Pharmacological characterization of 8-OH-DPAT-induced inhibition of rat hippocampal 5-HT release in vivo as measured by microdialysis.
Sharp T., Bramwell SR., Hjorth S., Grahame-Smith DG.
1. We have previously found that the putative 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) decreases hippocampal 5-hydroxytryptamine (5-HT) release in the anaesthetized rat, as measured by brain microdialysis. The present study attempted to characterize the receptor involved in this response using a range of monoamine receptor antagonists. 2. The classical 5-HT receptor antagonists, metergoline (5 mg kg-1 s.c.), methysergide (10 mg kg-1 s.c.) and methiothepin (10 mg kg-1 s.c.) each reduced dialysate levels of 5-HT which complicated their use as antagonists in these experiments. Nevertheless, pretreatment with metergoline but not methiothepin and methysergide partially reduced the 5-HT response to a maximally effective dose of 8-OH-DPAT (0.25 mg kg-1 s.c.). 3. The mixed 5-HT 1/beta-adrenoceptor antagonist pindolol (8 mg kg-1 s.c.) was without effect on spontaneous 5-HT output but attenuated the effect of both maximally (0.25 mg kg-1 s.c.) and submaximally (0.05 mg kg-1 s.c.) effective dose of 8-OH-DPAT. In comparison, propranolol (10 mg kg-1 s.c.) did not affect 5-HT output when injected alone and did not alter the response to 8-OH-DPAT (0.25 mg kg-1 s.c.). 4. The 5-HT2 receptor antagonist ritanserin (0.2 mg kg-1 s.c.) and the 5-HT3 receptor antagonist BRL 43694 (0.5 mg kg-1 s.c.) neither altered 5-HT output alone nor significantly changed the response to 8-OH-DPAT (0.25 mg kg-1 s.c.). 5. The 8-OH-DPAT (0.25 mg kg-' s.c.) response was not affected by pretreatment with either the dopamine D2-receptor antagonist sulpiride (10mgkg-1 s.c.) or the alpha/alpha 2-adrenoceptor antagonist phentolamine (10mg kg-1 s.c.). 6. We conclude from these data that the decrease of hippocampal 5-HT output induced by 8-OHDPAT does not involve 5-HT2, 5-HT3, adrenoceptors or dopamine D2-receptors and that activation of a 5-HT1 class of receptor seems probable. Full classification of the 8-OH-DPAT response awaits development of a suitably selective 5-HT1 receptor antagonist with low intrinsic activity at the somatodendritic 5-HT autoreceptor.