Receptor-genes cross-talk: effect of chronic 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior.
Dysfunction in brain serotonin (5-HT) system has been implicated in the psychopathology of anxiety, depression, drug addiction, and schizophrenia. The 5-HT(1A) receptors play a central role in the control of 5-HTergic neurotransmission. There are some scarce data showing cross-regulation between 5-HT receptors. Here, we investigated whether interaction exists between 5-HT(1A) receptor and genes encoding key members in brain 5-HT system. Chronic treatment with selective agonist of 5-HT(1A) receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) produced considerable decrease in hypothermic response to acute administration of 8-OH-DPAT in CBA/Lac mice indicating desensitization of 5-HT(1A) receptors. The decrease in 5-HT(1A) gene expression as well as decrease in the expression of gene encoding key enzyme in 5-HT synthesis, tryptophan hydroxylase-2 (TPH-2) in the midbrain, and the expression of the gene encoding 5-HT(2A) receptor in the frontal cortex was shown. There were no significant changes in 5-HT transporter mRNA level in the midbrain. Despite considerable decrease in the expression of the genes encoding tryptophan hydroxylase-2, 5-HT(1A) and 5-HT(2A) receptors, chronic 8-OH-DPAT treatment failed to produce significant changes in 5-HT(1A)-linked behavior (intermale aggression, open-field behavior, light-dark box, and pinch-induced catalepsy), suggesting compensatory and adaptive effect of genes suppression. The obtained data on the effect of 8-OH-DPAT-induced desensitization of 5-HT(1A) receptors on 5-HT(1A), 5-HT(2A) and TPH-2 gene expression demonstrated the role of 5-HT(1A) receptor as indirect regulator of gene expression. The results provide the first evidence of receptor-key genes interaction in brain 5-HT system and may have profound implications in understanding the functioning of the brain neurotransmitter systems.
Popova
N K
NK
Department of Behavioral Neurogenomics, Institute of Cytology and Genetics, Siberian Division of the Russian Academy of Science, Lavrentyeva Avenue 10, Novosibirsk 630090, Russia.
Naumenko
V S
VS
Cybko
A S
AS
Bazovkina
D V
DV
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology*; D000378:Agonistic Behavior / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004361:Drug Tolerance; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D044282:Receptor, Serotonin, 5-HT1A / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D014365:Tryptophan Hydroxylase / Q000096:biosynthesis / Q000235:genetics
D044402:Receptor, Serotonin, 5-HT2A; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase