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Glucocorticoid Effects on Mesotelencephalic Dopamine Neurotransmission Steven E Glucocorticoid Effects on Mesotelencephalic Dopamine Neurotransmission Steven E. Lindley, M.D., Ph.D., Tasha G. Bengoechea, Alan F. Schatzberg, M.D., and Dona L. Wong, Ph.D. Multiple neurochemical estimates were used to examine DA after alpha-methyl-para-tyrosine, suggesting that peripheral corticosterone (CORT) effects in dopaminergic neither DA neuronal activity nor release are altered by terminal regions. Acute CORT administration, which CORT. Moreover, neither gamma-hydroxybutyric acid elevated plasma CORT (5 h), slightly decreased lactone-induced increases in DOPA accumulation or stress- dihydroxyphenylacetic acid (DOPAC) to dopamine (DA) induced increases in DA utilization were influenced by ratios in the striatum but not in other regions examined. CORT replacement, indicating that neither autoreceptor Two weeks of adrenalectomy (ADX) increased both medial regulation of DA synthesis nor acute stress regulation of prefrontal cortex DOPAC/DA and homovanillic acid DA utilization are changed by CORT. The findings are (HVA)/DA and striatal HVA/DA. A reciprocal pattern of most consistent with direct inhibition of basal DA changes was observed with CORT replacement in ADX metabolism in the medial prefrontal cortex and striatum. animals. In contrast, CORT replacement in ADX animals The possible physiological and behavioral significance of did not significantly influence tyrosine hydroxylase this inhibition is being further explored. content, basal dihydroxyphenylalanine (DOPA) [Neuropsychopharmacology 21:399–407, 1999] accumulation after NSD 1015 treatment or the decline in Published by Elsevier Science Inc. KEY WORDS: Dopamine; Tyrosine hydroxylase; these systems may underlie the pathophysiology of Corticosterone; Medial prefrontal cortex; Nucleus some psychiatric disorders (Dinan 1996; Nemeroff 1993; accumbens; Striatum; Stress Piazza and Le Moal 1996; Schatzberg et al. 1985). For ex- Adverse environmental stimuli evoke a number of ample, the cognitive disturbances in psychotic de- physiological responses, including activation of the hy- pressed patients may be secondary to the effect of HPA pothalamic–pituitary-adrenal (HPA) axis and ascend- axis alterations on central dopaminergic neuronal activ- ing catecholaminergic neurons. Although these re- ity (Schatzberg and Rothschild 1988; Schatzberg et al. sponses are critical to an organism’s ability to adapt 1985; Wolkowitz 1994). metabolically and behaviorally to stressful events, it has In support of adrenal steroids influencing dopamine also been hypothesized that sustained alterations in (DA) neurotransmission, a number of behaviors be- lieved to be associated with dopaminergic neurons are influenced by corticosterone (CORT). For example, glu- From the Nancy Pritzker Neurobiology Laboratory, Department cocorticoids attenuate D2 receptor agonist-induced be- of Psychiatry and Behavioral Sciences, Stanford University School haviors (Cador et al. 1993; Cools and Peeters 1992; of Medicine, Stanford, California. Address correspondence to: Steven E. Lindley, M.D., Ph.D., Faunt and Crocker 1988; Faunt and Crocker 1989). In Nancy Pritzker Neurobiology Laboratory, Department of Psychia- addition, glucocorticoids facilitate stimulant self-admin- try and Behavioral Sciences, MSLS Building, Room P104, Stanford istration and stimulant-induced locomotor activity University School of Medicine, Stanford, CA 94305-5485. Received 28 May 1998; revised 25 September 1998; accepted 16 (Marinelli et al. 1994; Ortiz et al. 1995; Patacchioli et al. October 1998. 1997; Piazza et al. 1993; Rivet et al. 1989) and mediate NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 3 Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(98)00103-1 400 S.E. Lindley et al. NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 3 stress-induced sensitization of extracellular DA release sacrifice under methoxyflurane anesthesia. Corticoster- by cocaine (Rouge-Pont et al. 1995). one replacement was confirmed by radioimmunoassay Furthermore, indirect biochemical data support the and by monitoring body weight. Gamma-hydroxybu- hypothesis that adrenal steroids modulate these behav- tyric acid lactone (GBL, Sigma, St. Louis, MO) m-hydroxy- iors through an influence on mesotelencephalic DA benzylhydrazine (NSD 1015, Sigma) and alpha-methyl- neurotransmission. In vitro, CORT regulates tyrosine dl-para-tyrosine (Sigma) were all dissolved in 0.9% saline. hydroxylase (TH), the rate-limiting enzyme in DA syn- thesis (reviewed in Meyer 1985). For example, the glu- cocorticoid receptor agonist dexamethasone increases Restraint Stress TH expression in both PC12 cells (Baetge et al. 1981; Lewis et al. 1983) and the adrenal medulla (Stachowiak Animals were