Strain differences in basal and post-citalopram extracellular 5-HT in the mouse medial prefrontal cortex and dorsal hippocampus: relation with tryptophan hydroxylase-2 activity

• Published in: Journal of neurochemistry Vol. 103; no. 3; pp. 1111 - 1120
• Main Authors: Calcagno, E, Canetta, A, Guzzetti, S, Cervo, L, Invernizzi, R.W
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.11.2007; Blackwell Publishing Ltd; Blackwell
• Subjects: Animals; antidepressant drugs; Biochemistry; Biological and medical sciences; biosynthesis; Brain; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Citalopram; Citalopram - pharmacology; Dose-Response Relationship, Drug; drug effects; Drug Resistance; Drug Resistance - genetics; Extracellular Fluid; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Enzymologic - genetics; genetics; Genotype; Hippocampus; Hippocampus - metabolism; Hippocampus - secretion; intracerebral microdialysis; Isoenzymes; Isoenzymes - drug effects; Isoenzymes - genetics; Isoenzymes - metabolism; Male; metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Microdialysis; Molecular and cellular biology; Molecular genetics; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotransmitters; Pharmacology; Prefrontal Cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Rodents; secretion; Selective Serotonin Reuptake Inhibitors; serotonin; Serotonin - biosynthesis; Serotonin - secretion; Serotonin Uptake Inhibitors - pharmacology; Species Specificity; SSRIs; TPH-2; Transcription. Transcription factor. Splicing. Rna processing; Tryptophan; Tryptophan - metabolism; Tryptophan - pharmacology; Tryptophan Hydroxylase; Tryptophan Hydroxylase - drug effects; Tryptophan Hydroxylase - genetics; Tryptophan Hydroxylase - metabolism; Up-Regulation; Up-Regulation - drug effects; Up-Regulation - genetics; Vertebrates: nervous system and sense organs; Drug; Load; Serotonin; SSRIs; antidepressant drugs; Rodentia; Central nervous system; Tryptophan; Prefrontal cortex; Extracellular; Encephalon; Strain; Vertebrata; intracerebral microdialysis; Mammalia; Microdialysis; Mouse; TPH-2; Neurotransmitter; Swimming; Technique; citalopram; Hippocampus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04806.x

We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20-40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram's ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram ( Cervo et al. 2005 ), particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP's effect remains to be elucidated.