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Neurotrophic Factor Expression After CNS Viral Injury Produces Enhanced Sensitivity to Psychostimulants: Potential Mechanism for Addiction Vulnerability

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Neurotrophic Factor Expression After CNS Viral Injury Produces Enhanced Sensitivity to Psychostimulants: Potential Mechanism for Addiction Vulnerability The Journal of Neuroscience, 2000, Vol. 20 RC104 1of5 Neurotrophic Factor Expression After CNS Viral Injury Produces Enhanced Sensitivity to Psychostimulants: Potential Mechanism for Addiction Vulnerability Marylou V. Solbrig,1 George F. Koob,2 Loren H. Parsons,2 Tomoko Kadota,3 Nigel Horscroft,1 Thomas Briese,1 and W. Ian Lipkin1 1Departments of Neurology, Microbiology, and Molecular Genetics, University of California-Irvine, Irvine, California 92697- 4292, 2Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and 3Department of Anatomy, Chiba University School of Medicine, Chiba 260, Japan Hypothesized risk factors for psychostimulant, amphetamine, specific neurotrophin expression pattern triggered by striatal and cocaine abuse include dopamine (DA) receptor polymor- viral injury that increases tyrosine hydroxylase activity, an early phisms, HIV infection, schizophrenia, drug-induced paranoias, step in DA synthesis, to produce a phenotype of enhanced and movement disorders; however, the molecular, cellular, and amphetamine sensitivity. The reactive neurotrophin pattern pro- biochemical mechanisms that predispose to drug sensitivity or vides a molecular framework for understanding how CNS viral drive the development of addiction are incompletely under- injury, as well as other CNS adaptations producing similar stood. Using the Borna disease rat, an animal model of viral- growth factor activation profiles, may influence psychostimu- induced encephalopathy wherein sensitivity to the locomotor lant sensitivity. and stereotypic behavioral effects of D-amphetamine and co- Key words: virus; encephalitis; neurotrophin; Borna disease; caine is enhanced (Solbrig et al., 1994, 1998), we identify a rat; cocaine; amphetamine; dopamine There is increasing experimental evidence to support a role for with BDV are sensitive to the locomotor and stereotypic behav- neuronal growth factors in the CNS response to drug exposure ioral effects of D-amphetamine and cocaine (Solbrig et al., 1994, that outlasts the acute effects of drug. BDNF infusions into the 1998), have specific pathology in monoaminergic, prefrontal, and ventral tegmental area (VTA) or nucleus accumbens (NAc) en- limbic circuits (Solbrig et al., 1994) and provide a unique exper- hance cocaine-induced locomotor activity and conditioned re- imental model for exploring mechanisms by which persistent ward in animal models (Horger et al., 1999). Factors neuro- CNS infection can modify psychostimulant sensitivity. trophin-3 (NT-3) and basic FGF (bFGF) are increased in the Drug sensitivity is one predictor of addiction vulnerability. VTA by repeated administration of psychostimulants (Flores et Because of the BD rat’s psychostimulant sensitivity, the CNS al., 1998; Pierce et al., 1999). Glial cell line-derived neurotrophin adaptations to virus are presumed similar to the adaptations to factor (GDNF) knock-out mice have greater sensitivity to loco- schedules of drug use that produce increases in amphetamine or motor and behavioral effects of cocaine (Messer et al., 2000). cocaine sensitivity. Thus, the BD rat is used to elucidate links Growth factors, known to influence synaptic transmission (Bou- between cell physiology and reward circuit neuroadaptive mech- langer and Poo, 1999), which act as sensitizing agents (Shu and anisms common to viral and repeated drug use insult. Mendell, 1999) and regulate neuronal morphology (Connor and Neurotrophins, which generate cascades of cytoplasmic signals, Dragunow, 1998), may mediate the increases in dendritic length, potentially influence cytoplasmic protein mediators of psycho- dendritic spine density, and numbers of branched spines on me- stimulant sensitivity through stimulated kinase reactions. One dium spiny neurons of the NAc that follow repeated target for neurotrophin signaling may be tyrosine hydroxylase D-amphetamine (AMPH) or cocaine injections (Robinson and (TH) phosphorylation. TH is the rate-limiting step in dopamine Kolb, 1997, 1999). (DA) synthesis; enzymatic activity is enhanced by multiple ki- Borna disease virus (BDV) is a negative-strand RNA virus nases acting at several phosphorylation sites. Increased TH activ- epidemiologically linked to patients with histories of intravenous drug abuse (Bode et al., 1988) and to dopaminergic syndromes such as schizophrenia (Hatalski et al., 1997). Adult rats infected This article is published in The Journal of Neuroscience, Rapid Received June 8, 2000; revised July 25, 2000; accepted Aug. 3, 2000. Communications Section, which publishes brief, peer- This work was supported by National