Although often examined in isolation, a single neuromodulator typically has multiple cellular and synaptic effects. Here, we have examined the interaction of the cellular and synaptic effects of 5-HT in the lamprey spinal cord.

5-HT reduces the amplitude of glutamatergic synaptic inputs and the slow post-spike afterhyperpolarization (sAHP) in motor neurons. We examined the interaction between these effects using ventral root activity evoked by stimulation of the spinal cord. While 5-HT reduced excitatory glutamatergic synaptic inputs in motor neurons to approximately 60% of control, ventral root activity was not significantly affected. The reduction of the sAHP by 5-HT increased motor neuron excitability by reducing spike frequency adaptation, an effect that could in principle have opposed the reduction of the excitatory synaptic input. Support for this was sought by reducing the amplitude of the sAHP by applying the toxin apamin before 5-HT application. In these experiments, 5-HT reduced the ventral root response, presumably because the reduction of the synaptic input now dominated. This was supported by computer simulations that showed that the motor output could be maintained over a wide range of synaptic input values if they were matched by changes in postsynaptic excitability. The effects of 5-HT on ventral root responses were altered by spinal cord lesions: 5-HT significantly increased ventral root responses in animals that recovered good locomotor function, consistent with a lesion-induced reduction in the synaptic effects of 5-HT, which thus biases its effects to the increase in motor neuron excitability.