Identification and validation of central amygdala FGFR1 as a therapeutic target for alcohol use disorder using single-nucleus sequencing in rats

Abstract

A significant minority of alcohol users develop alcohol addiction, characterized by continued use despite negative consequences, referred to as compulsive-like. We previously showed that vulnerability to compulsive-like alcohol use can be modeled in rats using punished alcohol self-administration and in male rats is mediated by PKCδ+ neurons in the central nucleus of the amygdala (CeA). Here, we used cell-type-specific transcriptomics to identify molecular mechanisms underlying individual differences in this behavior. Transcriptional changes were restricted to a limited number of CeA neuronal populations, including PKCδ+ neurons, where weighted Gene Co-expression Network Analysis identified an upregulated co-expression module in punishment-resistant rats with FGFR1 as a druggable upstream regulator. Selective silencing of FgfR1 in PKCδ+ neurons normalized elevated PKCδ+ expression, and reduced punishment-resistant alcohol self-administration. This effect was recapitulated by systemic administration of the FgfR1-antagonist PD173074. These findings identify distinct CeA circuits that promote addiction vulnerability, and position FGFR1 as potential therapeutic targets. Compulsive alcohol use is a defining feature of alcohol addiction, but its mechanisms remain unclear. Here, authors show that FGFR1 signaling in central amygdala PKCδ+ neurons promotes compulsive alcohol use and may offer a therapeutic target.