Neocortex contains very few galanin neurons but receives a moderate galanin innervation from various subcortical loci. Recent data suggest that galanin helps regulate the tonic neuronal excitability of hippocampus and probably cerebral cortex but relatively little is known about the anatomy and functional regulation of cortical galanin systems. Therefore, we examined, in the rat, the effect of the intense but benign stimulus, cortical spreading depression (CSD), on the expression of galanin and galanin receptors (GalR1 and GalR2) in the neocortex and associated regions, revealing complex, multicellular responses. Thus, following acute, unilateral KCl-induced CSD, a delayed and transient induction (onset after 48 h, lasting ∼24 h) of galanin mRNA and peptide production occurred across the ipsilateral cerebral cortex in activated oligodendrocyte progenitor cells (OPCs), identified by specific NG2 proteoglycan immunostaining. An increase in GalR1 mRNA, immunoreactivity and receptor binding occurred in neurons within layers II and V of neocortex and in piriform cortex at 7–28 days after CSD, associated with a long-lasting depletion of galanin-positive nerve fibres in these regions. In contrast, GalR2 mRNA expression was largely unaltered after CSD. Additional novel findings in normal, adult brain were the detection of galanin mRNA and immunoreactivity in OPCs within the medial corpus callosum and in immature progenitor cells in the subventricular zone and rostral migratory stream. GalR1 and GalR2 mRNA was also present in these latter regions. These findings and the complex modulation of galanin and galanin receptors in multiple cell types (neurons/OPCs) following acute cortical activation/depression further demonstrate the potential plasticity of neuronal and non-neuronal galanin systems under physiological and pathological conditions and strongly suggest additional functions for this pleiotropic peptide in mammalian brain.