Effects of trazodone on neurotransmitter release from rat mossy fibre cerebellar synaptosomes.
The effects of trazodone and putative sigma (sigma) receptor ligands were investigated on KCl-stimulated release of glutamate (Glu) and gamma-aminobutyric acid (GABA) from cerebellar mossy fibre synaptosomes. Both trazodone and serotonin (5-HT) inhibited the increase of Glu and GABA release evoked by 15 mM KCl. Trazodone increased the inhibition of Glu release caused by 0.01 microM 5-HT, while it antagonized the inhibition induced by higher 5-HT concentrations. Despite the low affinity of trazodone for both sigma(1) and sigma(2) binding sites, with a pK(i) of 5.9 and 6.0 respectively, two sigma receptor ligands, (+)-3-[3-hydroxypheny]-N-(1-propyl)piperidine ((+)-3-PPP) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047) antagonized the effects of trazodone. The putative sigma receptor ligand N-allylnormetazocine ((+)-SKF 10,047) mimicked the inhibitory effect of trazodone. As with trazodone, (+)-3-PPP and BD 1047 antagonized the activity of (+)-SKF 10,047 but not that of 5-HT. On the whole, these results suggest that trazodone shares a common molecular target with sigma compounds distinct from that of 5-HT and is involved in K(+)-stimulated Glu and GABA release from mossy fibre cerebellar synaptosomes.
Pharmacological Department, ACRAF-Angelini Ricerche, P.le della Stazione s.n.c., 00040 S. Palomba-Pomezia, Rome, Italy.
B
B
Garrone
M
M
Magnani
M
M
Pinza
L
L
Polenzani
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects*; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014196:Trazodone / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018687:Antidepressive Agents, Second-Generation; D005029:Ethylenediamines; D010880:Piperidines; D017480:Receptors, sigma; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; D012701:Serotonin; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; C012134:SK&F 10047; C026539:preclamol; D010620:Phenazocine; D014196:Trazodone