Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences.
The aim of the present study was to investigate the mechanisms underlying the desensitization of 5-HT(1A) receptors in the dorsal raphe and hypothalamus of serotonin (5-HT) transporter knock-out mice (5-HTT -/-). The density of 5-HT(1A) receptors in the dorsal raphe was reduced in both male and female 5-HTT -/- mice. This reduction was more extensive in female than in male 5-HTT -/- mice. 8-OH-DPAT-induced hypothermia was absent in female 5-HTT -/- and markedly attenuated in 5-HTT +/- mice. The density of 5-HT(1A) receptors also was decreased significantly in several nuclei of the hypothalamus, amygdala, and septum of female 5-HTT -/- mice. 5-HT(1A) receptor mRNA was reduced significantly in the dorsal raphe region, but not in the hypothalamus or hippocampus, of female 5-HTT +/- and 5-HTT -/- mice. G-protein coupling to 5-HT(1A) receptors and G-protein levels in most brain regions were not reduced significantly, except that G(o) and G(i1) proteins were reduced modestly in the midbrain of 5-HTT -/- mice. These data suggest that the desensitization of 5-HT(1A) receptors in 5-HTT -/- mice may be attributable to a reduction in the density of 5-HT(1A) receptors. This reduction is brain region-specific and more extensive in the female mice. The reduction in the density of 5-HT(1A) receptors may be mediated partly by reduction in the gene expression of 5-HT(1A) receptors in the dorsal raphe, but also by other mechanisms in the hypothalamus of 5-HTT -/- female mice. Finally, alterations in G-protein coupling to 5-HT(1A) receptors are unlikely to be involved in the desensitization of 5-HT(1A) receptors in 5-HTT -/- mice.
Li
Q
Q
Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health Clinical Center, Bethesda, Maryland 20892-1264, USA. qianli@codon.nih.gov
Wichems
C
C
Heils
A
A
Lesch
K P
KP
Murphy
D L
DL
D000679:Amygdala / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006720:Homozygote; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D015151:Immunoblotting; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020665:Septum of Brain / Q000166:cytology / Q000378:metabolism; D012702:Serotonin Antagonists / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D012737:Sex Factors
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins