Various lines of evidence suggest a functional interaction between GABA(A) and Neuropeptide Y (NPY)-Y(1) receptor (Y(1)R) mediated transmissions in various brain regions, which can be important in the regulation of sedation, feeding, anxious behaviour and neuronal excitability. By using a transgenic mouse model carrying the murine Y(1)R gene promoter fused to the lacZ reporter gene (Y(1)R/LacZ mice), we showed that prolonged pharmacologically or physiologically induced changes in the cerebrocortical concentrations of the neuroactive steroids 3alpha-hydroxy-5alpha-pregnan- 20-one (3alpha,5alpha TH PROG) and tetrahydrodeoxycorticosterone (3alpha,5alpha TH DOC) increases Y(1)R/LacZ transgene expression in the central and medial amygdala, an effect similar to that induced by long-term treatment with positive modulators of the GABA(A) receptor complex (diazepam or abecarnil). We also demonstrated that fluctuations in the cerebrocortical concentrations of 3alpha,5alpha-TH PROG and 3alpha,5alpha TH DOC during voluntary ethanol consumption and ethanol withdrawal induces a marked increase in Y(1)R gene expression that becomes apparent 48 h after withdrawal. These data provide evidence that neuroactive steroids may play an important role in the functional interaction between the GABA(A) receptor and NPY-Y(1)R mediated pathways in the amygdala, which might represent an important regulatory mechanism for modulation of several functions, including ethanol withdrawal.