Pharmacological characterization of 8‐OH‐DPAT‐induced inhibition of rat hippocampal 5‐HT release in vivo as measured by microdialysis

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Abstract
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. The classical 5‐HT receptor antagonists, metergoline (5 mg kg−1 s.c.), methysergide (10 mg kg−1 s.c.) and methiothepin (10 mgkg−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.). The mixed 5‐HT1/β‐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.). 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.). The 8‐OH‐DPAT (0.25 mg kg−1 s.c.) response was not affected by pretreatment with either the dopamine D2‐receptor antagonist sulpiride (10 mg kg−1 s.c.) or the α1/α2‐adrenoceptor antagonist phentolamine (10 mg kg−1 s.c.). We conclude from these data that the decrease of hippocampal 5‐HT output induced by 8‐OH‐DPAT 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.