Distinct gene expression profiles in adult rat brains after acute MK-801 and cocaine treatments.
Uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists have been suggested to attenuate the self-administration and rewarding effects of psychostimulants. Microarrays containing 14,500 rat cDNAs were hybridized to identify alterations in gene expression levels in rat brain regions elicited by the uncompetitive NMDA receptor antagonist MK-801 (dizocilpine, 1 mg/kg), the dopamine agonist cocaine (20 mg/kg), or combined treatment (MK-801 15 min prior to cocaine) 4 h after injections. Total genes up regulated (Z-ratio >2) in parietal cortex and nucleus accumbens were 111 and 158, respectively. Total genes down regulated (Z-ratio <2) in the same tissues were 360 and 166, respectively. These genes fell into multiple molecular function gene ontology (GO) categories, but were highly represented in catalytic activities (44% of all genes), signal transduction (14%), protein (20%), nucleotide (18%), and nucleic acid (15%) binding. In nucleus accumbens, genes up regulated by MK-801 (87 genes) did not overlap those up regulated by cocaine (46 genes). Genes down regulated by MK-801 (33 genes) consisted of 2 overlapping genes with those down regulated by cocaine (89 genes). In parietal cortex, low numbers of overlapping regulated genes were also observed. Combined treatments also indicated low numbers (0-10) of genes commonly regulated when compared with single treatments alone. In situ hybridisation studies indicated significant increases in b-ZIP transcription factors (CREM, ICER, CBP, and c-fos) elicited by MK-801 and decreases in c-fos elicited by cocaine. The results indicate independent gene expression signatures following acute MK-801 and cocaine administration that appears to be largely non-overlapping and context dependent.
Storvik
Markus
M
Department of Neurobiology, A.I. Virtanen Institute, Kuopio 70211, Finland.
Tiikkainen
Pekka
P
van Iersel
Martijn
M
Wong
Garry
G
D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects* / Q000235:genetics*; D003042:Cocaine / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015342:DNA Probes; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling; D017403:In Situ Hybridization; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D017362:Cyclic AMP Response Element-Binding Protein; D015342:DNA Probes; D018076:DNA, Complementary; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012313:RNA; D016291:Dizocilpine Maleate; D003042:Cocaine