroidism. Motesanib. Hypothyroidism or increased TSH level is diagnosed in 22% to 69% of patients with metastatic differentiated or medullary thyroid carcinomas. The management of patients with thyroid dysfunction and related symptoms such as fatigue is undoubtedly a challenge to an oncologist.     

Effects of haloperidol and melatonin on the in situ activity of nigrostriatal tyrosine hydroxylase in male Syrian hamsters

Haloperidol, an antipsychotic drug, was tested for its effects on the in situ activity of nigrostriatal and hypothalamic tyrosine hydroxylase, in control male Syrian hamsters and in those receiving a high daily dose of melatonin. After receiving daily ip injections (1.25 mg/kg ip) of haloperidol for 21 days, the animals were sacrificed and brain tissue collected for analysis of dopamine and metabolites by HPLC with electrochemical detection. In situ activity of tyrosine hydroyxlase (TH) activity was determined by measuring the accumulation of L-Dopa after administration of the L amino acid decarboxylase inhibitor, mhydroxybenzylhydrazine. Tissue content of dopamine and its metabolites, DOPAC and HVA, was depressed in striatum of animals receiving haloperidol, and tyrosine hydroxylase (TH) activity was significantly decreased 20-24 h after the last injection (from 1823 +/- 63 to 1139 +/- 85 pg l-dopa/mg tissue). The decrease in TH activity in striatum was significantly inhibited by daily injections of a high dose of melatonin (2.5 mg/kg ip) (from 1139 +/- 85 to 1560 +/- 116 pg L-dopa/mg tissue). In the substantia nigra and in the hypothalamus, on the other hand, haloperidol significantly increased the activity of tyrosine hydroxylase. Melatonin administration did not significantly influence TH activity in the substantia nigra, but inhibited TH activity in the hypothalamus and in the pontine brainstem. One explanation for these data is that chronic haloperidol administration in Syrian hamsters increases TH activity in hypothalamus and substantia nigra, but decreases TH activity in striatum by a mechanism involving D2 presynaptic receptors and a melatonin sensitive kinase which regulates TH phosphorylation.     

Tyrosine Kinase Inhibitors and the Thyroid as Both an Unintended and an Intended Target

ObjectiveTo review the association of the tyrosine kinase inhibitor sunitinib with hypothyroidism as well as the mean time to onset, possible mechanisms, reversibility, and mean duration.MethodsWe performed a MEDLINE search of the English-language literature using a combination of words (“sunitinib,” “tyrosine kinase inhibitors,” “thyroid,” and “hypothyroidism”) to identify original studies and reviews on sunitinib and thyroid function.ResultsHypothyroidism was reported in 36% to 46% of patients who took sunitinib in prospective studies. A higher incidence (53% to 85%) was reported in studies containing both retrospective and prospective data. The mean time to onset of hypothyroidism after initiation of sunitinib therapy ranged from 12 to 50 weeks. The risk of development of hypothyroidism appears to increase with the increasing duration of sunitinib therapy, and the condition is likely reversible once therapy has been discontinued.ConclusionBaseline thyroid function tests should be performed before the initiation of sunitinib treatment. Because hypothyroidism can develop early in the course of therapy, thyroid function tests should be monitored frequently throughout the duration of treatment. Possible mechanisms for thyroid dysfunction include impaired thyroid hormone synthesis, a destructive thyroiditis preceding the development of hypothyroidism, and increased thyroid hormone clearance. If hypothyroidism is identified, levothyroxine therapy should be promptly initiated. (Endocr Pract. 2008;14:618-624)     

Effects of hyperthyroidism and hypothyroidism on glutamine metabolism by skeletal muscle of the rat.

1. The effects of hyperthyroidism and hypothyroidism on the concentrations of glutamine and other amino acids in the muscle and plasma and on the rates of glutamine and alanine release from incubated isolated stripped soleus muscle of the rat were investigated. 2. Hyperthyroidism decreased the concentration of glutamine in soleus muscle but was without effect on that in the gastrocnemius muscle or in the plasma. Hyperthyroidism also increased markedly the rate of release of glutamine from the incubated soleus muscle. 3. Hypothyroidism decreased the concentrations of glutamine in the gastrocnemius muscle and plasma but was without effect on that in soleus muscle. Hypothyroidism also decreased markedly the rate of glutamine release from the incubated soleus muscle. 4. Thyroid status was found to have marked effects on the rate of glutamine release by skeletal muscle per se, and may be important in the control of this process in both physiological and pathological conditions.     

