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Chronic Antidepressant Administration Decreases the Expression Of Proc. Natl. Acad. Sci. USA Vol. 87, pp. 7522-7526, October 1990 Neurobiology Chronic antidepressant administration decreases the expression of tyrosine hydroxylase in the rat locus coeruleus (depression/noradrenergic system/hnipramine/electroconvulsive seizures/fluoxetine) ERIC J. NESTLER*, ANNE MCMAHONt, ESTHER L. SABBANt, JOHN F. TALLMAN*, AND RONALD S. DUMAN* *Laboratory of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine and Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06508; and tDepartment of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595 Communicated by Charles F. Stevens, July 2, 1990 ABSTRACT Regulation of tyrosine hydroxylase expres- brain, no consistent reproducible effect of these treatments sion by antidepressant treatments was investigated in the locus on the biosynthetic pathway for norepinephrine has, to date, coeruleus (LC), the major noradrenergic nucleus in brain. Rats been established. were treated chronically with various antidepressants, and The rate-limiting enzyme in the synthesis of norepineph- tyrosine hydroxylase levels were measured in the LC by rine is tyrosine hydroxylase. Tyrosine hydroxylase is an inimunoblot analysis. Representatives of all major classes of -60-kDa protein abundant in noradrenergic and dopaminer- antidepressant medication-including imipramine, nortripty- gic cell bodies and distributed throughout the brain in termi- line, tranylcypromine, fluvoxamine, fluoxetine, bupropion, nal fields of these catecholaminergic systems. Activity ofthe iprindole, and electroconvulsive seizures-were found to de- enzyme is regulated rapidly by neurotransmitters and neu- crease levels of tyrosine hydroxylase immunoreactivit by ronal activity through its phosphorylation by several types of 40-70% in the LC. Decreased levels of enzyme himunoreac. protein kinase (for review, see refs. 13 and 14). More long- tivity were shown to be associated with equivalent decreases in term regulation ofthe enzyme is achieved through changes in enzyme mRNA levels. Antidepressant regulation of LC tyro- its expression, apparently at the level of gene transcription, sine hydroxylase appeared specific to these compounds, inas- by a variety of chronic perturbations (15-22). Such acute and much as chronic treatment ofrats with representatives ofother chronic regulation of tyrosine hydroxylase is thought to play classes of psychotropic drugs, including haloperidol, diaze- a critical role in modulating the functional activity of cate- pam, clonidine, cocaine, and morphine, failed to decrease cholaminergic neuronal systems in the brain. levels of this protein. The results demonstrate that chronic In the present study, the influence of chronic antidepres- antidepressants dramatically downregulate the expression of sant treatments on the expression of tyrosine hydroxylase tyrosine hydroxylase in the LC and raise the possibility that was examined in the LC. We show here that chronic admin- such regulation of the enzyme represents an adaptive response istration of every major class of antidepressant results in a of LC neurons to antidepressants that mediates some of their dramatic downregulation of tyrosine hydroxylase expression therapeutic actions in depression and/or other psychiatric specifically in the LC. The results raise the possibility that disturbances. downregulation of the biosynthetic pathway for norepineph- rine contributes to the molecular mechanisms through which Among the best studied actions of antidepressant treatments antidepressant treatments exert at least some oftheir multiple are their effects on the postsynaptic noradrenergic system. clinical actions. Thus, one of the most consistent adaptive responses to chronic administration of antidepressants, including electro- METHODS convulsive seizures (ECS), is a downregulation of the p- adrenergic receptor-coupled cAMP system (1-3). These In Vivo Drug Treatments. Male Sprague-Dawley rats (ini- treatments have also been shown more recently to regulate tial weight 150-200 g) received i.p. injections of imipramine additional postreceptor sites in this signal-transduction path- (15 mg/kg; Sigma), nortriptyline (15 mg/kg; Sigma); tranyl- way, including specific G protein subunits (4) and cAMP- cypromine (7.5 mg/kg; Sigma), fluvoxamine (15 mg/kg; dependent protein phosphorylation (5, 6). In addition to Duphar, Weesp, Holland), fluoxetine (15 mg/kg; Eli Lilly), regulation of the postsynaptic noradrenergic system, adap- bupropion (30 mg/kg; Burroughs Wellcome), iprindole (15 tive changes also occur in presynaptic noradrenergic ele- mg/kg; Wyeth-Ayerst), and haloperidol (1 mg/kg; McNeil ments in response to chronic antidepressant treatment. (i) Laboratories) once daily for 18 days or cocaine hydrochloride Chronic administration of some antidepressants has been (15 mg/kg; Sigma) twice daily for 14 days. Clonidine was shown to decrease a2-adrenergic receptor regulation of given in the drinking water (2 ,ug/ml) for 14 days with an cAMP production in cerebral cortex (7), an effect presumed average consumption of 300 ,ug/kg per day; morphine was to be localized, at least in part, to presynaptic noradrenergic administered by daily s.c. implantation of morphine pellets nerve terminals. (ii) These treatments have been found to (containing 75 mg of morphine base; National Institute on decrease the firing rates ofnoradrenergic neurons in the locus Drug Abuse) for 5 days with rats used on day 6; and diazepam coeruleus (LC) (8-10), the major noradrenergic nucleus in was administered by implantation of two sialastic capsules brain. (iii) Chronic drug administration has been shown to (containing 90 mg of diazepam; Hoffman-La Roche), a third alter levels of norepinephrine and its metabolites in cerebral capsule on day 10, with rats used on day 21. Control animals cortex in laboratory animals, as well as in blood, cerebro- received saline injections or underwent identical surgical spinal fluid, and urine in human subjects (see refs. 11, 12). procedures but did not receive drug implantations. ECS was While these findings suggest that chronic antidepressant administered once daily for 1-10 days through earclip elec- treatments may alter the synthesis of norepinephrine in the trodes (35 mA, 0.3 sec); control rats were handled in the same manner, but no current was applied. Unless otherwise spec- The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: LC, locus coeruleus; ECS, electroconvulsive sei- in accordance with 18 U.S.C. §1734 solely to indicate this fact. zures. 7522 Downloaded by guest on September 23, 2021 Neurobiology: Nestler et al. Proc. Natl. Acad. Sci. USA 87 (1990) 7523 ified, all animals were sacrificed by decapitation 18 hr after LC SN the last drug treatment or ECS. The above doses, durations of treatment, and routes of administration used for the various treatments were those that have been shown in previous studies to lead to chronic effects of these treatments (see refs. 11, 23-29). _ - __ .-TH Immunoblotting of Tyrosine Hydroxylase. LC and substan- tia nigra were excised from 0.75-mm-thick coronal cross- sections of brain by obtaining 15-gauge punches with a syringe needle (30). Isolated brain regions were homogenized (10 mg/ml) in 2% SDS, and aliquots (containing 25-75 ,ug of protein) were adjusted to contain 50 mM Tris (pH 6.7), 2% SDS, 4% (vol/vol) glycerol, 2% (vol/vol) 2-mercaptoethanol, + + Imipramine with bromophenol blue as a marker. The samples were then FIG. 1. Autoradiograms showing regulation of tyrosine hydroxy- subjected to one-dimensional SDS/polyacrylamide gel elec- lase immunoreactivity by chronic imipramine in the rat LC and trophoresis (with 7.5% acrylamide/0.3% bisacrylamide in the substantia nigra (SN). Levels of tyrosine hydroxylase immunoreac- resolving gels) and to immunoblotting analysis for tyrosine tivity were quantitated by immunoblot analysis as described. TH, hydroxylase exactly as described (22) using a commercially tyrosine hydroxylase. available rabbit polyclonal antiserum (1:250; Eugene Tech, Allendale, NJ) and 1251I-labeled goat anti-rabbit IgG (500 of enzyme immunoreactivity in the substantia nigra, a mid- cpm/pul; New England Nuclear). Resulting blots were dried brain nucleus enriched in dopaminergic cell bodies (Fig. 1 and and autoradiographed with the use of intensifying screens Table 1). (DuPont). Levels of immunolabeling were quantitated by Next, we studied whether decreased levels of tyrosine densitometry or by counting excised bands in a gamma hydroxylase immunoreactivity in the LC in response to counter. Levels of immunolabeling were normalized to pro- chronic imipramine are associated with equivalent changes in tein levels or "per punch," which contain reproducible levels levels ofmRNA for the enzyme, quantitated by Northern blot of protein (see ref. 30). In a typical experiment, six control analysis. Fig. 2 shows that chronic imipramine treatment and treated samples were analyzed on each immunoblot. decreased levels of tyrosine hydroxylase mRNA by -45% in Northern Blot Analysis of Tyrosine Hydroxylase mRNA. the LC. In contrast, chronic imipramine had no effect on Total mRNA was extracted from LC and substantia nigra by levels of enzyme mRNA in the substantia nigra (data not using published procedures (19). Briefly, brain regions were shown). In some experiments, levels of mRNA for dopamine isolated from control
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