Presynaptic modulation of 5-HT release in the rat septal region

5-HT released from serotonergic axon terminals in the septal nuclei modulates the activity of septal output neurons (e.g. septohippocampal cholinergic neurons) bearing somatodendritic 5-HT receptors. Therefore, we studied the mechanisms involved in the presynaptic modulation of 5-HT release in the lateral (LS) and medial septum (MS), and the diagonal band of Broca (DB). HPLC analysis showed that tissue concentrations of noradrenaline, dopamine and 5-HT were highest in DB (DB>MS>LS). Slices prepared from LS, MS and DB regions were preincubated with [3H]5-HT, superfused in the presence of 6-nitro-2-(1-piperazinyl)-quinoline (6-nitroquipazine) and electrically stimulated up to three times (first electrical stimulation period (S1), S2, S3; 360 pulses, 3 Hz, 2 ms, 26-28 mA). In all septal regions the Ca2+-dependent and tetrodotoxin-sensitive electrically-evoked overflow of [3H] was inhibited by the 5-HT1B agonist CP-93,129 and the α2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline tartrate (UK-14,304). Also the μ- and κ-opioid receptor agonists (d-Ala2, N-Me-Phe4, glycinol5)-enkephalin (DAMGO) and [trans-(1S,2S(-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzenacetamide hydro-chloride] (U-50,488H), respectively, acted inhibitory (although less potently), whereas the δ-opioid receptor agonist (d-Pen2, d-Pen5)-enkephalin (DPDPE), the dopamine D2 receptor agonist quinpirole and the adenosine A1 receptor agonist N6-cyclopentyladenosine were all ineffective; the GABAB receptor agonist baclofen had weak effects. All inhibitory effects of the agonists were antagonized by the corresponding antagonists (3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride (GR-55,562), idazoxan, naloxone, nor-binaltorphimine), which also significantly enhanced the evoked release of 5-HT at S1. It is concluded that 5-HT release in septal nuclei of the rat is modulated by presynaptic 5-HT1B autoreceptors, as well as by α2-, μ- and κ-opioid heteroreceptors. All of these receptors seem to be under a tonic inhibitory influence of the corresponding endogenous agonists and show qualitatively comparable modulatory properties along the dorso-ventral distribution of the 5-HT terminals.