Anxiolytic-like profile of mirtazapine in rat conditioned fear stress model: Functional significance of 5-hydroxytryptamine 1A receptor and alpha1-adrenergic receptor.
Mirtazapine is an antidepressant with a unique mechanism of action and has been categorized as a Noradrenergic and Specific Serotonergic Antidepressant (NaSSA). Although numerous clinical trials suggested the usefulness of mirtazapine for not only major depressive disorders but also a variety of anxiety disorders, efficacy studies in animal anxiety models have been rarely reported. The present study investigated a potential anxiolytic-like profile of mirtazapine in rat conditioned fear stress model. A 5-hydroxytryptamine (5-HT) 1A receptor partial agonist, buspirone (1-5 mg/kg) exhibited a significant reduction in freezing time, and its maximal effect was reversed by a selective 5-HT(1A) antagonist, WAY-100635 (1 mg/kg). Mirtazapine (1-10 mg/kg) also reduced the freezing time in a dose-related fashion, a substantial proportion (approx. 50%) of which was likewise antagonized by WAY-100635 (1 mg/kg). Mianserin (1-30 mg/kg), a structural analogue for mirtazapine, was ineffective. Furthermore, co-administration of alpha1 adrenoceptor antagonist, prazosin (0.03 mg/kg) completely reversed mirtazapine (10 mg/kg)-induced reduction of freezing time. These findings represent the first demonstration that the anxiolytic-like action of mirtazapine involves activation of 5-HT(1A) receptor and alpha1 adrenoceptor to different extents, and are compatible with one aspect of mirtazapine's pharmacological profile as NaSSA.
Kakui
Nobukazu
N
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd. 760, Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. nobukazu_kakui@meiji.co.jp
Yokoyama
Fumikazu
F
Yamauchi
Miki
M
Kitamura
Koichi
K
Imanishi
Taiichiro
T
Inoue
Takeshi
T
Koyama
Tsukasa
T
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D003214:Conditioning, Classical; D005239:Fear; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078785:Mirtazapine; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*
D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D018340:Receptors, Adrenergic, alpha-1; D044282:Receptor, Serotonin, 5-HT1A; D008803:Mianserin; D000078785:Mirtazapine; D011224:Prazosin