Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis.
An involvement of serotonin (5-HT) 1A receptors in the etiology of psychiatric disorders has been suggested. Hypo-responsiveness of the 5-HT1A receptor is linked to anxiety and constitutive deletion of the 5-HT1A receptor produces anxiety-like behaviors in the mouse. Evidence that 5-HT1A receptor inactivation increases the therapeutic effects of antidepressants has also been presented. The present studies used in vivo microdialysis and homologous recombination techniques to examine the contribution of 5-HT1A autoreceptors to these effects. Basal and fluoxetine-evoked extracellular concentrations of 5-HT were quantified in the striatum, a projection area of dorsal raphe 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 concentrations 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 greater in KO mice. In contrast, no differences in K(+)-evoked 5-HT concentrations were seen. Similarly, neither basal nor stimulation-evoked DA differed across genotype. Autoradiography revealed no differences between genotype in the density of 5-HT transporters or post-synaptic 5-HT2A receptors, an index of 5-HT neuronal activity. These experiments demonstrate that, under basal and KCl stimulated conditions, adaptive mechanisms in the 5-HT system compensate 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 enhanced response to fluoxetine in KO mice is consistent with pharmacological studies and suggests that adaptive mechanisms that occur in response to 5-HT1A receptor deletion are insufficient to oppose increases in 5-HT concentrations produced by acute inhibition of the 5-HT transporter.
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Integrative Neuroscience Unit, Behavioral Neuroscience Branch, NIDA Intramural Research Program, 21224, Baltimore, MD, USA.
Sibille
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Benjamin
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Toth
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Shippenberg
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D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011985:Receptors, Serotonin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology
D002352:Carrier Proteins; D004298:Dopamine; D005473:Fluoxetine; D006220:Haloperidol; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017661:Receptors, Presynaptic; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013134:Spiperone; C493231:Slc6a4 protein, mouse