Chronic Effects of Triiodothyronine in Combination with Imipramine on 5-HT Transporter, 5-HT1A

N EUROPSYCHOPHARMACOLOGY 2001 – VOL . 24 , NO . 6

? 2001 American College of Neuropsychopharmacology Published by Elsevier Science Inc.

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Chronic Effects of Triiodothyronine in Combination with Imipramine on 5-HT Transporter, 5-HT 1A and 5-HT 2A Receptors in Adult Rat Brain

X. Moreau, Ph.D., R. Jeanningros, Ph.D., and P. Mazzola-Pomietto, Ph.D.

Triiodothyronine (T3) has been shown to accelerate and potentiate the clinical response to tricyclic antidepressant (TCA) treatment in depressive disorders. The

neurobiological mechanisms underlying these therapeutic effects of T3 are still unknown. Since brain serotonin

(5-HT) changes have been implicated in the mode of action of TCA drugs, the effects of a chronic (7 or 21 days)

administration of imipramine (10 mg/kg/day) and of a low dose of T3 (4 ? g/kg/day), given alone or in combination, were investigated on the density of midbrain 5-HT transporters and of hippocampal 5-HT 1A and cortical 5-HT 2A receptors in adult Wistar rats. Neither single nor combined administration of imipramine and T3 for 7 days modified the density of 5-HT transporters and of 5-HT 1A

receptors. On day 21, the combination did not change imipramine- or T3-induced decrease in 5-HT transporter density whereas it prevented imipramine-induced increase in 5-HT 1A receptor density. Whatever the treatment duration, imipramine-T3 combination potentiated

imipramine-induced decrease in 5-HT 2A receptor density. On both day 7 and day 21, T3 given alone had no effects on the density of 5-HT 1A and 5-HT

2A receptors. These data indicate that T3 is able to modulate the long-term adaptive changes which occur at the postsynaptic level of 5-HT neurotransmission after antidepressant treatment. [Neuropsychopharmacology 24:652–662, 2001]

? 2001 American College of Neuropsychopharmacology.Published by Elsevier Science Inc.

KEY

WORDS : 5-HT transporter; 5-HT 1A receptor; 5-HT

2A

receptor; Tricyclic antidepressant; Triiodothyronine; Brain

Most of the physiological effects of thyroid hormones are mediated in periphery as well as in brain by tri-iodothyronine (T3), which mainly derived from the

monodeiodination of thyroxine (T4), the major secre-tory product of the thyroid gland. Therefore studies,which have assessed the efficacy of thyroid hormones in depression, have been largely centered on T3.

More than 20 studies have examined the effects of T3-antidepressant combination in the treatment of ma-jor depressive disorders (Aronson et al. 1996; Joffe and Sokolov 1994). The doses of T3 used were usually in the physiological range and framed its daily production rate. Only six studies have examined whether the addi-tion of T3 could accelerate the onset of action of tricyclic antidepressant (TCA) drug treatment (Coppen et al.1972; Feighner et al. 1972; Prange et al. 1969; Steiner et al. 1978; Wheatley 1972; Wilson et al. 1970). In four of

From INSERM U501, Faculté de Médecine Nord, Marseille,France

Address correspondence to: Pascale Mazzola-Pomietto, Ph.D.,INSERM U501, Faculté de Médecine Nord, Boulevard Pierre Dra- mard, 13916 Marseille Cedex 20, FRANCE. Tel.: ? 33 4 91 69 88 79;Fax: ?

33 4 91 65 17 76; E-mail: pascale.mazzola@medecine.univ-mrs.fr

Received May 19, 2000; revised October 25, 2000; accepted Octo-ber 30, 2000.

N EUROPSYCHOPHARMACOLOGY2001–VOL. 24, NO. 6T3 and Imipramine Combination on Brain 5-HT System653

them, T3 has been found to shorten the latency of the

therapeutic response to imipramine or amitriptyline

(Coppen et al. 1972; Prange et al. 1969; Wheatley 1972;

Wilson et al. 1970).

Other clinical investigations have examined whether

the association of T3 to TCA could convert treatment

nonresponders to responders (Aronson et al. 1996; Joffe

and Sokolov 1994). A particular interest was placed on

the use of T3 in euthyroid depressed patients refractory

to TCA treatment with amitriptyline or imipramine,

drugs which are considered to be the most effective an-

tidepressants (Rudorfer and Potter 1989). In a recent

meta-analysis including eight studies with a total of 292

euthyroid patients refractory to TCA therapy, it has

been reported that approximately 50% of patients

treated with T3 augmentation strategy became respon-

sive to antidepressant treatment (Aronson et al. 1996).

Interestingly, one study has compared the antidepres-

sant permissive action of physiological doses of T3 and

T4 in euthyroid depressed patients who did not re-

spond to TCA. It has been found that the response rate

to T3 was much better than that to T4 (Joffe and Singer

1990). Furthermore, preliminary evidence suggest that

the addition of T3 can also enhance the response rate to

other classes of antidepressant drugs such as selective

serotonin (5-HT) reuptake inhibitors and monoamine

oxydase inhibitors (Gupta et al. 1991; Joffe 1988, 1992).

The mechanisms that underlie the therapeutic effects

of T3 in depressive disorders are still unknown. No ani-

mal studies have examined the chronic effects of physi-

ological doses of T3 given alone or in combination with

an antidepressant on the neurotransmitter systems in-

volved in the pathophysiology and the treatment of de-

pressive disorders. To be in the physiological range, the

dose of T3 must frame its total daily production rate

which is of 4 ?g/kg in rats (Escobar-Morreale et al. 1996). The only previous studies that have examined

the chronic effects of T3 have used it at doses which

were of at least 100 ?g/kg/day (Gur et al. 1999; San-drini et al. 1996). Such doses are supraphysiologic.

