Gene expression of receptors and enzymes involved in GABAergic and glutamatergic neurotransmission in the CNS of rats behaviourally dependent on ethanol.

The steady state levels of the messenger RNA (mRNA) of eight GABA(A) receptor subunits, five glutamate receptor subunits and seven enzymes involved in the synthesis of glutamate and GABA were measured in eight regions of rat brain in a recently developed animal model of 'behavioural dependence' on ethanol. 'Behavioural dependence' including loss of control was induced by offering the rats the choice between ethanol and water over a 9-month period (Group A). This group was compared with a group given the choice between ethanol and water for only 2 months (not yet 'behaviourally dependent', Group B), a group forced to consume ethanol as sole fluid over a 9-month period (also not 'behaviourally dependent', Group C) and ethanol-naive control rats (Group D). All groups were sacrificed 1 month after the ethanol was withdrawn. The mRNA concentrations of all eight GABA receptor subunits, four out of the five subunits of different glutamate receptors and those of seven enzymes involved in GABA and glutamate production were reduced almost exclusively in the parieto-occipital cortex in Groups A and B, but not Group C. These data suggest that the synthesis of glutamate and GABA and the activities of their respective neurons are selectively impaired in the parieto-occipital cortex in the groups having consumed ethanol in a free-choice design, in which its rewarding properties can better take effect than after forced administration. As the parieto-occipital cortex is believed to contain emotional memory structures, it may be hypothesized that the glutamatergic and GABAergic neuronal systems in this area are involved in the development of memory for reward from ethanol. However, they are not specifically associated with 'behavioural dependence'.

Effects of pharmacological and nonpharmacological treatments on thyroid hormone metabolism and concentrations in rat brain.

The activities of the 5'I-deiodinase (5'D-I), 5'II deiodinase (5'D-II) and 5III-deiodinase (5D-III) isoenzymes and tissue concentrations of thyroxine (T4) and triiodothyronine (T3) were measured in up to 10 regions of the rat brain after acute and subchronic nonpharmacological (sleep deprivation, 12 h fasting, 14 days' calorie-reduced diet) and pharmacological (ethanol, haloperidol, clozapine, lithium, carbamazepine, desipramine, fluoxetine, tranylcypromine, and mianserin) treatments. All of these treatments induced significant and sometimes dramatic changes in 5'D-II activities and tissue concentrations of thyroid hormones and, to a lesser extent, in 5D-III activity. The activity of 5'D-I remained unaffected. The results revealed a surprising specificity for each type of treatment in terms of the isoenzyme and hormone affected, the direction of the change, the brain region affected and the time of day. The changes in thyroid hormone concentrations frequently failed to correspond in any way to those in deiodinase activities and unexpected effects such as inhibition of both 5'D-II and 5D-III were seen, indicating that there may be additional pathways of iodothyronine metabolism in the CNS. In conclusion, particularly 5'D-II activity and thyroid hormone concentrations in the CNS are highly sensitive to many different kinds of influence that may induce changes in neuronal activity. However, these changes in deiodinase activities do not ensure stable tissue concentrations of T3, but were, on the contrary, in most cases accompanied by marked changes T3 levels in the tissue. The implications of these findings for the physiological role of thyroid hormones in the CNS are discussed.

Effects of tranylcypromine on thyroid hormone metabolism and concentrations in rat brain.

The effect of 14 days administration of the anti-depressant tranylcypromine (TCP) on iodothyronine deiodinase activities and the concentrations of thyroxine (T4) and triiodothyronine (T3) were investigated in homogenates of up to nine regions of the rat brain. The activity of the 5III deiodinase isoenzyme, which catalyses the inactivation of T3 to 3,3'-diiodothyronine (3,3'-T2), was enhanced in eight brain regions. However, the brain levels of T4 were completely unchanged and the T3 concentrations were significantly reduced in the frontal cortex only. Therefore, we also measured the T3 concentrations of three subcellular fractions (nuclei, synaptosomes and mitochondria) of six brain regions. TCP induced a significant reduction in T3 levels in the synaptosomes of the frontal cortex and significant increases in the mitochondrial T3 concentrations in the amygdala. The latter effect was replicated after 14 days administration of 5 mg/kg desipramine. No effects of either drug on nuclear concentrations of T3 were seen in any brain region. As the amygdala is critically involved in the affective coloring of sensory stimuli, the increase in T3 concentrations in the mitochondria of this brain region may be of relevance for the mechanism of action of anti-depressant drugs.

Extraction and quantification of thyroid hormones in selected regions and subcellular fractions of the rat brain.

There is increasing evidence of an involvement of thyroid hormones in numerous physiological processes of the adult vertebrate brain. However, the only valid method available for measuring triiodothyronine (T3) in brain tissue is time-consuming and not sufficiently sensitive to determine hormone concentrations in small, but physiologically important areas such as the amygdala and septum. We therefore developed a protocol for reliable measurement of the concentrations of thyroxine (T4) and T3 in brain tissue. This was achieved by combining a new method of extracting iodothyronines with highly sensitive, accurate and reproducible radioimmunoassays (RIAs) in order to be able to detect T4 and T3 in homogenates and even subcellular fractions (nuclear, synaptosomal and mitochondrial) in up to 11 regions of the rat brain. The iodothyronines were extracted from tissue samples by adding 100% methanol containing 1 mM PTU. Recoveries of 72.8 +/- 5.5% and 83.2 +/- 3.3% for T4 and T3, respectively, were obtained. The RIA detection thresholds were 10 fmol/g for T4 and 18 fmol/g for T3. Only 0.2% of the antibody for T4 cross-reacted with T3 and 0.95% reverse T3. T3 antibody (0.05%) reacted with T4 and 0.01% with 3,5-T2. The T4 concentrations in the homogenates of selected areas of the brain ranged between 1 and 4 pmol/g, whereas those of T3 ranged between 0.5 and 4 pmol/g. The T3 levels ranged between 190 and 470 fmol/mg protein, 38 and 110 fmol/g protein and 25 and 180 fmol/mg protein in the nuclei, synaptosomes and mitochondriae, respectively. In conclusion, the newly developed method enabled us to determine both T4 and T3 concentrations in homogenates and T3 in subcellular fractions of regions of the brain as small as the septum and amygdala.

Gene expression of glucose transporters and glycolytic enzymes in the CNS of rats behaviorally dependent on ethanol.

The steady-state levels of messenger RNA (mRNA) of the glucose transporters 1 and 3 and the glycolytic enzymes hexokinase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate dehydrogenase were measured in up to seven brain regions of the rat in a recently developed animal model of 'behavioral dependence' on ethanol. Irreversible behavioral dependence, including loss of control, was induced by offering the rats the choice between ethanol and water over a 9-month period (Group A). This group was compared with a group given the choice between ethanol and water for only 2 months (not yet behaviorally dependent, Group B), a group forced to consume ethanol as sole fluid over a 9-month period (not behaviorally dependent, Group C) and ethanol-naive control rats. All groups were sacrificed 1 month after ethanol withdrawal. The mRNA concentrations of both neuronal glucose transporter 3 and the key glycolytic enzymes phosphofructokinase and pyruvate dehydrogenase were significantly reduced in the hippocampi of the rats behaviorally dependent on ethanol (Group A). No significant changes were seen in any of the remaining brain regions (e.g., cortical areas, limbic forebrain, amygdala, midbrain) in Group A, or in any brain area at all in Groups B and C. The results show that chronic consumption of ethanol in a free-choice situation may impair neuronal glucose uptake and glycolytic flux. This effect is manifested exclusively in the hippocampus and is specifically related to the development of behavioral dependence, since it was not found after forced administration of large amounts of ethanol (Group C).

3,3'-Diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors and of healthy subjects during acute stress.

