Abstract

The establishment of new behaviors requires epigenetic modifications that regulate the expression of genes underlying neuroplasticity in relevant circuits. Dopamine plays a central role in many physiological and pathological behavioral changes, including learning, memory, and addictive behaviors. In this study, we explored the relationship between dopaminergic neurotransmission and the epigenetic enzyme lysine-specific demethylase 1 (LSD1, KDM1a). LSD1 has a neurospecific isoform (neuroLSD1) generated by alternative splicing, which acts as a dominant-negative regulator, counteracting the ubiquitous LSD1 (uLSD1) functions. Notably, neuroLSD1 regulates immediate early gene expression, neuroplasticity, learning, and memory, making it a candidate regulator of dopamine-dependent behaviors. Our findings show that mice lacking neuroLSD1 have greater interindividual differences in their locomotor response to acute and repeated amphetamine (AMPH) exposure compared with their wild-type littermates. The analysis of the neurochemical effect of this psychostimulant using fast-scan cyclic voltammetry and microdialysis showed a reduced dopamine efflux in the nucleus accumbens (NAc). On the other hand, while a single dose of the AMPH did not alter uLSD1 and neuroLSD1 isoforms' expression, repeated AMPH administration led to a transient increase followed by a reduction of neuroLSD1 transcripts' abundance in the striatum and hippocampus. In conclusion, our data reveal a critical interplay between dopaminergic neurotransmission and the expression of LSD1 isoforms in the brain, highlighting their potential role in modulating dopamine-dependent behaviors. (Figure presented.). © 2025 International Society for Neurochemistry.