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SMALL RNA, MAJOR IMPACT: MIR-3594-5P-MEDIATED SEZ6 DOWNREGULATION REGULATES HEROIN INTAKE ESCALATION
Dimitra Karydaand 14 co-authors
Université Paris Cité
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS02-07PM-203
Presentation
Date TBA
Board: PS02-07PM-203
Event Information
Poster Board
PS02-07PM-203
Poster
View posterAbstract
Addiction, defined as compulsive drug-seeking behaviour and continued use despite long-term neuroadaptations, remains a major global public health challenge. Despite extensive research, the neurobiological mechanisms underlying opioid use disorder and the transition to addiction are not yet fully understood. The self-administration (SA) paradigm in animal models provides valuable insights into addiction-related neuroplasticity, as rats with extended drug access (“long access”, LgA) exhibit escalating drug consumption and compulsive drug-taking behaviours. Long-lasting structural and functional modifications underlying addiction-related synaptic plasticity are mediated by multiple signalling pathways, many of which remain to be identified.
This study aimed to identify novel signalling pathways associated with heroin escalation. Rats underwent heroin self-administration under two conditions: long access (LgA, 6 h/day) and short access (ShA, 1 h/day). miRNA expression in the dorsal striatum (DS) was analysed using miRNA microarray to identify the key miRNA and its target protein involved in escalated heroin intake. To assess functional relevance, siRNA injections were used to block target protein expression.
We reported that miR-3594-5p was upregulated in the DS of LgA rats at a late, but not early, stage of heroin escalation. SEZ6, encoding a transmembrane protein, was identified as a target of miR-3594-5p. Both SEZ6 mRNA and protein levels were selectively downregulated in the DS of LgA rats. To investigate the causal role of SEZ6 in heroin escalation, anti-Sez6 siRNA was injected into the DS during SA.
Our results show that SEZ6 downregulation prevents escalated heroin consumption, suggesting a protective role for this protein against addiction-like behaviour.
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