In this article we describe the development of a highly sensitive, accurate, and reproducible RIA for the measurement of 3,3'-diiodothyronine (3,3'-T2) in human serum and brain tissue. The detection limits were 1.8 fmol/g and 1.5 pmol/L in human brain tissue and serum, respectively. Serum concentrations of 3,3'-T2 were measured in 4 groups of patients with nonthyroidal illnesses (NTI), i.e. brain injuries (n = 15), sepsis (n = 24), liver disease (n = 22), and brain tumors (n = 23). The mean serum concentration of 3,3'-T2 in 62 healthy controls was 46.6 +/- 20.0 pmol/L. 3,3'-T2 levels declined significantly with increasing age. They were significantly lower in patients with brain injury (34.2 +/- 19.4 pmol/L; P = 0.006), were at the upper limit of normal in patients with sepsis (57.0 +/- 36.9 pmol/L; P = 0.06), and were elevated in patients with liver disease (72.6 +/- 56.7 pmol/L; P = 0.04) and brain tumors (89.0 +/- 40.9 pmol/L; P = 0.01). The serum levels of T3 were significantly lower than those in controls in all 4 patient groups. Serum concentrations of 3,3'-T2 were significantly enhanced in 9 patients with hyperthyroidism (85.4 +/- 43.0 pmol/L; P = 0.01) and were reduced in 12 patients with hypothyroidism (14.9 +/- 9.2 pmol/L; P = 0.001). In both normal brain tissue, obtained either intraoperatively or excised postmortem, and brain tumors, the concentrations of 3,3'-T2 ranged between 50-300 fmol/g. In healthy controls, 2 different forms of acute stress (sleep deprivation and delivering a lecture) significantly increased serum levels of T4 and T3, but did not affect those of 3,3'-T2 or 3,5-T2. In conclusion, our results show that, contrary to expectation, a low T3 syndrome in NTI is not always associated with low serum concentrations of 3,3'-T2. The production of 3,3'-T2 in NTI seems to be regulated in a disease-specific manner, resulting in unchanged, reduced, or elevated hormone concentrations.

Rat brain type II 5'-iodothyronine deiodinase activity is extremely sensitive to stress.

The effects of different kinds of acute stressor on thyroid hormone concentrations and deiodinase activities were investigated in four brain regions (frontal cortex, amygdala, hypothalamus, and cerebellum) and in the pituitaries and livers of adult male rats. Five groups of rats were killed after each of the following stressors: (a) an intraperitoneal injection of saline, (b) intragastric intubation, (c) and (d) two different forms of handling, being grasped as for intraperitoneal injection and being moved from one cage to another, and (e) a 2-h period spent in a slowly rotating drum. Two other groups were placed in the rotating drums for 10 and 19 h (sleep deprivation experiment), respectively. All stressors induced significant (in some cases up to 200%) increases in the activity of type II 5'-iodothyronine deiodinase, which catalyzes the deiodination of the prohormone L-thyroxine (T4) to the active metabolite 3,3',5-triiodo-L-thyronine (T3). As a consequence, the tissue concentrations of T4 fell, and those of T3 rose (sometimes by up to 300%). However, these changes were limited to selected areas of the brain that were specific for each stressor and were not seen in all brain regions investigated in any group. No clear-cut effects of stress were seen on the activities of the type III 5-iodothyronine deiodinase isoenzyme, which catalyzes the inactivation of T3, on liver or serum thyroid hormone concentrations or on liver of brain type I 5'-iodothyronine deiodinase activities. In summary, our results show that even mild and very brief stress can induce marked increases in T3 concentrations specifically in brain but not in liver or blood. Thus, contrary to common opinion, thyroid hormones may play an important physiological role in stress reactions, at least in tissues that contain type II 5'-iodothyronine deiodinase, such as brain and pituitary.

Effects of acute administration of ethanol and the mu-opiate agonist etonitazene on thyroid hormone metabolism in rat brain.

The effects of acute, low-dose administration of ethanol (1 g/kg bodyweight) and the mu-opioid receptor agonist etonitazene (30 microg/kg bodyweight) on the activities of the iodothyronine deiodinase isoenzymes were investigated in nine regions of the rat brain. The experiments were performed at three different times of the 24-h cycle (1300, 2100 and 0500 hours) and the rats were decapitated 30 and 120 min after administration of the respective drugs. Interest was focused on changes in the two enzymes that catalyze 1) 5'-deiodination of thyroxine (T4) to the biologically active triiodothyronine (T3), i.e. type II 5'-deiodinase (5'D-II) and 2) 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e. type III deiodinase (5D-III). 120 min after administration of ethanol and etonitazene 5D-III activity was selectively inhibited in the frontal cortex (at 1300 and 1700 hours) and the amygdala (at all three measuring times). The 5'D-II activity was significantly enhanced 30 min after administration of etonitazene in the frontal cortex, amygdala and limbic forebrain, and after administration of ethanol in the amygdala alone. These effects on 5'D-II activity were seen at 2100 hours only. In conclusion, the two different addictive drugs both reduced the inactivation of the physiologically active thyroid hormone T3 and enhanced its production. These effects occurred almost exclusively in the brain regions which were most likely to be involved in the rewarding properties of addictive drugs. As thyroid hormones have stimulating and mood-elevating properties, an involvement of these hormones in the reinforcing effects of addictive drugs seems conceivable.

