The impaired movement following spinal cord injury (SCI) may be partially restored in experimental animals by interventions with monoamine drugs or monoamine transplants. This fits our basic physiological knowledge, that monoamine drugs can activate spinal locomotor mechanisms when normal brainstem sources of activation have been experimentally blocked. However, if this concept is to be applied therapeutically to humans, our rudimentary understanding of the roles of serotonin (5-HT) and norepinephrine (NE) in the control of spinal locomotor function needs to be expanded. Little is known about the roles these transmitters play in the control of spinal neurons generating locomotor activity, including the neuronal targets and mechanisms of action. To achieve the long-term goal of developing and optimizing drug or transplant treatments for spinal injury, the objectives of this application are to determine the contribution and specific roles of monoaminergic pathways in the spinal control of locomotion. The overall hypotheses are as follows. (1) Locomotion is produced by the parallel activation of both descending reticulospinal and monoamine pathways. (2) The monoamine pathways program the excitability of spinal locomotor neurons and alter their responsiveness to both segmental and descending inputs, thus enabling a specific movement pattern. (3) The reticulospinal pathways command the movement. (4) This programming occurs in the spinal intermediate gray matter and ventral horn and involves both synaptic and paracrine neurotransmission. Walking-like neuronal rhythms will be induced by electrically stimulating the mesencephalic locomotor region of paralyzed, decerebrate, adult cats. Experimental variables studied during such fictive locomotion, and during its modulation by peripheral afferent input, will include intracellular and extracellular recordings of locomotor-related spinal neurons, local spinal 5-HT and NE release measured by microelectrode with innovative voltammetric methods, and various coordination parameters of the fictive locomotor rhythm. To test the above hypotheses we shall attempt to modify these variables by topical application or iontophoresis near recorded cells of monoaminergic receptor antagonists, and by reversible cold-block of descending monoaminergic pathways. ? ?
