Stimulation of the catecholaminergic and serotoninergic neurons in the rat brain by R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane, (-)-BPAP.
R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane HCl, (-)-BPAP, the recently developed selective and much more potent catecholaminergic/serotoninergic enhancer (CAE/SAE) substance than (-)-deprenyl enhances the performance of midbrain neurons, both in vivo and ex vivo, in a characteristic complex manner, presenting one bell shape dose/concentration effect curve in the low nanomolar range and another at higher micromolar range. For example, 4.7 +/- 0.10 nmol/g wet weight noradrenaline was released within 20 min from the quickly removed locus coeruleus of saline treated rats. This amount was increased 30 min after the subcutaneous administration of 0.0005 mg/kg (-)-BPAP to 15.4 +/- 0.55 nmol/g (P < 0.001). However, following the injection of a hundred times higher, 0.05 mg/kg, dose of (-)-BPAP, the amount of noradrenaline (4.3 +/- 0.25 nmol/g) released from the locus coeruleus did not differ from the control value. In ex vivo experiments, when the isolated locus coeruleus was soaked in an organ bath containing (-)-BPAP, the release of noradrenaline was significantly enhanced from 10(-16) M concentration, reached a peak effect at 10(-13) M concentration, but 10(-10) M (-)-BPAP was ineffective. A significant enhancer effect was detected also in the high concentration range from 10(-8) M, the peak effect was reached at 10(-6) M concentration and 10(-5) M (-)-BPAP was ineffective. (-)-BPAP enhanced in the low concentration range the performance of dopaminergic and serotoninergic neurons with a peak effect at 10(-13) and 10(-12) M concentration, respectively. The results with (-)-BPAP, the highly specific artificial enhancer substance, suggest that (i) high and low affinity "enhancer" receptors may exist in the brain, and (ii) that they may be identified with the recently cloned family of the "trace amine" receptors, activated by beta-phenylethylamine and tryptamine, the prototypes of the endogenous enhancer substances.
Department of Pharmacology and Pharmacotherapy, Faculty of General Medicine, Semmelweis University, P.O.B. 370, H-1445 Budapest, Hungary. jozsefknoll@hotmail.com
Joseph
J
Knoll
Ildikó
I
Miklya
Berta
B
Knoll
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*
C404200:1-(benzofuran-2-yl)-2-propylaminopentane; D001572:Benzofurans; D002395:Catecholamines; D012701:Serotonin; D004298:Dopamine