The therapeutic effects of antidepressant drugs in-

cluding TCA require 2 or 3 weeks to become manifest,

while their pharmacological actions are prompt and oc-

curred in less than few hours. The lag phase between

the initiation of the drug treatment and the onset of

clinical improvement suggests that the development of

antidepressant effects requires long-term adaptive

changes. Clinical investigations have provided robust

evidence that the therapeutic effects of antidepressants

are underlain by a sustained enhancement of the central

5-HT neurotransmission (Blier and de Montigny 1994;

Heninger and Charney 1987; Maes and Meltzer 1995).

Furthermore, animal studies have shown that, follow-

ing their chronic administration, almost all the antide-

pressant drugs induce an increase in the extracellular

5-HT levels in several brain areas. However, the precise mechanism of their action on the different entities of the central 5-HT system is incompletely understood.

The 5-HT transporter, which is localized on the cell bodies of 5-HT neurons in midbrain and on terminals in projection areas, plays an important role in the regula-tion of central 5-HT neurotransmission. However, the importance of its involvement in the mechanism action of TCA is still a matter of debate. A number of studies using selective radioligands have examined the effects of chronic administration of TCA on the number of 5-HT transporters in projection areas of 5-HT neurons such as hippocampus, cortex and hypothalamus (Cheetham et al. 1993; Dean et al. 1997; Dewar et al. 1993; Kovachich et al. 1992; Nankai et al. 1991; Wa-tanabe et al. 1993). However, their results are inconsis-tent. Following chronic administration of TCA such as imipramine or desipramine, it has been found either no change or a decrease in the number of 5-HT carriers. Otherwise, no studies using selective radioligands have examined whether a chronic treatment with TCA af-fects the number of midbrain 5-HT transporters. Only modification of the steady-state concentrations of the mRNA encoding for the 5-HT transporter has been studied in this brain area. Lesch et al. (1993) found a de-crease in the transporter mRNA levels following long-term treatment with imipramine.

The effects of a chronic TCA administration on postsynaptic 5-HT receptors have been most studied with regard to hippocampal 5-HT1A and cortical 5-HT2A receptors, because these receptors and their function are well characterized in these brain areas. In radioli-gand binding studies, prolonged administration of imi-pramine has always been found to increase hippocam-pal density of 5-HT1A receptors in Wistar rats (Klimek et al. 1994; Maj et al. 1996; Papp et al. 1994). Furthermore, electrophysiological works have constantly found a sensitization of hippocampal 5-HT1A receptors follow-ing chronic administration of different TCA (Chaput et al. 1991; de Montigny and Aghajanian 1978; Gallager and Bunney 1979; Gravel and de Montigny 1987). Other-wise, biochemical studies have shown that chronic ad-ministration of amitriptyline, imipramine, or de-sipramine leads to a decrease in the function of cortical 5-HT2A receptors through a reduction in receptor den-sity (Goodwin et al. 1984; Papp et al. 1994; Peroutka and Snyder 1980; Roth et al. 1998; Subhash and Jagadeesh 1997; Watanabe et al. 1993).

In the present article, we examined whether the ad-dition of a low dose of T3 equivalent to its daily pro-duction rate can change the effects induced by a chronic administration of imipramine on 5-HT neurotransmis-sion. The binding characteristics of midbrain and hypo-thalamic 5-HT transporters and of hippocampal 5-HT1A and cortical 5-HT2A receptors were investigated in adult Wistar rats. Another aim of the study was to ascertain whether the hormonal association might accelerate the

654X. Moreau et al.N EUROPSYCHOPHARMACOLOGY2001–VOL. 24, NO. 6

onset of changes in density of 5-HT transporters and re-ceptors induced by the TCA treatment. Therefore, we studied the influence of the different treatments after 7 or 21 days of their administration. In addition, the ef-fects of a chronic administration of a physiological dose of T3 given alone were also compared at the same time points.

MATERIALS AND METHODS

Animals

Male Wistar rats (IFFA CREDO, L’Arbresle, France) weighing 180–200 g at the beginning of the study were used. The animals were housed 4 to 5 per cage and maintained under standard laboratory conditions (22 ?1?C, 50–60% relative humidity, 12 hr light-dark cycle,

light on at 7:00 A.M.). Rats had free access to food and drink. All the procedures were conducted in accor-dance with French and Economic European Commu-nity laws and policies for care and use of laboratory an-imals.

Treatments

Four groups of animals were treated for 7 or 21 days with imipramine (10 mg/kg/day) and T3 (4 ?g/kg/ day), alone or combined, or with vehicle (0.1 mg/ml bovine serum albumin), delivered in the drinking wa-ter. Fresh drinking water was provided daily around 6:00 p.m. The amount of drug delivered every day was calculated according to the mean body weight and the volume of solution drunk by each cage of treated ani-mals. The body weight of each animal was recorded ev-ery 2 or 3 days. The volume drunk per cage was re-corded every day. Animals were killed by decapitation between 10:00 A.M. and noon on day 8 or 22.

Thyroid Hormone and TCA Assays

Immediately after death, the trunk blood was collected in centrifuge tubes. After centrifugation (2200 g, 8 min, 4?C), serum samples were collected and stored at ?70?C until assayed. Concentrations of free T3 (FT3) and T4 (FT4) were determined by radioimmunoassay and immunochemiluminiscent assay, respectively (Amerlex-MAB? FT3 and Amerlite-MAB? FT4, respec-tively, Johnson & Johnson Clinical Diagnostics, Les Ulis, France) and expressed in pM. Concentrations of TCA, which correspond to the concentration of imi-pramine plus its main metabolite desipramine, were determined by fluorescence polarization immunoassay (TDx/TDxFLx? Tricyclic Antidepressants assay, Abbott Laboratories, Chicago, USA) and expressed in ng/ml.Preparation of Brain Homogenates

Immediately after the trunk blood collection, the brain

was removed. Frontal cortex, hippocampus, hypothala-

mus, and midbrain were dissected out on ice. Cortex

and hippocampus were homogenized in ice-cold 50

mM Tris-HCl buffer, pH 7.7, and centrifuged (20000 g,

10 min, 4?C). After centrifugation, the supernatant was discarded and the membrane pellet was resuspended

and centrifuged as above. However, for the hippocam-

pus homogenates, a 15 min incubation at 35?C was car-ried out in between the two centrifugations to remove endogenous 5-HT. Hypothalamus and midbrain homo-genates were prepared as the cortical ones except that homogenization solution was buffered at pH 7.4. The fi-nal pellets were stored at ?80?C until subsequent radio-ligand binding assays.

Radioligand Binding Assays

Radioligand binding experiments were performed as previously described (Kulikov et al. 1999).

[3H]Citalopram Binding.Midbrain and hypothalamic membrane pellets were suspended in 50 mM Tris-HCl buffer, pH 7.4, containing 120 mM NaCl and 5 mM KCl at a protein concentration of approximately 0.3 and 0.15 mg/ml, respectively. The reaction was carried out for 60 min at 25?C in the presence of 8 concentrations of [3H]citalopram (0.12–16 nM).

[3H]8-OH-DPAT Binding.Hippocampal membrane pellets were suspended in 50 mM Tris-HCl buffer, pH 7.7, containing 5 mM CaCl2, 0.1% ascorbic acid, and 1?M pargyline at a protein concentration of approxi-mately 0.25 mg/ml. The reaction was carried out for 15 min at 35?C in the presence of 8 concentrations of [3H]8-OH-DPAT (0.06–8 nM).

[3H]ketanserin Binding.Cortical membrane pellets were suspended in 50 mM Tris-HCl buffer, pH 7.7, at a protein concentration of approximately 0.14 mg/ml. The reaction was carried out for 15 min at 35?C in the presence of 8 concentrations of [3H]ketanserin hydro-chloride (0.06–8 nM).

Incubations were stopped by adding 4 ml of the respec-tive cold Tris-HCl buffer and rapid vacuum filtration through Whatman GF/B glass fiber filters presoaked in an aqueous solution of polyethylenimine (0.3 % v/v). After two additional washes with 4 ml of Tris-HCl buffer, filters were dried for 1 hr at 70?C and immersed in 5 ml of Opti-Scint “High Safe” scintillation cocktail (LKB/Pharmacia, Les Ulis, France) for radioactivity counting. All determina-tions were done in duplicate.

Protein concentrations were determined according

N EUROPSYCHOPHARMACOLOGY2001–VOL. 24, NO. 6T3 and Imipramine Combination on Brain 5-HT System655

to the method of Bradford (1976) using bovine serum albumin (BSA) as standard.

The values of the maximal specific binding (Bmax, ex-pressed in fmol/mg protein), non-specific binding and of the dissociation constant (Kd, expressed in nM) were cal-culated by non linear iterative least squared regression, using the EBDA-LIGAND computerized program (Mun-son and Rodbard 1980). We verified that the experimental non-specific bindings defined in the presence of 1 ?M par-oxetine for [3H]citalopram, 10 ?M 5-HT for [3H]8-OH-DPAT, 10 ?M methysergide for [3H]ketanserin, were not

significantly different from those calculated by the EBDA-LIGAND program. The non-specific bindings represented about 5%, 15%, and 8% of total [3H]citalopram, [3H]8-OH-DPAT, and [3H]ketanserin bindings, respectively.

Chemicals

[3H]citalopram (85 Ci/mmol), [3H]8-OH-DPAT (127 Ci/mmol), and [3H]ketanserin hydrochloride (66.4 Ci/ mmol) were purchased from Dupont/NEN (Les Ulis, France). 3,3prime,5-tri-iodo-L-thyronine sodium salt, 5-HT creatinine sulfate, BSA, polyethylenimine, imi-pramine hydrochloride, and pargyline hydrochloride were purchased from SIGMA (St. Quentin-Fallavier, France). Methysergide maleate was purchased from Re-search Biochem (Natick, USA). Paroxetine was a gift from SmithKline & Beecham (Harlow, UK).

Data Analysis

All data are presented as means ? SEM. For the body weight data, a repeated measures design analysis of variance was used, with different treatments as the be-tween factor and time as the within factor. Significant treatments by time interactions were further explored using one-way analysis of variance (ANOVA) at each time point accompanied by Bonferroni-Dunn test where each treatment group was compared to the con-trol group. TCA data in animals treated with imi-pramine alone or in combination with T3 were ana-lyzed using a two-tail Student t-test. Hormonal and radioligand binding data were analyzed using one-way ANOVA followed by Bonferroni-Dunn test where each treatment group was compared to the control group unless mentioned.

RESULTS

Body Weight Changes

Table 1 shows the effects of a 21-day treatment with im-ipramine and T3, alone or in combination, on body weight gain. An overall ANOVA showed a significant treatment effect (F3,41? 2.99, p? .05), a significant time effect (F3,123? 664, p? .0001), and a significant interac-tion between time and treatment (F9,123? 5.2, p? .001). Further analysis revealed that only the combination im-ipramine-T3 induced a significant reduction in body weight gain on day 21.

TCA Concentrations

For 7- and 21-day treatment, there were no differences in the serum concentrations of TCA between animals treated with imipramine alone and those treated with the combination imipramine-T3 (F1,14? 0.76, NS; F1,14?0.26, NS, respectively) (Table 2).

Thyroid Hormone Concentrations

For 7- and 21-day treatment, one-way ANOVA gave an overall significant treatment effect on FT4 serum con-centrations (F3,25? 58.5, p? .0001; F3,36? 79.7, p?.0001, respectively). Further analysis revealed that treat-ment with T3 alone and with the combination imi-pramine-T3 induced a significant decrease in FT4 con-centrations on both days 7 and 21 (Figure 1).

For 7- and 21-day treatment, there were no differ-ences in FT3 serum concentrations between the differ-ent groups (F3,25? 2.22, NS; F3,36? 0.75, NS, respec-tively) (Figure 1).