removed from their cages, placed in Plas- et al. 1988). In addition, CORT increases the rate of ty- Labs rat restraints (Baxter, Hayward, CA) for 30 min. rosine phosphorylation in the ventral tegmental area, and sacrificed by decapitation. Control animals were containing the mesocortical and mesolimbic perikarya removed from their cages and immediately killed by (Nestler et al. 1989). Moreover, 50% of mesocortical, decapitation. mesolimbic, and nigrostriatal perikarya (A8–A10) are immunoreactive for type II glucocorticoid receptors (Harfstrand et al. 1986). However, previous in vivo Tissue Preparation studies directly investigating the effects of CORT on After removal from the adjoining housing area, pair- DA neurochemical estimates of neuronal activity have housed animals were immediately removed from their produced apparently conflicting results. For example, cages and sacrificed by decapitation. All experiments CORT has been observed to increase, decrease, or not were conducted during the first 2 hours of the light cy- alter DA utilization and extracellular DA release (Dunn cle, unless otherwise noted. Trunk blood was collected 1988; Imperato et al. 1992; Inoue and Koyama 1996; on ice, brains were removed, quick frozen on dry ice, Rothschild et al. 1985; Tanganelli et al. 1990; Thomas et and stored at 2808C. al. 1994; Wolkowitz et al. 1986). The present study, Frozen brains were sliced into 250-mm sections with therefore, utilized estimates of DA metabolism, synthe- a cryostat. The mPfx (AP 13.7–12.2 mm) was dissected sis, and turnover and TH expression to systematically with a scalpel, and striatum (AP 10.7 to 9.7 mm) was re- examine the effects of both acute and sustained alter- moved with stainless steel cannulae from frozen sec- ations in peripheral corticosterone on mesocortical, me- tions (Paxinos and Watson 1997). Tissue was dissected solimbic, and nigrostriatal DA neurotransmission. In within 24 to 72 h of slicing. The core and shell of the nu- addition, CORT effects on DA autoreceptor regulation cleus accumbens (AP 10.7–9.77 mm) were removed, as of DA synthesis and stress-induced stimulation of DA previously described (Deutch and Cameron 1992). Tis- utilization were investigated. sue was placed in 0.1 M perchloric acid with 0.1 mM EDTA and stored for no more than 2 weeks at 2808C until assay (modification of Palkovits 1973). METHODS Animals Neurochemical Assays Male Sprague–Dawley rats (175–200 gm; Simonsen Samples were thawed, homogenized by sonication, and Labs, Gilroy, CA) were maintained under controlled centrifuged for 2 min. Tissue pellets were dissolved in temperature and lighting (12/12 light/dark) with food 1.0 N NaOH, and proteins were determined (Bio-Rad, and water provided ad libitum. Animals were housed Richmond, CA). Cortical supernatants were filtered two per cage and acclimated for at least 7 days. Adrenal- through a 45-mm filter, and aliquots of supernatants ectomy was performed either by the vendor (Simonsen were injected directly on a C18 reverse phase analytical Labs) 2 weeks before experimentation or in house using column (5 mm, 250 3 4.6 mm; Biophase ODS, BAS, a dorsolateral approach and confirmed by plasma ra- West Lafayette, IN) protected by a precolumn cartridge dioimmunoassay of corticosterone. (5 mm, 30 3 4.6 mm, BAS), as previously described, with modification (Lindley et al. 1988). For cortical re- gions, a conditioning electrode set at 10.35 V and a Drugs dual analytical electrode cell set at 0.02 V and 20.32 V, Corticosterone 21-hemisuccinate (Steraloids Inc., New- respectively (ESA, Bedford, MA) were used. For other port, RI) was dissolved in water. For chronic studies, regions, a single analytical electrode set at 10.72 V was corticosterone pellets (21-day release; Innovative Re- used (BAS, West Lafayette, IN). Corticosterone was de- search, Sarasota, FL) were implanted SC 1 week before termined by RIA (ICN Biochem, Costa Mesa, CA). NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 3 Glucocorticoids on Dopamine Neurotransmission 401 Western Analysis of Tyrosine Hydroxylase Statistical Analyses The substantia nigra and ventral tegmental area (AP Statistical analyses in studies with single comparisons 3.7–2.7 mm) (Paxinos and Watson 1997) were removed were conducted using Student’s t-test. For multiple with stainless steel cannulae from frozen sections and comparisons, the effect of CORT treatment was ana- homogenized by sonication in Tris buffer (0.125 M Tris, lyzed by analysis of variance (ANOVA) followed by 0.1% SDS, pH 6.8). Samples were adjusted to a protein Bonferonni’s test for individual comparisons. Differ- concentration of 2 mg protein/ml in sample buffer [0.125 ences were considered significant if the probability of M Tris, 0.16% SDS, 5% glycerol (v/v), 0.08 M DTT, error was
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