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Volume 16, Number 15, Issue of August 1, 1996 pp. 4810-4815
Copyright ©1996 Society for Neuroscience

Comparative Study of Pre- and Postsynaptic 5-HT_1A Receptor Modulation of Anxiety in Two Ethological Animal Tests

Received March 4, 1996; revised April 30, 1996; accepted May 13, 1996.

Sandra E. File, Luis E. Gonzalez, and Nick Andrews

Psychopharmacology Research Unit, United Medical and Dental Schools of Guy's and St. Thomas's Hospitals Division of Pharmacology, Guy's Hospital, London SE1 9RT, United Kingdom

The purpose of this study was to determine the roles of the presynaptic 5-hydroxytryptamine_1A (5-HT_1A) receptors in the median raphé nucleus (MRN) and of the postsynaptic 5-HT_1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT_1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN had significant anxiolytic effects in all three test situations examined (social interaction, plus-maze trials 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT_1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT_1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-OH-DPAT (100 ng) had significant anxiogenic effects in the social interaction test and in plus-maze trial 2. These anxiogenic effects were antagonized by silent doses of 5-HT_1A receptor antagonists [(+)WAY 100135, 10 mg/kg s.c., and intrahippocampal (±)tertatolol, 3 µg, respectively], confirming mediation by 5-HT_1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT_1A receptor antagonist (±)tertatolol (3 µg) had any significant effect when administered to the dorsal hippocampus. This demonstrates that previous experience of a rat in the plus-maze has a major effect on the sensitivity of dorsal hippocampal 5-HT_1A receptors, as we have demonstrated previously for the 5-HT_1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT_1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT_1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT_1A receptor agonists are given systemically.

Key words: 5-HT_1A; hippocampus; median raphé nucleus; elevated plus-maze; social interaction; anxiety

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