M. He et al., Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis, BRAIN RES, 902(1), 2001, pp. 11-17
An involvement of serotonin (5-HT) 1A receptors in the etiology of psychiat
ric disorders has been suggested. Hypo-responsiveness of the 5-HT1A recepto
r is linked to anxiety and constitutive deletion of the 5-HT1A receptor pro
duces anxiety-like behaviors in the mouse. Evidence that 5-HT1A receptor in
activation increases the therapeutic effects of antidepressants has also be
en presented. The present studies used in vivo microdialysis and homologous
recombination techniques to examine the contribution of 5-HT1A autorecepto
rs to these effects. Basal and fluoxetine-evoked extracellular concentratio
ns of 5-HT were quantified in the striatum, a projection area of dorsal rap
he neurons (DRN), of wild-type (WT) and 5-HT1A receptor knock out (KO) mice
. The density of 5-HT transporters was also determined. Basal 5-HT concentr
ations did not differ in WT and KO mice. Fluoxetine (10 mg/kg) increased 5-
HT concentrations in both genotypes. This increase was, however, 2-fold gre
ater in KO mice, In contrast, no differences in Kt-evoked 5-HT concentratio
ns were seen. Similarly, neither basal nor stimulation-evoked DA differed a
cross genotype, Autoradiography revealed no differences between genotype in
the density of 5-HT transporters or post-synaptic 5-HT2A receptors. an ind
ex of 5-HT neuronal activity. These experiments demonstrate that, under bas
al and KCI stimulated conditions, adaptive mechanisms in the 5-HT system co
mpensate for the lack of 5-HT1A autoreceptor regulation of DRN. Furthermore
, they suggest that the absence of release-regulating 5-HT1A autoreceptors
in the DRN can not account for the anxiety phenotype of KO mice. The enhanc
ed response to fluoxetine in KO mice is consistent with pharmacological stu
dies and suggests that adaptive mechanisms that occur in response to 5-HT1A
receptor deletion are insufficient to oppose increases in 5-HT concentrati
ons produced by acute inhibition of the 5-HT transporter. Published by Else
vier Science B.V.