The molluscan neuropeptide FMRFamide has an inhibitory effect on transmitter release from the presynaptic sensory neurons in the neural circuit for the siphon withdrawal reflex. We have explored whether FMRFamide also acts postsynaptically in motor neurons in this circuit, focusing on the LFS motor neurons. FMRFamide typically produces a biphasic response in LFS neurons: a fast excitatory response followed by a prolonged inhibitory response. We have analyzed these postsynaptic actions and compared them with the mechanism of FMRFamide's inhibition of the presynaptic sensory neurons. The transient excitatory effect of FMRFamide, which desensitizes rapidly, is due to activation of a TTX- insensitive, Na(+)-dependent inward current. The late hyperpolarizing phase of the FMRFamide response results from activation of at least two K+ currents. One component of the hyperpolarizing response is active at rest and at more hyperpolarized membrane potentials, and is blocked by 5 mM 4-aminopyridine, suggesting that it differs from the previously described FMRFamide-modulated K+ currents in the presynaptic sensory neurons. In addition, FMRFamide increases a 4-aminopyridine-insensitive K+ current. Presynaptically, FMRFamide increases K+ conductance, acting via release of arachidonic acid. In the LFS motor neurons, application of arachidonic acid mimicked the prolonged, hyperpolarizing phase of the FMRFamide response; 4-bromophenacyl bromide, an inhibitor of phospholipase A2, selectively blocked this component of the FMRFamide response. Thus, FMRFamide may act in parallel pre- and post- synaptically to inhibit the output of the siphon withdrawal reflex circuit, producing this inhibitory effect via the same second messenger in the sensory neurons and motor neurons, though a number of the K+ currents modulated in these two types of neurons are different.

The molluscan neuropeptide FMRFamide has a number of inhibitory actions on the sensory neurons and motoneurons mediating the defensive gill and siphon withdrawal reflex pathway of Aplysia californica. Exogenous application of FMRFamide has a biphasic, dual-polarity effect on the majority of LFS siphon motoneurons, causing a transient depolarization followed by a prolonged hyperpolarization. FMRFamide induces this response in LFS neurons by causing an increase in multiple ionic currents, including a transient Na+ current, a slow prolonged Na+ current, a 4-aminopyridine (4-AP)-sensitive K+ current and a 4-AP-insensitive K+ current. We have found that a subset of LFS neurons exhibits an exclusively excitatory, biphasic response to FMRFamide, consisting of a transient depolarization followed by a prolonged depolarization of reduced magnitude. Over a period of 29 months, we consistently observed an increase in the incidence of the exclusively excitatory response during the summer months (June to September). From October to May, we observed an exclusively excitatory response to FMRFamide in 19 % of LFS neurons; yet, in the summer months, 51 % of LFS neurons exhibited this response pattern. We compared the ionic basis of the exclusively excitatory response to FMRFamide with the ionic mechanisms mediating the more frequently observed excitatory/inhibitory response. The exclusively excitatory response involves three of the same ionic components as the more typical excitatory/inhibitory response, including the activation of a transient Na+ current, a slow prolonged Na+ current and a 4-AP-insensitive K+ current. The principal difference between the two response types is that FMRFamide fails to activate a 4-AP-sensitive K+ current in those LFS neurons that exhibit an exclusively excitatory response to the peptide. In addition, LFS neurons with an exclusively excitatory response tend to show a coordinated increase in the magnitude of the inward current component of the FMRFamide response. Together, these changes during the summer months may enable this modulatory peptide to bring LFS neurons to suprathreshold levels of activity for eliciting a siphon withdrawal and should substantially alter the neuromodulatory effects of the peptide.