[3H]Citalopram Binding

For 7-day treatment, there was no overall difference in Bmax of [3H]citalopram binding in midbrain between the different groups (F3,28? 1.25, NS) (Figure 2A). By contrast, one-way ANOVA on day 21 gave an overall significant effect of treatment on Bmax (F3,41? 9.83, p?.0001) (Figure 2B). Further analysis revealed that imi-pramine and T3 treatment, alone or combined, signifi-cantly decreased Bmax. However, the decrease in Bmax induced by imipramine or T3 alone did not differ sig-nificantly from that induced by the combination of these treatments. For 7- and 21-day treatment, there were no overall differences in Kd of [3H]citalopram binding in midbrain between the different groups (F3,28?0.53, NS; F3,41? 1.53, NS, respectively) (Table 3).

For 7- and 21-day treatment, there were no overall differences in either Bmax (F3,31? 0.81, NS; F3,36? 0.45, NS) (Figure 2) or Kd (F3,31? 0.13, NS; F3,36? 0.34, NS) (Table 3) of [3H]citalopram binding in hypothalamus between the different groups.

[3H]8-OH-DPAT Binding

For 7-day treatment, one-way ANOVA did not yield to an overall significant treatment effect on Bmax of [3H]8-OH-DPAT binding in hippocampus (F3,33? 0.92, NS)

656X. Moreau et al.N EUROPSYCHOPHARMACOLOGY 2001–VOL . 24, NO . 6

(Figure 3A). By contrast, one-way ANOVA on day 21gave an overall significant treatment effect on Bmax (F 3,42 ? 4.82; p ? .01) (Figure 3B). Further analysis re-vealed that treatment with the combination imi-pramine-T3 or with T3 alone had no effects on Bmax whereas treatment with imipramine alone induced a significant increase in Bmax. Furthermore, Bmax was also significantly higher in imipramine-treated animals than in those receiving the imipramine-T3-combination.For 7-day, but not 21-day treatment, one-way ANOVA showed an overall significant treatment effect on Kd of [3H]8-OH-DPAT binding (F 3,33 ? 9.53, p ? .0001; F 3,42 ?0.39, NS, respectively) (Table 3). Further analysis re-vealed that on day 7, only T3 given alone produced a significant increase in Kd.

[3H]ketanserin Binding

For 7- and 21-day treatment, one-way ANOVA gave an overall significant treatment on Bmax (F 3,33 ? 12.7, p ?0.0001; F 3,38 ? 32.2, p ? .0001, respectively) (Figure 4) and Kd (F 3,33 ? 6.3, p ? .05; F 3,38 ? 6.90, p ? .001, respectively)(Table 3) of [3H]ketanserin binding in frontal cortex. Fur-ther analysis revealed that Bmax of animals treated with imipramine alone or with the combination of imipramine and T3 were significantly decreased on both days 7 and 21. Treatment with T3 alone had no effect on https://www.wendangku.net/doc/803549814.html,parisons of the mean Bmax values of imipramine-and imipramine-T3–treated animals yield to significant differences both on days 7 and 21. The imipramine-T3

combination induced decreases in Bmax that were of a greater extent than those produced by imipramine alone.For 7-day treatment, Kd of [3H]ketanserin was decreased only in the group of animals receiving the combined treatment. However, for 21-day treatment, all the three groups of treated animals had a decrease in Kd.

Table 1.Effects of a 21-day Treatment with Imipramine and T3, Alone or Combined, on Body Weight Gain in Adult Rats

Treatment days Body Weight (g)

Control Imipramine Imipramine ? T3

T30207.7 ? 3.1208.9 ? 2.5208.7 ? 2.2200.4 ? 1.87254.5 ? 3.5249.9 ? 2.2247.9 ? 2.5247.1 ? 2.214286.5

? 5.3271.6 ? 6.8269.5 ? 5.2280.1 ? 4.021

324.2 ? 4.8

302.8 ? 8.9

293.8 ? 6.5*

316.6 ? 4.0

Values represent the means body weight ? SEM from 10 animals per treatment group.*p ? .05, significantly different from control animals, Bonferroni-Dunn test.

Table 2.Effects of a 7- or 21-day Treatment with

Imipramine Given Alone or in Combination with T3 on Serum Concentrations of TCA

Treatment days Serum concentrations of TCA (ng/ml)Imipramine Imipramine ? T3

768.2 ? 7.872.5 ? 11.321

88.2 ? 7.3

80.1 ? 13.9

Serum concentrations of TCA represent the sum of the concentrations of imipramine and of its metabolite, desipramine. Values represent the mean ? SEM from 8 animals per treatment group.

Figure 1.Effects of imipramine and T3 treatment alone or combined, for 7 (A) or 21 (B) days on serum FT4 and FT3concentrations. Each bar represents the mean ? SEM from at least 8 independent determinations per treatment group.***p ? .001 when compared to control animals.

N EUROPSYCHOPHARMACOLOGY 2001–VOL . 24, NO . 6T3 and Imipramine Combination on Brain 5-HT System 657

DISCUSSION

The present study was designed to evaluate whether the association of a physiological dose of T3 to imi-pramine treatment could potentiate and accelerate adaptive changes produced by the TCA administration on the density of midbrain and hypothalamic 5-HT transporters and of hippocampal 5-HT 1A and cortical 5-HT 2A receptors in adult Wistar rats. So, the effects of imipramine and T3 given alone were compared to those induced by the imipramine-T3 combination after 1- and 3-week treatments. Three-week treatment was chosen as a conservative equivalent of the typical 3-week pe-riod required for the development of a quantitative an-tidepressant response in depressed patients. One-week treatment was chosen because in some clinical trials on hormonal augmentation strategy of antidepressant treatment, T3 was reported to lead to a therapeutic re-sponse as soon as the first week of initiation of TCA treatment (Joffe et al. 1995).

