IN-VITRO AND IN-VIVO ACTIVITY OF 1-(1-NAPHTHYL)PIPERAZINE AT TERMINAL5-HT AUTORECEPTORS IN GUINEA-PIG BRAIN

The effect of 1-(1-naphthyl)piperazine (NP) on the 5-HT terminal autor eceptor modulating 5-HT release was investigated in vitro and in vivo. In vitro 5-HT release was measured in slices of guinea-pig substantia nigra and hypothalamus prelabelled with H-3-5-HT, superfused with Kre bs solution and depolarized electrically. NP, at 0.1 and 1 mu mol/l, d id not modify the calcium-dependent release of 3H-5-HT elicited by ele ctrical stimulation using a frequency of 5 Hz, however at 0.1 mu mol/l NP shifted to the right the inhibition curve of the non-selective aut oreceptor agonist, 5-carboxamidotryptamine, in both regions. In hypoth alamus when using lower frequencies (1 Hz or 0.2 Hz) or under pseudo-o ne-pulse stimulation, NP decreased the release of H-3-5-HT at 1 mu mol /l. In vivo microdialysis was used to measure extracellular levels of endogenous 5-HT in the substantia nigra of freely moving guineapigs. T he endogenous release of 5-HT was tetrodotoxin (TTX)-sensitive, indica ting a neuronal origin of this efflux. NP, administered through the mi crodialysis probe (1-100 mu mol/l), increased the levels of extracellu lar 5-HT in concentration-dependent and TTX-sensitive manner. These re sults suggest that in vitro NP acts as a 5-HT autoreceptor partial (an t)agonist in the substantia nigra and hypothalamus of guinea-pigs, and as a full antagonist in vivo. However, NP administered systemically a t 10 mg/kg i.p., did not modify the levels of extracellular 5-HT in th e substantia nigra. This lack of systemic effect of NP probably result s from its interaction at other receptors that modify 5-HT neurotransm ission. In particular, NP is an agonist at 5-HT,, somatodendritic rece ptors in the raphe nucleus, an action which would decrease the release of 5-HT.