Dopamine receptor gene expression in an animal model of 'behavioral dependence' on ethanol.

The steady-state levels of messenger RNA (mRNA) of five cloned dopamine (D) receptors were measured in five brain regions in rats in a recently developed animal model of 'behavioral dependence' on ethanol. One group of rats was given the choice between ethanol and water over a 9-month period and developed 'behavioral dependence' on ethanol (group a). This group was compared with a group given the choice between ethanol and water for only 2 months (not yet behaviorally dependent, group b), a group forced to consume ethanol as sole fluid over a 9-month period (not behaviorally dependent, group c) and ethanol-naive control rats. All groups were sacrificed 1 month after ethanol withdrawal. The concentrations of mRNA of D3-receptors in the limbic forebrain (which included the nucleus accumbens) were significantly lowered in groups a and b, but unchanged in group c. D3 mRNA levels were reduced in the hippocampus of group b and unchanged in the cortex, amygdala and striatum. No significant changes in the mRNA concentrations of D1-, D2-, D4- or D5-receptors were seen in the five brain regions in any group. In conclusion, chronic consumption of ethanol under the 'free-choice condition', which may best induce the drug-rewarding effect, leads to specific changes in the D3-receptor gene expression which were not seen after forced ethanol administration. Changes in D3 mRNA levels were, however, not a specific correlate of 'behavioral dependence', as they were also detected in rats not yet 'behaviorally dependent' (group b).

Elevated 3,5-diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors.

This study reports the development of a highly sensitive and reproducible RIA for the measurement of 3,5-diiodothyronine (3,5-T2) in human serum and tissue. The RIA employs 3-bromo-5-[125I]iodo-L-thyronine (3-Br-5-[125I]T1) as tracer, which was synthesized carrier free by an interhalogen exchange from 3,5-dibromo-L-thyronine (3,5-Br2T0). The detection limits were 1.0 fmol/g and 0.8 pmol/L in human brain tissue and serum, respectively. T3, diiodothyroacetic acid, and 3-monoiodothyronine cross-reacted with a 3,5-T2 antibody to the extent of 0.06%, 0.13%, and 0.65%, respectively. Serum concentrations of 3,5-T2 were measured in 62 healthy controls and 4 groups of patients with nonthyroidal illness, i.e. patients with sepsis (n = 24), liver diseases (n = 23), head and/or brain injury n = 15), and brain tumors (n = 21). The mean serum level of 3,5-T2 in the healthy subjects was 16.2 +/- 6.4 pmol/L. Concentrations of 3,5-T2 were significantly elevated in patients with sepsis (46.7 +/- 48.8 pmol/L; P < 0.01), liver diseases (24.8 +/- 14.9 pmol/L; P < 0.01), head and/or brain injury (24.1 +/- 11.3 pmol/L; P < 0.05), and brain tumors (21.6 +/- 4.8 pmol/L; P < 0.01). In all 4 patient groups, serum levels of T3 were significantly reduced, confirming the existence of a low T3 syndrome in these diseases. Serum concentrations of 3,5-T2 were significantly elevated in patients with hyperthyroidism (n = 9) and were reduced in patients with hypothyroidism (n = 8). The levels of T4, T3, and 3,5-T2 were measured in normal human tissue samples from the pituitary gland and various brain regions and in brain tumors. In normal brain tissue, the concentrations of 3,5-T2 ranged between 70-150 fmol/g, and the ratio of T3 to 3,5-T2 was approximately 20:1. In brain tumors, however, T3 levels were markedly lower, resulting in a ratio of T3 to 3,5-T2 of approximately 1:1. Recent findings suggest a physiological, thyromimetic role of 3,5-T2, possibly stimulating mitochondrial respiratory chain activity. Should this prove to be correct, then the increased availability of 3,5-T2 in nonthyroidal illness may be one factor involved in maintaining clinical euthyroidism in patients with reduced serum levels of T3 during nonthyroidal illness.

Thyroid hormone metabolism in the rat brain in an animal model of 'behavioral dependence' on ethanol.