Short-term effect of stress on tyrosine hydroxylase activity

The short-term influences of stress on the activities of tyrosine hydroxylase in vivo and in vitro were examined in mice. The in vivo tyrosine hydroxylase activity was estimated by the rate of dopa accumulation which was measured at 30 min after the injection of NSD-1015 (100 mg kg), an aromatic l-amino acid decarboxylase inhibitor, intraperitoneally and was compared with tyrosine hydroxylase activity measured in vitro. For the in vivo assay, both the accumulation of dopa (tyrosine hydroxylase activity) and that of 5-hydroxytryptophan (tryptophan hydroxylase activity) and the levels of monoamines and the metabolites (noradrenalin, adrenalin, dopamine, normetanephrine, 3-methoxytyramine and serotonin) and those of precursor amino acids, tyrosine and tryptophan, were investigated in ten different brain regions and in adrenals. The amount of dopa accumulation in the brain as a consequence of decarboxylase inhibition, in vivo tyrosine hydroxylase activity, was significantly increased by stress, in nerve terminals (striatum, limbic brain, hypothalamus, cerebral cortex and cerebellum) and also in adrenals. The effect of stress on tyrosine hydroxylase activity in vitro at a subsaturating concentration of 6-methyltetrahydropterin cofactor was also observed in nerve terminals (striatum, limbic brain, hypothalamus, and cerebral cortex). The amount of 5-hydroxytryptophan accumulation, the in vivo tryptophan hydroxylase activity, was also significantly increased in bulbus olfactorius, limbic brain, cerebral cortex, septum and lower brain stem. The influence of stress was also observed on the levels of precursor amino acids, tyrosine and tryptophan and monoamines in specific brain parts. These results suggest that the stress influences both catecholaminergic neurons and serotonergic neurons in nerve terminals in the brain. This effect was also observed on tyrosine hydroxylase activity in vitro in nerve terminals. However, in adrenals, the influence by stress was not observed on the in vitro activity, although dopa accumulation was increased.     

Age-related changes in the thyroid hormone effects on malondialdehyde-modified proteins in the rat heart.

To determine the age-related changes in thyroid hormone (TH) effects on malondialdehyde (MDA)-modified proteins in cardiac tissue, rats at 4, 12, and 25 months of age were studied. Hyperthyroidism was induced with daily injection of L-triiodothyronine (15 microg/100 g) intraperitoneally for 10 days. Hypothyroidism was induced with 0. 025% methimazole in the drinking water for 4 weeks. MDA proteins were measured with immunoblots using a specific anti-MDA antiserum. MDA was measured as thiobarbituric acid reactive substance. Hypothyroidism in 4-month-old rats was associated with significant reduction in MDA proteins compared to euthyroid rats (13.4 +/- 5.9% vs. 99.8 +/- 10.4% of controls P < 0.001). Hyperthyroidism did not result in a significant change of MDA proteins. In aged rats, neither hypothyroidism nor hyperthyroidism was associated with significant changes in cardiac MDA proteins. The changes in MDA proteins did not correlate with cardiac MDA concentrations. In young rats, the MDA concentrations (nmol/mg) were significantly reduced in hypothyroidism (2.71 +/- 0.21) and were increased in hyperthyroidism (8.19 +/- 0.78) compared to euthyroid values (5.06 +/- 0.71) P < 0. 01. In aged rats, cardiac MDA content was significantly increased during both hyperthyroidism and hypothyroidism. We conclude that alterations in MDA protein content is yet another potential biochemical effect of TH in cardiac tissue. This particular effect is significantly blunted with age.     

Effect of Hypo- and Hyperthyroidism on Hexokinase in the Developing Cerebellum of the Rat

Abstract: Total hexokinase levels (units/g tissue) have been measured during postnatal development of the cerebellum in control, hypothyroid, and hyperthyroid rats. In addition, distribution of hexokinase in the developing cerebellum has been observed with an immunofluorescence method. Hypothyroidism delays the normally observed postnatal increase in total hexokinase activity, whereas hyperthyroidism accelerates the increase. In normal animals, hexokinase levels in maturing Purkinje cells pass through a transient increase, with maximal levels at approximately 8 days postnatally followed by rapid decline to relatively low levels by 12 days; hypothyroidism delays this transient increase and subsequent decline, but hyperthyroidism does not appear to affect markedly the timing of this phenomenon. Cerebellar glomeruli are relatively enriched in hexokinase content, as judged by their intense fluorescence. Hypothyroidism delays the development of intensely stained glomeruli. Hyperthyroidism did not appear to cause precocious increase in numbers of glomeruli but may have increased the rate at which the hexokinase was assimilated by newly formed glomeruli. The effects of hypo- and hyperthyroidism on total cerebellar hexokinase levels are interpreted in terms of the effect of thyroid hormone on the biochemical maturation of synaptic structures rich in hexokinase.     

