Effects of a 5-HT7 receptor antagonist DR4004 on the exploratory behavior in a novel environment and on brain monoamine dynamics in mice.
The present study examined whether serotonin (5-hydroxytryptamine; 5-HT)7 receptors play a role in the modulation of emotionality in mice using the selective 5-HT7 receptor antagonist 2a-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)butyl]-2a,3,4,5-tetrahydrobenzo (c,d)indol-2-(1H)-one (DR4004). The emotionality of mice was evaluated in terms of exploratory activity in the hole-board test. The mice treated with DR4004 (2.5-10 mg/kg, i.p.) displayed a dose-dependent decrease in locomotor activity by moving less distance in the hole-board, and statistically significant decreases were observed at 5 and 10 mg/kg. On the other hand, DR4004 (10 mg/kg, i.p.) did not affect spontaneous motor activity. In a neurochemical study, decreases in amygdaloid dopamine and 5-HT turnover were observed in mice in which locomotor activity in the hole-board test was attenuated following the administration of DR4004 (10 mg/kg, i.p.). Also, a simple linear regression analysis revealed that locomotor activity on the hole-board was significantly correlated with dopamine and 5-HT turnover in amygdala. Furthermore, co-injection of the selective dopamine reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)piperazine (GBR12909; 1.25-5 mg/kg, i.p.) or the selective 5-HT reuptake inhibitor fluvoxamine (20 mg/kg, i.p.) significantly reversed the DR4004 (10 mg/kg, i.p.)-induced decrease in locomotor activity in the hole-board test. These findings constitute the behavioral evidence that 5-HT7 receptors may play a role in the modulation of emotionality. Furthermore, it is also suggested that amygdaloid dopamine and 5-HT neuronal systems may be involved in this modulation.
Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Tokyo 160-8402, Japan. ht0417@tokyo-med.ac.jp
Hiroshi
H
Takeda
Minoru
M
Tsuji
Hideaki
H
Ikoshi
Tomoko
T
Yamada
Jiro
J
Masuya
Makio
M
Iimori
Teruhiko
T
Matsumiya
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects*; D016666:Fluvoxamine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D013997:Time Factors
D015306:Biogenic Monoamines; D004298:Dopamine; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; D016666:Fluvoxamine; D007211:Indoles; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013469:Sulpiride; C461261:(1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-hydroxy-3-phenylpropyl) piperazinyl decanoate); C472242:DR-4004; C104425:serotonin 7 receptor