The Importance of Serotonin for Orbitofrontal Function

The orbitofrontal cortex (OFC) receives a dense serotonin (5-hydroxytryptamine, or 5-HT) innervation from the dorsal raphe nucleus, with a smaller contribution from the median raphe nucleus. The reciprocal innervation from the OFC enables the OFC to regulate not only its own 5-HT input but the 5-HT input to the rest of the forebrain. This article reviews the evidence from studies in rodents and primates that implicate 5-HT in the OFC in the ability of animals to adapt their responding to changes in reward contingencies in the environment. A consensus is emerging that reductions in orbitofrontal 5-HT, whether the result of localized infusions of 5,7-dihydroxytryptamine (5,7-DHT), peripheral treatment with parachloroamphetamine (PCA) or para-chlorophenylalanine (PCPA), or chronic cold stress impairs this ability. Genetic variation in the 5-HT transporter can also affect this ability. An explanation regarding insensitivity to reward loss is ruled out by the finding that marmosets with 5-HT reductions in the OFC display a decline of responding as rapid as that of control animals when reward is withheld during extinction of a two-pattern discrimination task. The failure of these same animals to explore alternative stimuli during extinction, along with the recent electrophysiological evidence that dorsal raphe nucleus neurons encode future motivational outcomes, implicates orbitofrontal 5-HT in the process by which animals either exploit current resources or explore alternative resources based on current reward expectations.