Relationship between the antiaggressive properties of buspirone and the time of day

Abstract

Buspirone administered in the morning or evening completely suppressed the interspecies aggressiveness of isolated rats expressed as attacks on and bites of mice; muricidal behavior (killing of mice) was blocked by the drug only if it was administered in the evening. Electrolytic destruction of serotonin-containing structures of the midbrain levels the phase dependence of the antimuricidal properties of buspirone. Key Words: buspirone; aggression; suture nuclei; serotonin receptorsBuspirone is a new-generation anxiolytic differing from the benzodiazepine tranquilizers [2]. Its anxiolytic action is associated with its effects on the pre-and postsynaptic serotonin receptors of the first type of the A subtype (S1A) [13]. Antiaggressive properties of buspirone and other S1A-receptor agonists have been described [7,10]. The S~A receptors appear to play an important role in the regulation of aggressive behavior. Experimental data indicate patent changes of this form of behavior in the course of the day and changes in the binding capacity of the S~A receptors [9,12]. This study was aimed at finding out whether the antiaggressive properties of buspirone depend on the time of its administration. MATERIALS AND METHODSAn experimental model of pathological aggression was created by combining destruction of the nuclei of the midbrain suture and social deprivation for 2 weeks or by social deprivation alone. The experiments were carried out with 26 outbred male rats weighing 230 to 270 g, in which the dorsa~ and mediat nuclei of the midbrain suture were destroyed electrolytically, 28 inDepartment of Human and Animal Physiology, State University; Department of Pharmacology, Siberian Medical University, Tomsk (Presented by P. V. Sergeev, Member of the Russian Academy of Medical Sciences) tact rats, and 10 sham-operated animals of the same weight. The suture nuclei were destroyed by preimplanted nichrome electrodes [1] with a device for electrolysis at a 1-1.5 mA current for 20 sec with polar alterations. In the sham-operated animals the electrodes were implanted at the same sites, but embedded at a depth of 4 mm from the bone. The rats were kept under a standard photoregimen and fed standard diets with free access to food and water. On day 2-3 after the operation the animals were isolated. Aggressive behavior was assessed on day 14 of isolation before and 20 and 60 min after the injection of buspirone (intraperitoneally in a dose of 5 mg/kg of an 0.1% aqueous solution or in the right brain ventricle in a dose of 5 I~g in 5 pl of normal saline) or its solvent. Buspirone was provided by Prof. T. A. Voronina, Head of the Psychopharmacology Laboratory at the Research Institute of Pharmacology, Russian Academy of Medical Sciences. One group of animals was administered the drug at 9 o'clock in the morning, the other at 7 o'clock in the evening. Intact animals were isolated for longer periods (21-30 days). The aggressiveness of the rats was assessed from their behavior toward mice put in the cage. The latency of the first aggressive act...

Serotoninergic mechanism underlying the dependence of some neurotropic effects of lithium hydroxybutyrate on circadian phase of administration

“…In particular, LHB-indueed suppression of the central serotoninergie system can to a certain extent determine the elevation of ITI, since the serotoninergie system restricts activation of the antinociceptive mechanisms in short-term painful stimulation and potentiates it in other influences [2]. The absence of the effect of morning injections of LHB on the level of aggression in isolated animals with destroyed nuclei raphe [6] can also be attributed to suppression of the serotoninergie system due to inh~ition of serotonin metabolism. Prolongation of wakefulness in the sleepwake cycle induced by morning [5] administration of the drug (despite its sedative effect) can also be related to inhibition of the central serotonin metabolism and suppression of the serotoninergic system, which is intimately involved into mechanisms triggedng the slow-wave sleep [3].…”

“…In contrast to the above-described effects, LHB injected in the evening stimulates serotonin synthesis against the background of its reduced catabolism and exhibites pronounced antiaggressive effect [6]. Enhanced anabolism of serotonin after evening injections of LHB probably underlies its peculiar effect on the sleep structure [5]: prolonged slow-wave sleep, increased latency of the first phase of paradoxical sleep, and shortened duration of the paradoxical sleep [3].…”