Institutes of Health Grant DA 00376 (M.V.S.) and NS 29425 (W.I.L.). We thank C. Ribak for helpful discussion and R. reviewed papers online, not in print. Rapid Communications Kwon for technical assistance. Animal care and handling procedures were in are posted online approximately one month earlier than they compliance with institutional and National Institutes of Health guidelines. All experimental protocols and procedures were approved by the University of would appear if printed. They are listed in the Table of California-Irvine Institutional Animal Care and Use Committee. This is publication Contents of the next open issue of JNeurosci. Cite this article number 13021-NP from The Scripps Research Institute. as: JNeurosci, 2000, 20:RC104 (1–6). The publication date is Correspondence should be addressed to Dr. Marylou Solbrig, Emerging Diseases Laboratory, Gillespie Neuroscience Research Building, Room 3107, University of the date of posting online at www.jneurosci.org. California-Irvine, Irvine, CA 92697-4292. E-mail [email protected]. Copyright © 2000 Society for Neuroscience 0270-6474/00/200001-05$15.00/0 http://www.jneurosci.org/cgi/content/full/4627 2of5 J. Neurosci., 2000, Vol. 20 Solbrig et al. • CNS Viral Injury, Neurotrophins, and Drug Abuse ity, in turn, would enhance dopaminergic pharmacological effects, CA). TH was quantified by Western blotting using rabbit anti-TH poly- such as those of the indirect DA agonists D-amphetamine and clonal antibody (AB151; Chemicon, Temecula, CA) at 1:5000 dilution, an HRP-conjugated secondary antibody with an ECL-Plus detection system cocaine. (Amersham, Arlington Heights, IL), and phosphorimaging analysis To test the hypothesis that neuronal growth factors contribute (Storm 840 PhosphorImager, Molecular Dynamics). Actin detected by to the enhanced behavioral response to D-amphetamine and mouse anti-actin monoclonal antibody (MAB 1501; Chemicon) served as cocaine in BD rats, we examined neurotrophin transcript levels in a control for protein concentration loaded (n ϭ 4–6 per group). striatum (caudate putamen and nucleus accumbens) and mid- For immunohistochemistry, anesthetized animals were perfused with buffered 4% paraformaldehyde; brains were removed, post-fixed, and brain (substantia nigra pars compacta plus ventral tegmental cryoprotected. Twenty micromolar slide-mounted sections were immu- area), neuropil microenvironments of DA termini and cell bodies, nostained with rabbit anti-TH serum (Protos Biotech, New York, NY) at respectively. Using pharmacological and biochemical techniques 1:1000, a biotinylated anti-rabbit secondary antibody, enhanced with Ј to identify changes in DA synthetic steps, we suggest a specific avidin-biotinylated enzyme complexes, and reacted in 3,3 - diaminobenzidine (DAB) (n ϭ 3 per group). neurotrophin expression pattern is related to increased TH func- TH activity assay. TH activity was measured in soluble fractions of tion in surviving dopaminergic terminals. isolated brain regions by HPLC detection of L-DOPA. Striatal and mesencephalic sections were homogenized in (1:4 w/v) 10 mM potassium MATERIALS AND METHODS phosphate, pH 7.4, then centrifuged at 14,000 ϫ g in 10K Nanosep tubes (Pall Filtron Corporation, Northborough, MA). Seven hundred micro- Subjects. Four-week-old male Lewis rats (Charles River Laboratories, gram protein aliquots were incubated at 37°C for 10 min in 100 mM Wilmington, MA) were intracerebrally infected with BDV by injection of sodium acetate buffer, pH 6, in the presence of: L-tyrosine, D,L-6-methyl- 1.6 ϫ 10 4 tissue culture infectious dose units, strain He/80–1, into the 5,6,7,8-tetrahydropterine-HCl (6MPH4) (Sigma), catalase (Boehringer right lateral ventricle (BD rats) (Solbrig et al., 1994) or sham-infected Mannheim), an aromatic L-amino acid decarboxylase inhibitor: with sterile PBS (NL rats). Six weeks later, infected rats and age- 3-hydroxybenzylhydrazine 2HCl (NSD-1015) (Research Biochemicals, matched, sham-infected rats were tested or killed. Animal care and Natick, MA), and ferrous ammonium sulfate (Naoi et al., 1988) (n ϭ 6–7 handling procedures were in compliance with institutional and National per group). Institutes of Health guidelines. All experimental protocols and proce- TH phosphorylation and immunoprecipitation. Neutralized acid extracts dures were approved by the University of California-Irvine Institutional of striatal brain homogenates were subjected to direct-back or indirect- Animal Care and Use Committee. back phosphorylation (Guitart and Nestler, 1989). Twenty microgram Tissue preparation. For nucleic acid, protein, and neurochemical anal- aliquots of neutralized supernatants were phosphorylated with 0.03 ␮gof yses, rats were decapitated, and brains were removed. The striatum purified catalytic subunit of cAMP-dependent protein kinase (PKA-c) 32 (caudate putamen and nucleus accumbens) was dissected from a 2-mm- (Sigma) or5UofPKAholoenzyme (Sigma)
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