Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment up-regulates cortical expression of neuropeptide mRNAs and down-regulates immediate-early gene (IEG) mRNAs specifically in the barrel cortex, and not in other brain regions. The present data suggest a central role of neuropeptides in the fine-tuning of sensory cortical circuits by long-term experience.