Metabotropic -aminobutyric acid receptors (GABA_BRs) play a critical role in inhibitory synaptic transmission in the hippocampus. However, little is known about a possible long-term effect requiring transcriptional changes. Here, using microarray technology and RT-PCR of RNA from cultured rat embryonic hippocampal neurones, we report the profile of genes that are up- or down-regulated by activation of GABA_BRs by baclofen but are not changed by baclofen in the presence of the GABA_BR CGP55845A. Our data show for the first time regulation of transcription of defined mRNAs following specific GABA_B receptor activation. The identified genes can be grouped into those encoding signal transduction, endocytosis/trafficking and structural classes of proteins. For example, butyrylcholinesterase (BuChE), brain-derived neurotrophic factor (BDNF) and COPS5 (Jab1) genes were up-regulated whereas Rab8 interacting protein and Rho GTPase activating protein 4 (ARHGAP4) were down-regulated. These results provide important baseline genomic data for future studies aimed at investigating the long-term effects of GABA_BR activation in neurones such as their roles in neuronal growth, pathway formation and stabilisation and synaptic plasticity.