Role of 5-HT1A receptors in the basolateral amygdala on 3,4-methylenedioxymethamphetamine-induced prosocial effects in mice

3,4-methylenedioxymethamphetamine (MDMA) is a recreational drug abused worldwide and is known to induce unique prosocial effects such as increased sociability and empathy in rodents, non-human primates, and humans (Hermle et al., 1993; Kamboj et al., 2018; Bedi et al., 2010; Morley et al., 2005; Thompson et al., 2007; Heifets et al., 2019; Curry et al., 2018; Kuteykin-Teplyakov and Maldonado, 2014; Pitts et al., 2017). MDMA has been attracting attention as a potential therapeutic agent for psychiatric disorders due to its positive effects on sociability. Recent pilot studies have shown a reduction in social anxiety in autistic adults with MDMA-assisted psychotherapy and its ameliorating effect against severe post-traumatic stress disorder (PTSD) in a phase 3 study (Danforth et al., 2018; Mitchell et al., 2021).

MDMA acts on serotonin (5-hydroxytryptamine; 5-HT) transporters (SERTs) and increases synaptic 5-HT concentrations via a reverse transport mechanism and reuptake inhibition (Kamilar-Britt and Bedi, 2015; Heifets and Malenka, 2016). 5-HT in the brain is essential for prosocial behaviors (Muller et al., 2016; Takumi et al., 2020; Fernández et al., 2018; Kiser et al., 2012). Previous studies have shown that systemic administration of selective 5-HT reuptake inhibitors (SSRIs) ameliorates social deficiencies in autism spectrum disorder (ASD) mouse models (Gould et al., 2011) and that 5-HT depletion in the brain causes social communication impairments in mice (Beis et al., 2015). Based on these results, it seems likely that the MDMA-induced increase in central 5-HT levels and the subsequent stimulation of 5-HT receptors are associated with its prosocial effects. Even though the involvement of SERTs and several 5-HT receptor subtypes has been implicated (Morley et al., 2005; Heifets et al., 2019; Pitts et al., 2017; Nardou et al., 2019), the detailed mechanisms underlying MDMA-induced prosocial effects have not been fully elucidated. To address these issues, we first examined whether modulation of SERTs is required for MDMA-induced prosocial effects and then identified which 5-HT receptor subtype(s) is responsible for its effects using the social approach (SA) test, which we have recently developed to assess sociability (Mukai et al., 2020). The medial prefrontal cortex (mPFC) and basolateral nucleus of amygdala (BLA) have been reported to play pivotal roles in social behaviors (Bicks et al., 2015; Kuga et al., 2022; Katayama et al., 2009; Bickart et al., 2014; Selimbeyoglu et al., 2017; Felix-Ortiz et al., 2016). Additionally, 5-HT is known to modulate neural activity in these brain regions (Wallace et al., 2014; Rainnie, 1999). Therefore, we investigated the possible involvement of the mPFC and BLA in MDMA-induced prosocial effects induced by local drug administration.

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