Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences.
Our previous studies found that serotonin transporter (SERT) knock-out mice showed increased sensitivity to minor stress and increased anxiety-like behavior but reduced locomotor activity. These mice also showed decreased density of 5-hydroxytryptamine (5-HT1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT1A receptors in the hypothalamus. The expression of the 5-HT1A genes is controlled by the 5-HT1A promoter, so that they are only expressed in 5-HT1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT1A receptors in the medial hypothalamus; this effect was accompanied by elimination of the exaggerated adrenocorticotropin responses to a saline injection (minor stress) and reduced locomotor activity but not by a change in increased exploratory anxiety-like behavior. (2) To further confirm the observation in SERT-/- mice, Ad-1AP-antisense was injected into the hypothalamus of normal mice. The density and the function of 5-HT1A receptors in the medial hypothalamus were significantly reduced in Ad-1AP-antisense-treated mice. Compared with the control group (injected with Ad-track), Ad-1A-antisense-treated mice showed a significant reduction in locomotor activity, but again no changes in exploratory anxiety-like behaviors, tested by elevated plus-maze and open-field tests. Thus, the present results demonstrate that medial hypothalamic 5-HT1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors.
Li
Qian
Q
Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, Texas 77555-0431, USA. i@utmb.edu
Holmes
Andrew
A
Ma
Li
L
Van de Kar
Louis D
LD
Garcia
Francisca
F
Murphy
Dennis L
DL
D000256:Adenoviridae / Q000235:genetics; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D002460:Cell Line; D003345:Corticosterone / Q000378:metabolism; D016373:DNA, Antisense / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology*; D005260:Female; D005822:Genetic Vectors / Q000494:pharmacology; D006801:Humans; D007033:Hypothalamus, Middle / Q000502:physiology*; D007267:Injections; D007668:Kidney; D008124:Locomotion / Q000502:physiology; D008297:Male; D018782:Maze Learning; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D010121:Oxytocin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins; D013312:Stress, Physiological / Q000503:physiopathology*
D016373:DNA, Antisense; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D044282:Receptor, Serotonin, 5-HT1A; D010121:Oxytocin; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone