Alcohol-heightened aggression in mice: attenuation by 5-HT 1A receptor agonists

Abstract

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.

Escalated Aggression after Alcohol Drinking in Male Mice: Dorsal Raphé and Prefrontal Cortex Serotonin and 5-HT1B Receptors

“…In conclusion, one of the most consistent findings in aggression research is that 5-HT agonists decrease aggressive behavior in multiple species, under various conditions involving receptors in the 5-HT 1 and 5-HT 2 families (Olivier and Mos, 1986;Sanchez et al, 1993;Muehlenkamp et al, 1995;Miczek et al, 1998Miczek et al, , 2007Fish et al, 1999;de Almeida et al, 2001). The heightened aggressive behavior that we have shown after medial prefrontal microinjection of CP-94,253 is intriguing because it (1) further confirms that the 5-HT 1B receptor is one of the few receptors that specifically modulates aggressive behavior and (2) reveals that selective increases in aggressive behavior are possible via a serotonergic mechanism.…”

“…The greater relative affinity of CP-93,129 for the 5-HT 1A receptor may account for why this ligand was able to effectively reduce heightened aggressive behavior in contrast to CP-94,253 when infused into a region abundant with 5-HT 1A receptors. Nonetheless, the resistance of Alc-heightened aggression to modulation by both ( + )8-OH-DPAT and CP-94,253 does indicate that this form of escalated aggression is not under direct modulation by the DRN and that the acute, pro-aggressive effect of 1.0 g/kg Alc is sufficient to counteract the antiaggressive effects of these ligands (Miczek et al, 1998;Fish et al, 1999).…”

“…The influence of the 5-HT 1 family of receptors on aggressive behavior has been extensively studied and has revealed that 5-HT 1 receptor agonists can dose dependently reduce aggression alone and in the presence of Alc (Olivier and Mos, 1986;Olivier et al, 1995;Miczek et al, 1998;Fish et al, 1999;de Boer and Koolhaas, 2005;Olivier and Van Oorschot, 2005;de Almeida et al, 2006). The 5-HT 1B receptor is of particular interest because of the behaviorally specific anti-aggressive effects of receptor-selective 5-HT 1B agonists although the effectiveness of one of the most potent 5-HT 1B agonists, CP-94,253, depends on the type of aggressive behavior being studied and the route of administration.…”

Aggression Escalated by Social Instigation or by Discontinuation of Reinforcement (“Frustration”) in Mice Inhibition by Anpirtoline: A 5-HT1B Receptor Agonist

“…The present experiments attempt to study extinction-induced aggression in mice, a species that has become of considerable interest because of developments in molecular genetics ). Whether or not heightened aggression resulting from discontinued reinforcement is characterized by a distinctive profile of serotonergic activity remains to be explored.Activation and antagonism of several 5-HT receptor subtypes in the 5-HT 1 and 5-HT 2 families suppress aggressive behavior (Sanchez et al 1993;de Almeida and Lucion 1994;Olivier et al 1995;de Almeida and Lucion 1997;Miczek et al 1998;de Almeida et al 2001). Experimental deletion of the gene coding for the 5-HT 1B receptor as well as pharmacological studies implicate this receptor subtype in aggressive behavior (Saudou et al 1994;Mos et al 1992).…”

Interaction of nitric oxide and serotonin in aggressive behavior

“…Both male and female mice that lack functional expression of the 5-HT 1B receptor gene (5-HT 1B Ϫ/Ϫ ) are more aggressive (Saudou et al, 1994;Bouwknecht et al, 2001), consistent with the anti-aggressive effect of several 5-HT 1B agonists including eltoprazine (Olivier et al, 1990), CP-94,253 (Fish et al, 1999;Chiavegatto et al, 2001), zolmitriptan , and anpirtoline (Rilke et al, 2001;Miczek and de Almeida, 2001;de Almeida and Miczek, 2002). Although agonists at 5-HT 1A receptors also decrease aggression in rodents (Olivier et al, 1995;Miczek et al, 1998), the mutant mice lacking 5-HT 1A receptors are more anxious, less reactive, and possibly less aggressive (Zhuang et al, 1999). Studies of behavioral phenotype in mice derived from a tissue-specific knockout strategy, which discriminates between 5-HT 1A presynaptic autoreceptor and 5-HT 1A postsynaptic receptor, could clarify this controversy.…”