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The Journal of Neuroscience, December 1, 2004, 24(48):10868-10877; doi:10.1523/JNEUROSCI.3223-04.2004

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Behavioral/Systems/Cognitive
Medial Hypothalamic 5-Hydroxytryptamine (5-HT)_1A Receptors Regulate Neuroendocrine Responses to Stress and Exploratory Locomotor Activity: Application of Recombinant Adenovirus Containing 5-HT_1A Sequences

Qian Li,^1,2 Andrew Holmes,³ Li Ma,² Louis D. Van de Kar,⁴  Francisca Garcia,⁴ and Dennis L. Murphy²

¹Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, Texas 77555-0431, ²Laboratory of Clinical Science, National Institute of Mental Health-National Institutes of Health (NIH), and ³Section on Behavioral Science and Genetics, National Institute on Alcohol Abuse and Alcoholism-NIH, Bethesda, Maryland 20892, and ⁴Department of Pharmacology, Loyola University Chicago, Maywood, Illinois 60153

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-HT_1A) receptors in the hypothalamus, amygdala, and dorsal raphe. To evaluate the contribution of hypothalamic 5-HT_1A receptors to these phenotypes of SERT knock-out mice, two studies were conducted. Recombinant adenoviruses containing 5-HT_1A sense and antisense sequences (Ad-1AP-sense and Ad-1AP-antisense) were used to manipulate 5-HT_1A receptors in the hypothalamus. The expression of the 5-HT_1A genes is controlled by the 5-HT_1A promoter, so that they are only expressed in 5-HT_1A receptor-containing cells. (1) Injection of Ad-1AP-sense into the hypothalamus of SERT knock-out mice restored 5-HT_1A 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-HT_1A 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-HT_1A receptors regulate stress responses and locomotor activity but may not regulate exploratory anxiety-like behaviors.

Key words: 5-HT_1A promoter; ACTH; ¹²⁵I-MPPI binding; elevated plus maze; open-field test; SERT knock-out

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Received Aug 6, 2004; revised October 17, 2004; accepted October 18, 2004.

This article has been cited by other articles:

				D. Popa, C. Lena, C. Alexandre, and J. Adrien Lasting Syndrome of Depression Produced by Reduction in Serotonin Uptake during Postnatal Development: Evidence from Sleep, Stress, and Behavior J. Neurosci., April 2, 2008; 28(14): 3546 - 3554. [Abstract] [Full Text] [PDF]

				C. L. Wellman, A. Izquierdo, J. E. Garrett, K. P. Martin, J. Carroll, R. Millstein, K.-P. Lesch, D. L. Murphy, and A. Holmes Impaired Stress-Coping and Fear Extinction and Abnormal Corticolimbic Morphology in Serotonin Transporter Knock-Out Mice J. Neurosci., January 17, 2007; 27(3): 684 - 691. [Abstract] [Full Text] [PDF]

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