Changes in the activities of adenosine-metabolizing enzymes in six regions of the rat brain on chemical induction of hypothyroidism.

1. Rats (4 weeks old) were made hypothyroid by treatment with propylthiouracil and a low-iodine diet for a further period of 4 weeks. Synaptosomal membranes, myelin and 105,000 g soluble fractions were obtained from six regions of the brain. 2. Hypothyroidism resulted in 2-5-fold increases in membrane-bound 5'-nucleotidase activity in synaptosomal fractions obtained from cerebellum, cortex, striatum and hippocampus. By contrast, myelin 5'-nucleotidase activity was slightly increased only in the medulla oblongata. 3. Hypothyroidism did not change adenosine deaminase activity, but decreased adenosine kinase activity by approx. 40% in soluble fractions obtained from cerebellum, hippocampus, striatum and hypothalamus. 4. It is suggested that these changes in hypothyroidism, in particular the increases in 5'-nucleotidase activity, could enhance the neuromodulatory effect of adenosine to decrease neurotransmitter release.     

Effect of thyroidal state on the gastrointestinal transit and emptying of young broilers

1. In newly hatched broilers, propylthiouracil and thyroid powder added to the diet produced hypothyroidism and hyperthyroidism, respectively. After 4-5 days of treatment body and thyroid weight changed, but no differences in body temperature were found. 2. The hyperthyroidal animals had high mortality rate and the hypothyroidal ones showed significantly lower glycemia values. 3. The gastrointestinal transit and emptying of 8 and 15 days old hypo-, hyper- and euthyroidal broiler chicks were measured using 14C-PEG-4000 as a marker. 4. Hypothyroidism prolonged GI transit and emptying, whereas hyperthyroidism modified these parameters in a way dependent of the elapsed time after the test meal: at 0.5 and 1 hr transit and emptying were quick, but at 2 and 4 hr the transit was slow. 5. Hyperthyroidism also delayed the transit of large bowel intraluminal contents in 15-day-old chickens. 6. These results are very similar to those of starvation, suggesting an important interaction between diencephalon, thyroid gland and GI motility in young chickens.     

Influence of hypo- and hyperthyroidism on the turnover rate of noradrenaline, dopamine and serotonin in various rat cerebral structures]

The effect of chronic treatment with tyroxine (T4) or propylthiouracile (PTU) on the turnover of norepinephrine (NE), dopamine (DA) and 5-hydroxytryptamine (5-HT) has been studied in various areas of the rat brain (brain stem, hypothalamus, striatum and "rest of the brain"). The turnover of NE and DA was determined by the decay in endogenous levels after inhibition of tyrosine hydroxylase by alpha-methylparatyrosine and the turnover of 5-HT was evaluated by the initial accumulation of endogenous 5-HT after inhibition of monoamine oxydase by pargyline. T4 treatment accelerated the release of DA from the striatum but had no significant effects on NA release in the various cerebral areas : nevertheless the NE endogenous level was significantly reduced in the brain stem. PTU treatment delayed the release of DA and NA only from the "rest of the brain". Concerning 5-HT, the only significant variation was observed in the hypothalamus of PTU-treated rats and implied increased turnover. The possible relations between the changes in cerebral monoamines turnover and the behavioural alterations which are observed in thyroid disfunction are discussed.     

Brown adipose tissue cell respiration in hypo- and hyperthyroidism after stimulation with selective and non selective beta-adrenergic agonists.

Brown adipocyte respiration was measured in isolated cells from hypothyroid, hyperthyroid and euthyroid Sprague-Dawley male rats. Hypothyroidism was induced by providing drinking water containing methimazole and hyperthyroidism was induced by addition of thyroid powder to the diet. Brown adipose tissue (BAT) cells were isolated by collagenase digestion and oxygen consumption (VO2) was measured by Clark type oxygen electrodes. BAT cell respiration was stimulated by selective and nonselective beta-adrenergic agonists: BRL 35135A (BRL) and Isoprenaline (ISO). Basal BAT cells respiration did not differ according to thyroid status. Maximal VO2 responses of BAT adipocytes from hypothyroid rats were significantly lower than in euthyroidism after ISO and BRL. The reduced response was more marked for ISO than for BRL. The thermogenic sensitivity was significantly greater in euthyroid than is hypothyroid cells for ISO, but not for BRL. The euthyroid-hyperthyroid differences were not significantly different. These results suggest: basal respiration of BAT cells in hypo- and hyperthyroidism does not reflect the overall changes in whole body metabolism; the decreased thermogenic response in hypothyroidism might be due to decreased beta-adrenoceptor numbers and/or decreased intracellular thyroxine-triiodothyronine conversion; changes in sensitivity to ISO and BRL in vitro reflect the changes seen in VO2 in vivo.     

Effects of dysthyroidism on central catecholaminergic neurons

After 15 years of research, it is clear that alterations in thyroidal status affect catecholaminergic neurons in the developing as well as in the adult brain. Experiments on fetal catecholaminergic brain areas grafted into the anterior eye chamber of adult thyroidectomized rat have shown the thyroid hormone dependency of the morphological differentiation of catecholaminergic neurons originating from the substantia nigra and the locus coeruleus. Furthermore, thyroid hormones also affect the metabolism of catecholaminergic neurons. Neonatal hypothyroidism induced either by ¹³¹I or by an antithyroid drug decreases the concentration of dopamine, noradrenaline and the activity of tyrosine hydroxylase at least in whole brain studies. Treatments with l-thyroxine of neonatally thyroidectomized rats reverse these neurochemical changes in a both time and dose dependent manner. These presynaptic modifications are associated with a decrease in the number of catecholaminergic receptors in different brain areas. On the opposite, experimental neonatal hyperthyroidism induced by daily administration of l-triiodothyronine increases the synthesis as well as the utilization of catecholamines. These changes are also associated with an alteration of catecholaminergic receptors. Despite numerous studies, there is, so far, no clear conclusion on the effects of neonatal dysthyroidism on the development of each catecholaminergic group. However, from these studies, it appears that the intensity of neonatal dysthyroidism greatly varies, depending of the monoamine and the brain area studied. The utilization of fetal brain cell cultures growing in a chemically defined medium has permitted to demonstrate the direct effect of thyroid hormones on fetal brain cells and the morphological effects of triiodothyronine on the size and the neurite length and arborization of fetal hypothalamic dopaminergic neurons.In the adult brain, hypothyroidism induced by surgical thyroidectomy, decreases the rate of catecholamines synthesis, decreases the number of alpha noradrenergic receptors and has no effect on striatal dopaminergic receptors. In contrast, hyperthyroidism increases the rate of catecholamines synthesis and induced an hypersensitivity of noradrenergic receptors. The intensity of the effects of dysthyroidism seems to be dependent on the monoamine and the brain area studied.In conclusion, it can be proposed that in the neonate thyroid hormones act on CA neuron activity mostly through a morphogenetic effect whereas in the adulthood they directly affect CA metabolism.     

Hoffman's syndrome: muscle stiffness,pseudohypertrophy and hypothyroidism

Primary hypothyroidism is a chronic and insidious disease caused by failure of thyroid hormone production. We observed a 38-year-old woman admitted to our hospital due to progressive proximal weakness, muscle pain and fatigue during mild exercise. Laboratory tests showed features of rhabdomyolysis and hypothyroidism. After examination of the thyroid, we reached a diagnosis of Hashimoto's thyroiditis and hypothyroid myopathy. Hypothyroidism should be considered as a differential diagnosis of creatine kinase elevation; actually, neuromuscular symptoms and signs occur in most newly diagnosed patients with thyroid diseases. Hypothyroidism presenting as muscle stiffness and pseudohypertrophy is called 'Hoffman's syndrome'.     

Effects of thyroid hormones on the evolution of monoamine oxidase activity in the brain and heart of the developing rat

The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.     

Thyroid hormones and the creatine kinase system in cardiac cells

The paper reviews the current evidence on the role of thyroid hormones in regulating the creatine kinase energy transfer system at multiple structures in cardiac cells. 1) Thyroid hormones modulate the overall synthesis of phosphocreatine (PCr) by increasing the rate of mitochondrial oxidative phosphorylation. 2) Thyroid hormones regulate the total activity of creatine kinase and its isoenzyme distribution. In comparison with normal thyroid state (euthyroidism), hypothyroidism is characterized by decreased total creatine kinase activity owing to diminished fraction of creatine kinase. On the other hand, hyperthyroidism, while causing no change in total creatine kinase activity, leads to increased fractions of neonatal isoforms of creatine kinase, and, in case of prolonged hyperthyroidism, to decreased fraction of mitochondrial creatine kinase. The latter change is associated with partial uncoupling between mitochondrial creatine kinase and adenine nucleotide translocase reflected by decreased PCr/O ratio. 3) Hyperthyroidism leads to increased passive sarcolemmal permeability due to which the leakage of creatine along its concentration gradient occurs. As a result of (i) increased sarcolemmal permeability for creatine, (ii) uncoupling of mitochondrial PCr synthesis, and (iii) increased energy utilization rate the steady state intracellular PCr content decreases under hyperthyroidism which, in turn, increases the myocardial susceptibility to hypoxic damage. Thyroid state also modulates the protective effects of exogenous PCr on energetically depleted myocardium.     

Activity of enzymes involved in norepinephrine biosynthesis in the brown adipose tissue of the developing rat. Influence of hypothyroidism

The activities of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) were measured in vitro in the brown adipose tissue (BAT) of control and hypothyroid developing rats. Neonatal hypothyroidism slows the development of TH activity, as manifest in lower BAT TH activity, relative to controls, up to 20 days. This effect is more pronounced when the onset of hypothyroidism is induced prenatally. No clear effect of hypothyroidism on DBH activity was evident.     

Thyroid-induced changes in the growth of the Liver,Kidney, and Diaphragm of Neonatal Rats

Eu-, hypo- and hyper-thyroid rats were studied 12 days postpartum. Hypothyroidism was induced by administering propylthiouracil (PTU) via the mother's drinking water beteen late gestation and throughout lactation. This procedure effectively blocked the normal early postnatal surge of T₃ and T₄. In contrast, hyperthyroidism was induced in the young pups by daily injections of T₄ from day 3 postpartum. The effects of these experimental manipulations of thyroid status on the rates of protein turnover and growth of the liver, kidney, and diaphragm were studied and compared with measurements made on appropriate euthyroid control tissues. Tissue rates of protein synthesis were decreased in response to hypothyroidism with consequent growth retardation of all three tissues and the whole animal. In contrast, the three body tissues responded very differently to the induction of hyperthyroidism. Hepatic rates of protein synthesis and growth were completely unaffected by thyroid excess. The response of the diaphragm was essentially the reverse of that seen with hypothyroidism, i.e., the enhanced rates of protein synthesis and protein degradation leading to muscle hypertrophy. The rates of protein turnover in the kidney were also increased, but unlike the diaphragm the net result was renal atrophy. Clearly, thyroid hormones influence the normal rapid growth of the neonate and its individual tissues. However, beyond a certain concentration the threshold of responsiveness to these hormones seems to vary between individual tissues. © 1994 Wiley-Liss, Inc.     

Effects of p,p''-DDT on the Rat Brain Concentrations of Biogenic Amine and Amino Acid Neurotransmitters and Their Association with p,p''-DDT-Induced Tremor and Hyperthermia

Male, Fischer strain 344 adult rats were given various doses (25-100 mg/kg) of p,p'-DDT by oral gavage, and levels of biogenic amines, their metabolites, and amino acid neurotransmitters, tremor activity, and rectal temperature were measured at several intervals (2, 5, 12, and 24 h) after dosing. Dose-related increases in rectal temperature and in tremor activity were observed at 50-100 mg/kg 12 h after dosing. Tremorigenic doses of DDT increased the 5-hydroxyindoleacetic acid (5-HIAA) level in hypothalamus, brainstem, and striatum, whereas doses of 75 and 100 mg/kg increased the 3-methoxy-4-hydroxyphenylglycol (MHPG) level in hypothalamus and brainstem and the 3,4-dihydroxyphenylacetic acid level in striatum. Six amino acids were assayed in the brainstem, hypothalamus, and striatum; aspartate and glutamate levels were increased only in brainstem at 25-100 mg/kg. No consistent changes in concentrations of taurine, glutamine, glycine, or gamma-aminobutyric acid were observed in any of the regions assayed. Time-related increases in rectal temperature were seen 2-12 h after dosing, and the presence of tremor was observed 5-12 h after dosing; for both the time of peak effect was at 12 h. The DDT-induced hyperthermia and tremor were associated with dose- and time-related increases in levels of 5-HIAA, MHPG, aspartate, and glutamate. It is suggested that an increase in the turnover rate of 5-hydroxytryptamine (5-HT) may be responsible for the DDT-induced hyperthermia, whereas increases in the metabolism of 5-HT and norepinephrine may be involved in the tremor.