Differential inhibition of serotonin release by 5-HT and NA reuptake blockers after systemic administration.
The inhibition of serotonin (5-HT) release produced by antidepressants varying in relative selectivity for blocking uptake of 5-HT and noradrenaline (NA) was compared. Release was measured by microdialysis in anesthetized rats with nerve terminal 5-HT uptake inhibited by local infusion of citalopram (1 microM) through a dialysis probe in hippocampus. With 5-HT uptake first blocked in hippocampus, systemic injection of uptake inhibitors produced decreases in dialysate 5-HT, presumably due to autoreceptor stimulation in the raphe. The largest decreases (about 60-70%) in 5-HT were produced by the selective 5-HT uptake inhibitors sertraline, paroxetine and citalopram. Nonselective blockers caused less suppression of release. Thus, the maximum decrease in 5-HT was 35% after clomipramine, a less selective 5-HT uptake inhibitor, and < or = 30% after the nonselective 5-HT/NA uptake blockers imipramine and amitriptyline, 5-HT was not decreased after maprotiline, a selective NA uptake blocker. Pretreatment with (+)WAY100135 to block 5-HT1A autoreceptors, abolished the inhibition of 5-HT release produced by systemic sertraline, clomipramine and imipramine. One explanation for the difference between selective and nonselective inhibitors with respect to central 5-HT release, is the excitatory effect of (alpha 1) adrenergic receptor stimulation on 5-HT neuronal discharge. However, pretreatment with alpha-methyl-p-tyrosine to deplete NA, did not influence the inhibition of 5-HT release produced by imipramine.
Auerbach
S B
SB
Department of Biological Sciences, Nelson Biological Laboratories, Rutgers University, Piscataway, NJ, USA.
Lundberg
J F
JF
Hjorth
S
S
D015057:1-Naphthylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D020280:Sertraline; D013997:Time Factors
D015057:1-Naphthylamine; D015283:Citalopram; D007099:Imipramine; D009638:Norepinephrine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline