Comparative study of pre- and postsynaptic 5-HT1A receptor modulation of anxiety in two ethological animal tests.

The purpose of this study was to determine the roles of the presynaptic 5-hydroxtryptamine1A (5-HT1A) receptors in the median raphé nucleus (MRN) and of the postsynaptic 5-HT1A 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-HT1A 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 trails 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-0H-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-HT1A receptor antagonists [(+)WAY 100135, 10 mg/kg s.c., and intrahippocampal (+/-)tertatolol, 3 microg, respectively], confirming mediation by 5-HT1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT1A receptor antagonist (+/-)tertatolol (3 microgram) 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-HT1A receptors, as we have demonstrated previously for the 5-HT1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT1A 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-HT1A receptor agonists are given systemically.