This is the first study to demonstrate that both chronic administrations of imipramine and T3 trigger a time-regulatory effect on the density of midbrain 5-HT transporters. Only a 3-week treatment with imipramine and T3 given alone produced a significant decrease in the binding of [3H]citalopram. In addition, we found that T3 and imipramine did not have additive effects since the combination of these treatments did not en-hance the downregulation of 5-HT transporters in-duced by T3 and imipramine given alone. These results suggest that T3 and imipramine decrease the midbrain 5-HT transporter density through different mecha-nisms. Further investigations are needed to identify the mechanism that underlies the effect of T3. It is possible that the decrease in the number of transporters induced by imipramine reflects a downregulation process,which is secondary to a reduction in the steady-state concentrations of their mRNA. Supporting evidence for this come from the findings of Lesch et al. (1993) who observed that 3 weeks administration of imipramine in-duced a large decrease in the mRNA levels of 5-HT transporters in midbrain. On the other hand, the down-regulation of 5-HT transporters could have a functional

impact and led to a reduction of 5-HT uptake rate. In

Figure 2.Effects of imipramine and T3 treatment alone or combined, for 7 (A) or 21 (B) days on Bmax of [3H]-citalopram binding to 5-HT uptake sites in midbrain and hypothalamus. Each bar represents the mean ? SEM from at least 8 independent deter-minations per treatment group. **p ? .01, ***p ?.001 when compared to control animals.

658X. Moreau et al.N EUROPSYCHOPHARMACOLOGY2001–VOL. 24, NO. 6

agreement with this view, Pi?eyro et al. (1994) reported that chronic administration of a selective inhibitor of 5-HT uptake reduced the effectiveness of 5-HT trans-port by decreasing the number of transporter sites in rat hippocampus.

By contrast to their effects on the density of midbrain 5-HT transporters, neither imipramine and T3 alone nor the combination of these treatments modified the num-ber of 5-HT transporters in hypothalamus. It is of note that no earlier works have examined the influence of T3 and of the TCA-T3 combination on the number of 5-HT transporters in this brain area. Otherwise, the present data are in line with those of Nankai et al. (1991) who observed that a 10-day treatment with desipramine (10 mg/kg/day) did not alter the number of 5-HT carriers in rat hypothalamus. A possible explanation for the lack of effect of imipramine treatment on the density of hy-pothalamic 5-HT transporters may be related to the fact that we used a dose of imipramine, which was not suffi-cient to block 5-HT transport. Supporting evidence for this come from the findings of Thomas et al. (1987) who reported that only chronic treatments with doses of imi-pramine greater than 20 mg/kg/day were able to in-hibit 5-HT uptake rate into hypothalamic synaptosomes.

In the present study, neither 1-week administration of imipramine and T3 alone nor 1-week administration of the combination imipramine-T3 modified the bind-ing of [3H]8-OH-DPAT to hippocampal 5-HT1A recep-tors. No previous studies have examined the effect of 1-week administration of TCA given alone or in combi-nation with a low dose of T3 on the density of hippo-campal 5-HT1A receptors. Our results on the lack of ef-fect of a low dose of T3 are in line with those of Sandrini et al. (1996) who reported that even a high dose of T3 administered for 1 week did not induce any change in the number of these receptors.

Our data on the effect of a 3-week administration of imipramine on the binding of [3H]8-OH-DPAT to hip-pocampal 5-HT1A receptors in Wistar rats confirm the findings of previous studies. Two- to four-week treat-ments with different TCA have always been found to increase the density of hippocampal 5-HT1A receptors in Wistar rats (Klimek et al. 1994; Maj et al. 1996; Papp et al. 1994). The mechanism by which imipramine mod-ulates the number of 5-HT1A receptors is poorly under-stood but does not seem to involve transcriptional regu-lation. Burnet et al. (1994) reported that a chronic treatment with imipramine increased the density of hippocampal 5-HT1A receptors without altering the mRNA levels of these receptors.

By contrast to the effect of 3-week administration of imipramine, 3-week administration of the combination imipramine-T3 failed to increase the density of 5-HT1A receptors in Wistar rats. Imipramine-T3–treated ani-mals had a number of 5-HT1A receptors that was signifi-cantly less than imipramine-treated animals but that did not differ from controls. One possible explanation for the lack of effect of the imipramine-T3 combination on 5-HT1A receptors may be that T3 and imipramine have an opposite effect on the density of these recep-tors. However, this possibility seems unlikely because a 3-week administration of T3 alone did not affect the density of 5-HT1A receptors whereas that of imipramine increased it. Another possible explanation for the lack of effect of the imipramine-T3 combination may be that the addition of T3 alters the pharmacodynamic of imi-pramine. However, this possibility seems also unlikely because we found no difference in the serum concentra-tions of TCA between animals that received imi-pramine alone and those that received the combination imipramine-T3. Moreover, previous studies have shown that chronic addition of T3 to imipramine treat-

Table 3.Effects of a 7- or 21-day Treatment with Imipramine and T3, Alone or Combined, on the Kd Values (nM) for

[3H]citalopram Binding to 5-HT Uptake Sites, [3H]8-OH-DPAT Binding to 5-HT1A Receptors, and [3H]ketanserin Binding to 5-HT2A Receptors in Various Regions of Rat Brains

Treatment

Days Control Imipramine Imipramine ? T3T3

[3H]citalopram

Midbrain7 1.43 ? 0.09 1.58 ? 0.20 1.48 ? 0.14 1.35 ? 0.07

21 1.48 ? 0.08 1.42 ? 0.08 1.70 ? 0.15 1.42 ? 0.11 Hypothalamus7 1.66 ? 0.06 1.72 ? 0.11 1.71 ? 0.10 1.74 ? 0.14

21 1.65 ? 0.06 1.60 ? 0.07 1.67 ? 0.10 1.57 ? 0.07 [3H]8-OH-DPAT

Hippocampus70.88 ? 0.050.87 ? 0.030.92 ? 0.10 1.21 ? 0.05* 210.82 ? 0.080.88 ? 0.050.90 ? 0.080.87 ? 0.08 [3H]ketanserin

Frontal cortex70.51 ? 0.060.43 ? 0.070.25 ? 0.05*0.65 ? 0.07 210.52 ? 0.050.33 ? 0.03**0.28 ? 0.04**0.30 ? 0.04** Values represent the means ? SEM from at least 8 independent determinations.

*p? .05; **p? .001: significantly different from control animals, Bonferroni-Dunn test.

N EUROPSYCHOPHARMACOLOGY 2001–VOL . 24, NO . 6T3 and Imipramine Combination on Brain 5-HT System 659

ment failed to alter the disposition and the metabolism of imipramine in periphery as well as in brain (Breese et al. 1972; Garbutt et al. 1979). Taken together, these data indicate that the chronic addition of a physiological dose of T3 has prevented the effect of the antidepres-sant on the density of 5-HT 1A receptors. As it has been shown that an increase in the hippocampal number of these receptors could be associated with an increase in their responsiveness (Welner et al. 1989), it will be inter-esting to determine whether the combination imi-pramine-T3 has also a functional impact on 5-HT 1A re-ceptors by preventing the appearance of a state of supersensitivity.

In the present study, 1- and 3-week administration of imipramine reduced the binding of [3H]ketanserin to cortical 5-HT 2A receptors. These data confirm and ex-tend the findings of previous studies. The downregula-tion of cortical 5-HT 2A receptor binding after 2- to

4-week treatment with different TCA drugs is a well-established observation. However, this is the first inves-tigation to demonstrate that 1-week treatment with imi-pramine is able to reduce the number of cortical 5-HT 2A receptors. Several studies have shown that repeated ad-ministration of drugs with 5-HT 2A antagonist properties induced a rapid downregulation of 5-HT 2A receptors (Eison and Mullins 1996; Roth et al. 1998). Because imi-pramine has a relatively high affinity for 5-HT 2A recep-tors and antagonist activity at these receptors, it is not surprising that its administration for 1 week decreased the number of cortical 5-HT 2A receptors. The mecha-nism responsible for the paradoxical downregulation of cortical 5-HT 2A receptors by TCA or by 5-HT 2A antago-nists has been studied incompletely (Roth et al. 1998).However, it is unlikely that transcriptional regulation of 5-HT 2A receptors is involved. Chronic administration of imipramine and of atypical antidepressant with 5-HT 2A receptor antagonist property such as mianserin did not alter 5-HT 2A receptor mRNA concentrations in rat cortex (Burnet et al. 1994; Roth and Ciaranello 1991).Furthermore, it has been found that mianserin de-creased the density of 5-HT 2A receptors in stably trans-fected cells (Newton and Elliot 1997).

Unlike imipramine, T3 given for 1 and 3 weeks did not affect the density of cortical 5-HT 2A receptors. Our find-ings are apparently discordant with those of Sandrini et al.(1996) who found a reduction in the cortical density of 5-HT 2A receptors after 1 week of T3 administration. How-ever, it is of note that these authors gave a supraphysio-logical dose of T3 whereas we used a physiological one.The main finding of the present study is that the ad-dition of T3 to imipramine amplified the downregula-tion of cortical 5-HT 2A receptors caused by the antide-pressant. Both 1- and 3-week treatment with imipramine-T3 combination enhanced the downregula-tion rate of 5-HT 2A receptors (?47% and ?38%, respec-tively). Furthermore, the extent of the downregulation induced by a 1-week administration of the combination was greater than that induced by a 3-week administra-tion of imipramine.

All the TCA drugs downregulate 5-HT 2A receptors with a time frame that is correlated to their clinical effi-cacy (Lafaille et al. 1991). In addition, it has been re-cently demonstrated that the sole downregulation of 5-HT 2A receptors, when induced by an intracerebroven-tricular administration of a receptor-specific antisense oligonucleotide, was sufficient to achieve an antide-pressant-like effect in mice (Sibille et al. 1997). These findings, together with our data, suggest that the ability of T3 to shorten the delay for the clinical efficacy of TCA drugs may lie, at least in part, in its capacity to en-hance the downregulation rate of 5-HT 2A receptors caused by the chronic administration of TCA. The potentiating effect of T3 on imipramine-induced down-regulation of 5-HT 2A

receptors seems to be the conse-

Figure 3.Effects of imipramine and T3 treatment alone or combined, for 7 (A) or 21 (B) days on Bmax of [3H]8-OH-DPAT binding to 5-HT 1A receptors in hippocampus. Each bar represents the mean ? SEM from at least 8 independent determinations per treatment group. *p ? .05 when com-pared to control animals; significantly different from imi-pramine-T3-treated animals: $p ? .05.

660X. Moreau et al.N EUROPSYCHOPHARMACOLOGY 2001–VOL . 24, NO . 6

quence of an enhancing action of T3 on imipramine-induced increase in the extracellular 5-HT levels in cor-tex. Recent microdialysis studies have shown that chronic administration of imipramine and clomi-pramine increased the extracellular 5-HT levels in rat cortex (Bel and Artigas 1996; Gur et al. 1999). Further-more, Gur et al. (1999) observed that in frontal cortex chronic treatment with the combination clomipramine-T3 potentiated the increase in the extracellular 5-HT levels induced by T3 or clomipramine alone.

Finally, our data on the chronic effects of single and combined imipramine and T3 administrations on the serum concentrations of thyroid hormones confirm and extend those of previous studies. As Kennedy et al.(1997), we observed that a chronic administration of im-ipramine did not alter the serum concentrations of FT3and FT4. In the present study, we also reported that FT4, but not FT3, concentrations were decreased after chronic administration of the combination imipramine-

T3. It is of note that no earlier animal studies have ex-amined the effects of TCA-T3 combination of the serum availability of thyroid hormones. It is likely that the ef-fect of the combination on these hormones results from the sole action of T3. We found that, like the adminis-tration of the imipramine-T3 combination, T3 adminis-tration decreases FT4 levels without altering those of FT3. Our data with T3 alone confirm those of Barsano et al. (1994) who observed that, in rats, the administration of T3 at a dose equivalent to its daily production rate decreased FT4 concentrations without affecting those of FT3. It is likely that the administration of a low dose of T3 has activated the mechanisms of negative feedback of the thyroid axis, which led to a decrease in the en-dogenous production of T4 and T3 (Barsano et al. 1994).However, no changes in the serum concentrations of T3were observed because the reduction in the endoge-nous production of T3 was compensated by the admin-istration of a low dose of T3. These findings and our data suggest that neither imipramine and T3 given alone nor the combination of these treatments have pro-vided their effects on the central 5-HT entities by over-coming the capacity of the thyroid axis to regulate the hormone availability.