Thyroid hormone metabolism was investigated in the frontal cortex and amygdala in groups of rats either 'behaviorally dependent' on ethanol or chronically exposed to ethanol, but not 'dependent'. The activities of the 5'II deiodinase isoenzyme, which catalyzes the deiodination of thyroxine (T4) to the active metabolite triiodothyronine (T3), was elevated in the frontal cortex in both the 'behaviorally dependent' and the 'non-dependent' rats. The activities of the 5-II deiodinase isoenzyme, which catalyzes the inactivation of T3 to 3,3'-T2 was, however, selectively inhibited in the amygdalas of the rats 'behaviorally dependent' on ethanol, but normal in the 'non-dependent' rats. This suggests that increases in intracellular concentrations of T3 in the amygdala may be specifically related to reward mechanisms and the development of 'behavioral dependence' on ethanol.

Effects of lithium and carbamazepine on thyroid hormone metabolism in rat brain.

The effects of lithium (LI) and carbamazepine (CBM) on thyroid hormone metabolism were investigated in 11 regions of the brain and three peripheral tissues in rats decapitated at three different times of day (4:00 A.M., 1:00 P.M., and 8:00 P.M.). Interest was focused on the changes in the two enzymes that catalyze: (1) the 5'deiodination of T4 to the biologically active T3, i.e., type II 5'deiodinase (5'D-II) and (2) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e., type III 5 deiodinase (5D-III). A 14-day treatment with both LI and CBM induced significant reductions in 5D-III activity. However, 5'D-II activity was elevated by CBM and reduced by LI, both administered in concentrations leading to serum levels comparable with those seen in the prophylactic treatment of affective disorders. The effects were dose dependent, varied according to the region of the brain under investigation, and strongly depended on the time of death within the 24-hour rhythm. The consequences of these complex effects of LI and CBM on deiodinase activities for thyroid hormone function in the CNS and also their possible involvement in the mechanisms underlying the mood-stabilizing effects of both LI and CBM remain to be investigated.

Phenolic and tyrosyl ring iodothyronine deiodination and thyroid hormone concentrations in the human central nervous system.

In the present study we investigated the biochemical properties of in vitro phenolic (5'D) and tyrosyl (5D) ring deiodination and the tissue concentrations of T4, T3, and rT3 in adult human central nervous system (CNS) tissue. All samples were obtained from nontumoral tissue at autopsy (n = 6) or neurosurgical operation (n = 5). Both phenolic and tyrosyl ring deiodinase activities were demonstrable in all samples obtained intraoperatively, whereas only tyrosyl ring deiodination was evident in the tissues obtained postmortem. The phenolic ring deiodination pathway corresponded to the type II 5'-deiodinase isoenzyme with regard to its high affinity for T4 and rT3 (Km = 2.2 and 2.4 nmol/L, respectively), its insensitivity to 6-propyl-n-2-thiouracil (PTU), and the sequential reaction mechanism. No PTU-sensitive 5'-deiodination of rT3 was demonstrable. Tyrosyl ring deiodination of both T4 and T3 showed typical type III 5D kinetics (Ka, 6.5 nmol/L for T4 and 3.4 nmol/L for T3) and was PTU insensitive. Nanomolar concentrations of tissue T4, T3, and rT3 were detected in samples obtained both intraoperatively and postmortem. They were very similar to the absolute values of the apparent Km for T4, T3, and rT3 in the phenolic and tyrosyl ring deiodination pathways. In conclusion, we have demonstrated the coexistence of both phenolic and tyrosyl ring deiodinase activities in the human CNS. Their kinetic characteristics, substrate specificity, and reaction mechanisms are very similar to the corresponding type II 5'- and type III 5-iodothyronine deiodinase activities in rat brain. In contrast to the findings in the rat CNS, no PTU-sensitive phenolic ring deiodinase (i.e. type I 5'D) activity was found in the human CNS. This may explain the relatively high tissue concentrations of rT3.

The effects of desipramine on thyroid hormone concentrations in rat brain.

