Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression.
Polymorphism of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of brain serotonin (5-HT), is associated with less synthesis of brain 5-HT in DBA/2J and BALB/c than in C57BL/6J and 129/Sv mice. We selected the forced swimming test, a mouse model used to assess the antidepressant potential of drugs, and neurochemical techniques to study strain differences in the response to citalopram, a selective 5-HT reuptake inhibitor. Citalopram reduced immobility time in C57BL/6J and 129/Sv mice but had no such effect in DBA/2J and BALB/c mice. The drug reduced accumulation of 5-hydroxytryptophan (5-HTP), an indicator of 5-HT synthesis, in C57BL/6J and 129/Sv mice but much less in DBA/2J and BALB/c mice. Pretreatment with tryptophan raised 5-HTP accumulation and reinstated the antidepressant-like effect of citalopram in DBA/2J and BALB/c mice, whereas pharmacological inhibition of 5-HT synthesis prevented the effect of citalopram in C57BL/6J and 129/Sv mice. Because there were no strain differences in catecholamine synthesis, locomotor activity, and brain levels of citalopram at the end of the behavioral test, the results suggest that the failure of citalopram to reduce immobility time in DBA/2J and BALB/c mice is attributable to genotype-dependent impairment of 5-HT synthesis. Interstrain comparisons could probably be a useful strategy for understanding the mechanisms underlying the response to selective serotonin reuptake inhibitors.
Cervo
Luigi
L
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy.
Canetta
Alessandro
A
Calcagno
Eleonora
E
Burbassi
Silvia
S
Sacchetti
Giuseppina
G
Caccia
Silvio
S
Fracasso
Claudia
C
Albani
Diego
D
Forloni
Gianluigi
G
Invernizzi
Roberto W
RW
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology*; D017931:DNA Primers; D003863:Depression / Q000201:enzymology* / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity; D013550:Swimming; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism*
D018687:Antidepressive Agents, Second-Generation; D017931:DNA Primers; D015283:Citalopram; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase