Mouse cerebral cortex slices will synthesize [3H]glycogen in vitro. Vasoactive intestinal polypeptide (VIP) stimulates the enzymatic breakdown of this [3H]glycogen. The concentration giving 50% of maximum effectiveness (EC50) is 26 nM. Under the same experimental conditions norepinephrine also induces a concentration-dependent [3H]glycogen hydrolysis with an EC50 of 500 nM. The effect of VIP is not mediated by the release of norepinephrine because it is not blocked by the noradrenergic antagonist d-1-propranolol and is still present in mice in which an 85% depletion of norepinephrine was induced by intracisternal 6-hydroxydopamine injections. Other cortical putative neurotransmitters such as gamma-aminobutyric acid, aspartic acid, glutamic acid, somatostatin, and acetylcholine (tested with the agonist carbamylcholine) do not induce a breakdown of [3H]glycogen. This glycogenolytic effect of VIP and norepinephrine, presumed to be mediated by cyclic AMP formation, should result, at the cellular level, in an increased glucose availability for the generation of phosphate-bound energy. Given the narrow radial pattern of arborization of the intracortical VIP neuron and the tangential intracortical trajectory of the noradrenergic fibers, these two systems may function in a complementary fashion: VIP regulating energy metabolism locally, within individual columnar modules, and norepinephrine exerting a more global effect that spans adjacent columns.