The effects of the antidepressant desipramine on the tissue concentrations of thyroxine and triiodothyronine in 9 different regions of the brain and also in the pituitary and liver were investigated in male rats. The investigations were carried out at three different times of the light/dark cycle: 5 a.m., 1 p.m. and 11 p.m. After fourteen days' treatment with 20 mg/kg/day desipramine by gavage the concentrations of triiodothyronine in the frontal and parieto-occipital cortex were significantly higher than in the saline-treated controls, those in the hippocampus lower and those in the 6 remaining brain regions the same. In 8 areas of the brain the concentrations of thyroxine were lower in the desipramine-treated rats and the tissue ratios of triiodothyronine to thyroxine were enhanced in 6 regions. These effects are most likely the result of the action of desipramine on the activity of the isoenzyme 5'II deiodinase. This enzyme catalyzes the deiodination of thyroxine to triiodothyronine in rat brain and its activity has recently been reported to be enhanced by desipramine. The observed effects were dose-dependent and also strongly dependent upon the time within the 24 h light/dark cycle at which the hormone concentrations were measured. No effects of desipramine were seen in the pituitary or liver after 14 days' treatment, or in various areas of the central nervous system 24 h after administration. In view of the psychotropic properties of thyroid hormones, it seems possible that the observed increases in triiodothyronine concentrations, particularly in cortical areas, are involved in the mechanisms of action of desipramine.

The influence of desipramine on thyroid hormone metabolism in rat brain.

The effect of the antidepressant desipramine (DMI) on the activities of the three iodothyronine deiodinase isoenzymes involved in the central metabolism of thyroid hormones were investigated in 11 brain regions and 3 peripheral tissues in the rat. The investigations were carried out at three different times during the light/dark cycle: 5 A.M., 1 P.M. and 11 P.M. Interest is focused on changes in the two enzymes that catalyze: i) the 5'deiodination of T4 to the biologically active T3, i.e., type II 5'deiodinase (5'D-II), and ii) the 5 (or inner-ring) deiodination of T3 to the biologically inactive 3,3'T2, i.e., type III 5 deiodinase (5D-III). Fourteen days' treatment with 20 mg/kg DMI, but not with 5 mg/kg DMI, induced significant increases in 5'D-II in eight different areas of the CNS. The regions affected were identical to those that receive noradrenergic input from the locus coeruleus. Even control animals showed a circadian rhythm of 5'D-II activity in some brain regions, and the effects of DMI also depended on the time of death within the 24-hr rhythm. 5D-III was not affected. Serum T4 were lower after administration of DMI, most probably because of enhanced tissue uptake of T4. This is in line with the corresponding finding in depressed patients, indicating that similar changes in both central and peripheral thyroid hormone metabolism may occur after antidepressant pharmacotherapy in both humans and rats. These data support the hypothesis that interactions with the CNS metabolism of the thyroid hormones may be involved in the mechanisms of action of DMI.

Subchronic administration of fluoxetine to rats affects triiodothyronine production and deiodination in regions of the cortex and in the limbic forebrain.

The effects of subchronic administration of the antidepressant fluoxetine (15 mg/kg i.p., 14 days) on thyroid hormone metabolism were investigated in 11 regions of the CNS and three peripheral tissues in the rat. Fluoxetine significantly enhanced the activity of the 5'II-deiodinase isoenzyme (5'D-II), which catalyzes the deiodination of the inactive prohormone thyroxine (T4) to the active compound triiodothyronine (T3) in areas of the cortex, the limbic forebrain and the striatum. The activity of the 5D-III deiodinase isoenzyme (5D-III), which catalyzes the further deiodination of T3 to the inactive metabolite 3,3'-T2, was inhibited in the first two of these areas. The areas affected were roughly the same as those with the highest density of 5-HT2 receptors in rat brain. Theoretically, the enhancement 5'D-II activity, together with a concomitant decrease in 5D-III activity, should lead to a rise in T3 concentrations. Whether or not these effects are involved in the as yet unknown mechanism of action of this antidepressant compound is discussed.

The influence of sleep deprivation on thyroid hormone metabolism in rat frontal cortex.

The effects of 24 h sleep deprivation (SD) on central thyroid hormone metabolism were investigated in rat frontal cortex. SD induced a significant rise in the activity of iodothyronine type II 5'-deiodinase (5'D-II), which catalyzes the conversion of thyroxine (T4) to triiodothyronine (T3) in the rat central nervous system (CNS). Tissue concentrations of T4 remained unchanged, whereas levels of T3 increased to more than 150% of the corresponding levels measured in control rats. Serum concentrations of T4 and T3 were also significantly enhanced by SD--an effect that has previously been described in depressed patients having undergone the same procedure. These results suggest that SD can dramatically increase T3 concentrations (and possibly function) in rat CNS. Whether or not these findings are of relevance in regard to the well-known antidepressant effect of SD in psychiatric patients with major depressive disorders remains to be established.