title: Effects of GABAB ligands alone and in combination with paroxetine on hippocampal BDNF gene expression.
abstract: Brain-derived neurotrophic factor (BDNF) has been suggested as a target for antidepressant treatment and chronic antidepressant drug administration shows a 'biphasic effect' on BDNF mRNA in rat hippocampus (transient decrease followed by an increase). In comparison, following acute administration only, an inhibitory action on BDNF gene expression is detected. The present study aimed to understand the mechanism behind the acute inhibitory action on BDNF gene expression by investigating the possible involvement of γ-aminobutyric acid (GABA) receptors in mediating this effect. Rats were injected with either saline, the GABA(A) selective compound 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), the benzodiazepine flunitrazepam or the GABA(B) selective compound baclofen. BDNF mRNA levels were measured 4h later using in-situ hybridization. Baclofen (10mg/kg, i.p.), but not THIP (10mg/kg, i.p.) or flunitrazepam (10mg/kg, i.p.), administration resulted in significant inhibition of BDNF mRNA expression in the cornu ammonis 3 and dentate gyrus but not in the cornu ammonis 1 region of the hippocampus. The inhibitory effect of baclofen on hippocampal BDNF mRNA expression was significantly attenuated by pre-treatment the selective GABA(B) antagonists, CGP 46381 and CGP 55845 (10mg/kg, i.p.). The inhibitory action by the selective serotonin re-uptake inhibitor (SSRI) paroxetine on hippocampal BDNF mRNA was also attenuated by CGP 46381. Our findings suggest a role for GABA(B), but not GABA(A), receptor-mediated mechanisms in the inhibitory regulation of basal hippocampal BDNF gene expression. Our results indicate that GABA(B) receptor activation may play a role in the antidepressant drug-induced inhibition of BDNF gene expression in the hippocampus.
authors.affiliation: Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Khundakar
authors.forename: Tyra S C
authors.initials: TS
authors.lastname: Zetterström
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008024:Ligands; D008297:Male; D017374:Paroxetine / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D008024:Ligands; D010721:Phosphinic Acids; D011412:Propanolamines; D012333:RNA, Messenger; D018080:Receptors, GABA-B; C085075:CGP 55845A; D017374:Paroxetine; D001418:Baclofen