In vitro and in vivo activity of 1-(1-naphthyl)piperazine at terminal 5-HT autoreceptors in guinea-pig brain.
The effect of 1-(1-naphthyl)piperazine (NP) on the 5-HT terminal autoreceptor 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 3H-5-HT, superfused with Krebs solution and depolarized electrically. NP, at 0.1 and 1 mumol/l, did not modify the calcium-dependent release of 3H-5-HT elicited by electrical stimulation using a frequency of 5 Hz, however at 0.1 mumol/l NP shifted to the right the inhibition curve of the non-selective autoreceptor agonist, 5-carboxamidotryptamine, in both regions. In hypothalamus when using lower frequencies (1 Hz or 0.2 Hz) or under pseudo-one-pulse stimulation, NP decreased the release of 3H-5-HT at 1 mumol/l. In vivo microdialysis was used to measure extracellular levels of endogenous 5-HT in the substantia nigra of freely moving guinea-pigs. The endogenous release of 5-HT was tetrodotoxin (TTX)-sensitive, indicating a neuronal origin of this efflux. NP, administered through the microdialysis probe (1-100 mumol/l), increased the levels of extracellular 5-HT in concentration-dependent and TTX-sensitive manner. These results suggest that in vitro NP acts as a 5-HT autoreceptor partial (ant)agonist in the substantia nigra and hypothalamus of guinea-pigs, and as a full antagonist in vivo. However, NP administered systemically at 10 mg/kg i.p., did not modify the levels of extracellular 5-HT in the substantia nigra. This lack of systemic effect of NP probably results from its interaction at other receptors that modify 5-HT neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)
Moret
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Centre de Recherche Pierre Fabre, Castres, France.
Briley
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D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004558:Electric Stimulation; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006900:Hydroxylation; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D014364:Tryptophan / Q000378:metabolism
D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D013779:Tetrodotoxin; C048241:1-(1-naphthyl)piperazine; D014364:Tryptophan