Evidence that carbon monoxide can serve as an intercellular messenger in brain, a role much like that demonstrated for nitric oxide in various tissue, prompted us to investigate whether carbon monoxide participates in long-term potentiation (LTP), the cellular mechanism that may underlie certain forms of learning and memory. Although LTP is triggered in the postsynaptic neuron, at least some fraction of LTP is expressed presynaptically as an increase in the quantity of neurotransmitter released. Thus, a retrograde signal must form the communication link between the postsynaptic site of induction and the presynaptic site of expression. To test whether carbon monoxide might act as a retrograde signal in LTP, we have investigated the effect on LTP of inhibitors of the enzyme haem oxygenase-2, which catalyses the production of carbon monoxide in the brain. We find that these inhibitors prevent the induction of LTP and have no effect on one form of long-term depression. Furthermore, they will reverse LTP that is already established.