Altered Emotional States in Knockout Mice Lacking 5-HT1A or 5-HT1B Receptors

Abstract

Dysfunctions of the serotonergic system have been implicated in a number of psychiatric disorders including depression, anxiety and disorders of impulse control. To model these disorders we have generated mice with altered serotonergic systems. Specifically, we have created mice that lack or express reduced levels of two serotonin receptors: 5-HT1A and 5-HT1B receptors. These receptors are localized both on serotonergic neurons where they act as autoreceptors and on non-serotonergic neurons. As a result, the 5-HT1A and 5-HT1B receptors control the tone of the serotonergic system and mediate some of the postsynaptic effects of serotonin. Agonists of these receptors are currently used in the treatment of migraine and anxiety disorders. Mice lacking these receptors develop, feed, and breed normally and do not display any obvious abnormalities. However, when analyzed in a number of behavioral paradigms, the 5-HT1A and 5-HT1B knockout mice display a number of contrasting phenotypes. While the 5-HT1B knockout mice are more aggressive, more reactive, and less anxious than the wild-types, the 5-HT1A knockouts are less reactive, more anxious, and possibly less aggressive than the wild-types. We are currently investigating with tissue-specific knockout mice which neural circuits are responsible for these phenotypes.

Knockout Mice Reveal Opposite Roles for Serotonin 1A and 1B Receptors in Prepulse Inhibition

“…Consistent with these results, the 5-HT 1A agonist flesinoxan increased PPI, whereas anpirtoline decreased both PPI and habituation in intact 129Sv mice. The opposite roles of 5-HT 1A and 5-HT 1B receptors in modulating PPI are consistent with their opposite effects on a number of other behavioral responses (Zhuang et al 1999).…”

“…Consistent with these results, the 5-HT 1A agonist flesinoxan increased PPI, whereas anpirtoline decreased both PPI and habituation in intact 129Sv mice. The opposite roles of 5-HT 1A and 5-HT 1B receptors in modulating PPI are consistent with their opposite effects on a number of other behavioral responses (Zhuang et al 1999).No phenotypic difference in PPI was observed in 1AKO mice, although a small increase in PPI was found in 1BKO mice (Figure 1). The phenotypic increase in PPI observed in 1BKO mice is consistent with earlier reports (Dulawa et al 1997) and the present findings that RU24969 and anpirtoline decrease PPI in WT, but not 1BKO mice.…”

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.…”

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

“…Once administered, serotonin agonists, which include 5-hydroxytryptophan, L-tryptophan and selective serotonin reuptake inhibitors, markedly attenuate hyperactivity in the DAT-KO mice. 34 In addition, mice lacking the 5HT1B receptor show hyperactivity, increased aggression and behavioral deinhibition [35][36][37][38][39] and 5HT4 receptor knockout mice show attenuated novelty-induced exploratory activity. 40 Finally, 5HT2 receptor agonists modulate hyperlocomotor activity in rats, and monoamine oxidase inhibitors reduce impulsiveness in animal models of ADHD.…”