Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine.
The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.
Berendsen
H H
HH
Department of Neuropharmacology, N.V. Organon, Oss, The Netherlands. h.berendsen@organon.akzonobel.nl
Broekkamp
C L
CL
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D000078785:Mirtazapine; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013649:Taste / Q000187:drug effects
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000662:Amphetamines; D000929:Antidepressive Agents, Tricyclic; D005473:Fluoxetine; D008803:Mianserin; D000078785:Mirtazapine; D011719:Pyrazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C014896:6-chloro-2-(1-piperazinyl)pyrazine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine