title: Pathway-specific engagement of ephrinA5-EphA4/EphA5 system of the substantia nigra pars reticulata in cocaine-induced responses.
abstract: The nucleus accumbens (NAc) serves as a key neural substrate that controls acute and adaptive behavioral responses to cocaine administration. In this circuit, inputs from the NAc are transmitted through two parallel pathways, named the direct and indirect pathways, and converge at the substantia nigra pars reticulata (SNr). Our previous study using reversible neurotransmission blocking (RNB) of each pathway revealed that the dual stimulation of the SNr by both pathways is necessary for the acute response, but that the direct pathway predominantly controls the adaptive response to repeated cocaine administration. This study aimed at exploring the pathway-specific mechanism of cocaine actions at the convergent SNr. We examined a genome-wide expression profile of the SNr of three types of experimental mice: the direct pathway-blocked D-RNB mice, the indirect pathway-blocked I-RNB mice, and wild-type mice. We identified the up-regulation of ephrinA5, EphA4, and EphA5 specific to D-RNB mice during both acute and adaptive responses to cocaine administration. The activation by EphA4 and EphA5 in the SNr of wild-type mice by use of the immunoadhesin technique suppressed the adaptive response to repeated cocaine administration. Furthermore, cocaine exposure stimulated the phosphorylation of Erk1/2 in ephrinA5-expressing SNr cells in a direct pathway-dependent manner. The results have demonstrated that the ephrinA5-EphA4/EphA5 system plays an important role in the direct pathway-dependent regulation of the SNr in both acute and adaptive cocaine responses and would provide valuable therapeutic targets of cocaine addiction.
authors.affiliation: Department of Systems Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Hikida
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yawata
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Shigetada
authors.initials: S
authors.lastname: Nakanishi
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D036386:Ephrin-A5 / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D036122:Receptor, EphA4 / Q000235:genetics* / Q000378:metabolism; D036123:Receptor, EphA5 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D013744:Tetanus Toxin / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000779:Anesthetics, Local; D036386:Ephrin-A5; D013744:Tetanus Toxin; D036122:Receptor, EphA4; D036123:Receptor, EphA5; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003042:Cocaine