Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion

Carbon monoxide (CO), produced in the body by the enzyme heme oxygenase (HO ), has been suggested as a retrograde synaptic messenger with a prominent r ole in the long- term potentiation (LTP) of certain areas of the brain. LTP of sympathetic ganglia is 5-HT3 receptor-dependent and has been shown to r equire nitric oxide for the maintenance, but not for the induction, phase. We investigated the possibility of CO being required for the induction of g anglionic LTP. Pretreatment of rat isolated superior cervical ganglia with oxyhemoglobin (25- 100 muM) completely blocked LTP. In the same ganglia, pr olonged washout of oxyhemoglobin did not uncover any potentiation of the co mpound action potential. Oxyhemoglobin had no significant effect on the mai ntenance phase in ganglia with established LTP. Pretreatment of ganglia wit h the HO inhibitor zinc protoporphyrin- IX (ZnPP) (10 muM) completely and i rreversibly prevented the expression of tetanus- evoked LTP. However, in th e same ganglia, after superfusion of CO in the presence of ZnPP, tetanic st imulation readily evoked LTP. No effect was seen on the maintenance phase w hen ZnPP was superfused on ganglia with established LTP. Pretreatment of ga nglia with the 5-HT3 receptor antagonist ondansetron (0.4 muM) alone comple tely and irreversibly blocked LTP. However, in the presence of CO, ondanset ron did not block LTP. These results suggest that activation of 5-HT3 recep tors may be involved in the production of CO. The results also suggest that CO, probably originating outside the presynaptic nerve terminal, is involv ed in the induction of LTP.