Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Abstract

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.

The effect of the novel alpha–2–adrenoceptor agonist naphthylmedetomidine on pulse rate, arterial blood pressure and sedation in rabbits

“…This is the first report on the use of naphthylmedetomidine in rabbits. This and the recently published study (Votava et al. 2008), indicate that less sedation is induced by naphthylmedetomidine compared with medetomidine.…”

“…1994). The sedative and anti‐aggressive effects of this drug have been reported (Votava et al. 2008).…”

Reduced Levels of Serotonin 2A Receptors Underlie Resistance of Egr3-Deficient Mice to Locomotor Suppression by Clozapine

“…, Lynch et al (2011), MacDonald et al (1991), Moore et al (1992), O'Dell et al (2000), Oduola et al (2004), Philibin et al (2005), Rasmussen and Fink-Jensen (2000),Redrobe and Bourin (1997),Simon et al (2000),Vanderwolf (1991),Vanover et al (2006),Votava et al (2008),Yan et al (2007),Zarnowski et al (1994), andZhu et al (2004).…”

Experience with a naphthylmedetomidine – ketamine – hyaluronidase combination in inducing immobilization in anthropoid apes

“…Because of the central sympatholytic effect, medetomidine causes a drop in blood pressure and bradycardia [6, 9]. The effect of naphthylmedetomidine has been described as qualitatively different from the effects of medetomidine or dexmedetomidine in mice, rabbits, or rhesus macaques [3, 10, 11]. Depending on the dose, naphthylmedetomidine reduces the frequency and length of aggression in aggressive mice, increasing their latency period from the first instance.…”

“…At comparable doses, naphthylmedetomidine is not expected to produce the large and widespread effects that are otherwise seen with full and highly specific α 2 ‐AR agonists, such as medetomidine or dexmedetomidine [4, 13]. Recently, its effects on behavioral profile in mice [10] and cardiorespiratory function in rabbits [3] and rhesus macaques [11] have been described. The experiments with mice found that naphthylmedetomidine, even in the smallest doses, considerably impacted aggression, while locomotor activities were retained.…”