In conclusion, the present results show that T3 can modulate the effects of TCA on their serotonergic tar-gets. Of particular interest, the action of T3 in potentiat-ing the downregulation of cortical 5-HT 2A receptors in-duced by a chronic administration of imipramine might explain, at least in part, its antidepressant properties.

ACKNOWLEDGMENTS

We thank Mrs. H. Rescigno for her technical assistance and Dr. P.J. Lejeune (Laboratoire de Biochimie Endocrinienne et Métabolique, Faculté de Médecine, Marseille) for his help in thyroid hormone determinations.

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大学生毕业晚会主持词

大学生毕业晚会主持词 A：青春是一曲荡气回肠的歌，三年前我们怀着彩色梦想走进了鄂大，三年中我们有过欢笑，流过泪水，经历磨炼，得到成长 B：三年后的今天，我们在这里重温青春过往，因为明天就将各奔天涯。也正因为此，今夜，我们承载了太多的祝福与惦念，寄托了太多的关怀与企盼。 C：今晚，让我们再一次重温，那些感动过我们的人和事：灯火通明的教学楼里用功的身影，篮球场上捍卫集体尊严的男儿霸气，满是欢声笑语的宿舍边不着边际的闲谈…… D：又一个三年轮回之后，在同样微凉的夏夜，你是否会记起校园里的梧桐树，你是否会记起日记本里的书签，那些五彩缤纷的日子？ A：无数个三年之后，你们的思念是否会有增无减？在你成长的岁月里，在你闯荡社会的每一天，是否会有那么几个瞬间让你渴望回到过去 B：让我们静静享受一下挑战，在日复一日与时间的赛跑中，你会变得更加坚强，更加神采奕奕！又一个青春之旅从今晚启航，又一个光阴的故事在今晚讲述 C：亲爱的同窗，不要带着离别的愁绪，因为明天又是一个新的起点，因为我们相信再次相逢，我们还是一首动人的歌！D：很高兴今天能有这个机会同大家相聚一堂，共叙离别。就让今天铭刻在我们心间，让母校留住我们的风采！ A：今天，我们也非常荣幸的请到了…… B：下面让我们用热烈的掌声有请……上台讲话 结束语A：欢快的舞蹈表达不尽我们对母校的敬意 B：热情的赞歌唱不尽我们对母校的一腔深情

C：流火的六月，我们将带着恩师的叮咛，怀着必胜的信心，走向新的征程 D：绚烂的七月，我们将载着母校的祝愿，带着亲人的希望，向着新的征程扬帆起航A：老师们，同学们，欢送10级毕业生联欢晚会合：到此结束 A李：毕业，是一个沉重的动词； 刘：毕业，是一个让人一生难忘的名词； 李：毕业，是感动时流泪的形容词； 刘：毕业，是当我们以后孤寂时候，带着微笑和遗憾去回想时的副词； 李：毕业，是我们夜半梦醒，触碰不到而无限感伤的虚词。 刘：若干年后，假如我们还能够想起那段时光，也许这不属于难忘，也不属于永远，而仅仅是一段记录了成长经历的回忆。 李：尊敬的各位领导老师 刘：亲爱的各位同学们 合：大家晚上好！ 李：很荣幸和大家相聚在这激情如火的六月，在这充满忧伤的六月！ 刘：很高兴和大家相聚在“放心去飞，20年后再相聚—毕业晚会”现场！ 李：我是李扬 刘：我是刘伟清 李：今天晚会现场非常荣幸的邀请到院系的各位领导和老师们。 刘：让我们首先欢迎…… 李：灿烂的星空曾经铭刻你我的笑容

湘艺版五年级音乐《长白山下的歌谣》教学设计

湘艺版五年级音乐《长白山下的歌谣》 教学设计 《长白山下的歌谣》教学设计 教材版本：湘艺版音乐教材 教学对象：五年级上期 一、教学案例： （一）题：《长白山下的歌谣》音乐综合 （二）教材版本：湘版新标实验教材 （三）年级：五年级 （四）教具准备：钢琴、AI、打击乐器、朝鲜族服饰、长鼓、金达莱花。 （五）教学目标： ①、认知目标：认真听赏朝鲜民歌《道拉基》，学习三拍子节奏特点。 ②、能力目标：通过小组合作学习（设计身势节奏、用长鼓为歌曲伴奏、即兴歌舞等形式）培养学生的创新能力、合作能力，体验朝鲜族民歌的韵律。 ③、情感目标：通过感受性学习歌曲《金达莱花开朵朵红》，了解朝鲜族人民勤劳淳朴、团结互助、热情好客、能歌善舞的优良传统与民族风情。 （六）设计思路： 五十六个民族五十六枝花，生活在吉林省长白山脚下的

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2.铃声清脆鼓铿锵，天山铃舞尽展情，来自天山的自然是蝶飞花影动，美丽各不同，那就让我们停下脚步，一饱眼福，欣赏由xxx为我们带来的舞蹈《天山铃舞》 3. 军中有歌，歌才动情，军旅里飞来一只熟悉的百灵，不错下面就由请xxx为大家献上一首耳熟能详的老歌，《军中飞来一只百灵》 4.炫酷才叫时尚，八零后心之向往，相信大家都一样，需要个性张扬。今天我们特意请来了城市建设学院的武状元优秀团队，为大家献上一段充满活力的XXX，感谢他们的到来，大家掌声欢迎! 5.相信大家都看过一部曾经风靡一时的电影，那是周杰伦曾经推出的一部年度巨献《不能说的秘密》.里面的四手联弹一定给大家留下了不可磨灭的深刻印象，旋律依旧在脑中回响。不过经典一样可以复制，精彩一样能够粘贴，下面给大家带来的这个惊喜，可谓是非常具有特色，一样是所见不多，机会难得。下面请欣赏xxxx为大家带来的，钢琴四手连弹《军队进行曲》 6.幽幽云水意.漫漫古典情. 诗情画境的晕染为我们带来流动的娴静。请大家随着动人的舞蹈穿越书法的妙境，伴随优雅的琴韵体会超越喧嚣的古韵墨香。下面请欣赏xxx为您带来的xxxx 7.四年的岁月流光见证了你我在XX学院的欢欣成长，相信由很多即将走出校园的`同学都想倾诉衷肠，下面我们就请出来自05对外汉语的毕业生代表xxx听听她如何表达。

校园艺术节主持词开场白

校园艺术节主持词开场白（一） 男：尊敬的各位领导、各位来宾。 女：亲爱的老师们、同学们。 合：大家好！ 男：聆听十月的讯息，秋风吹拂大地； 女：走进十月的校园，我们充满活力！ 男：今天，我们相聚这儿，绽放灿烂的笑容；凝聚我们的勇气； 女：今天，我们相聚这儿，放飞我们的希望，追求我们的梦想！ 男：校园的艺术是知识的一种新的升华，校园的生活是多彩的音乐的合奏。 女：校园艺术节是师生展示各自文艺风采、凸显个性魅力的一个最佳舞台。 合：xx中学第x届校园艺术节开幕式现在开始！（鸣礼炮） 男：下面进行升旗仪式，请仪仗队入场。 女：请全体起立，升国旗、奏国歌！ 男：请大家入座。今天来到我们会场的领导有：xx、xx、xx…… 女：让我们用热烈的掌声对他们的到来表示欢迎！ 男：另外许多家长代表也来到了我们的会场，一个成功的学生背后总有辛勤付出的家长，您辛苦了！ 女：让我们用热烈的掌声对他们表示感谢！ 男：回首我们走过的这一个学年，经过全校师生上下一心、卓有成效的努力，我校各项工作都取得了骄人的成绩：校容校貌焕然一新，常规管理扎实有效，教学质量跃上新高。

女：成绩已然过去，面对未来，我们信心百倍。下面有请x校长讲话。 （鼓掌感谢x校长的精彩致辞） 环节一：教师合唱《走进新时代》、《团结就是力量》 男：我们xx人是这样的热情奔放！ 女：我们xx人是这样的团结激昂！ 男：我们的手牵在一起，就是战胜困难的力量！ 女：我们的心连在一起，就是坚不可摧的铜壁铁墙！ 男：让我们与优美同行，与高雅同行，与时代同行 女：请欣赏教师合唱《走进新时代》和《团结就是力量》。 指挥：xx 领唱：xx 环节二：舞蹈《开门红》 女：扬起你欢乐的嘴角，带上你的好心情，在这个特别的日子里跟我们一起感受这花样年华。

毕业典礼晚会主持词

毕业典礼晚会主持词X 花开花落，又是一年毕业季，我们毕业典礼就要开始举办，下面是搜集整理的毕业典礼晚会主持词，欢迎阅读。更多资讯请继续关注毕业典礼栏目! 毕业典礼晚会主持词(一) A：青春是一曲荡气回肠的歌，三年前我们怀着彩色梦想走进了鄂大，三年中我们有过欢笑，流过泪水，经历磨炼，得到成长 B：三年后的今天，我们在这里重温青春过往，因为明天就将各奔天涯。也正因为此，今夜，我们承载了太多的祝福与惦念，寄托了太多的关怀与企盼。 C：今晚，让我们再一次重温，那些感动过我们的人和事：灯火通明的教学楼里用功的身影，篮球场上捍卫集体尊严的男儿霸气，满是欢声笑语的宿舍边不着边际的闲谈…… D：又一个三年轮回之后，在同样微凉的夏夜，你是否会记起校园里的梧桐树，你是否会记起日记本里的书签，那些五彩缤纷的日子? A：无数个三年之后，你们的思念是否会有增无减?在你成长的岁月里，在你闯荡社会的每一天，是否会有那么几个瞬间让你渴望回到过去 B：让我们静静享受一下挑战，在日复一日与时间的赛跑中，你会变得更加坚强，更加神采奕奕!又一个青春之旅从今晚启航，又一个光阴的故事在今晚讲述 C：亲爱的同窗，不要带着离别的愁绪，因为明天又是一个新的起点，因为我们相信再次相逢，我们还是一首动人的歌!D：很高兴今天能有这个机会同大家相聚一堂，共叙离别。就让今天铭刻在我们心间，让母校留住我们的风采! A：今天，我们也非常荣幸的请到了…… B：下面让我们用热烈的掌声有请……上台讲话

结束语 A：欢快的舞蹈表达不尽我们对母校的敬意 B：热情的赞歌唱不尽我们对母校的一腔深情 C：流火的六月，我们将带着恩师的叮咛，怀着必胜的信心，走向新的征程 D：绚烂的七月，我们将载着母校的祝愿，带着亲人的希望，向着新的征程扬帆起航 A：老师们，同学们，欢送10级毕业生联欢晚会合：到此结束 A李：毕业，是一个沉重的动词; 刘：毕业，是一个让人一生难忘的名词; 李：毕业，是感动时流泪的形容词; 刘：毕业，是当我们以后孤寂时候，带着微笑和遗憾去回想时的副词; 李：毕业，是我们夜半梦醒，触碰不到而无限感伤的虚词。 刘：若干年后，假如我们还能够想起那段时光，也许这不属于难忘，也不属于永远，而仅仅是一段记录了成长经历的回忆。 李：尊敬的各位领导老师 刘：亲爱的各位同学们 合：大家晚上好! 李：很荣幸和大家相聚在这激情如火的六月，在这充满忧伤的六月! 刘：很高兴和大家相聚在“放心去飞，20年后再相聚—毕业晚会”现场! 李：我是李扬