Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A1 and A2A receptors. The effects of caffeine at the level of the lumbar spinal central pattern generator (CPG) network for hindlimb locomotion are lacking. We assessed the effects of caffeine to the locomotor function of the spinal CPG network via extracellular ventral root recordings using the isolated neonatal mouse spinal cord preparation. Addition of caffeine and of an A1 receptor antagonist significantly decreased the cycle period accelerating the ongoing locomotor rhythm, while decreasing burst duration reversibly in most preparations suggesting the role of A1 receptors as the primary target of caffeine. Caffeine and an A1 receptor antagonist failed to stimulate ongoing locomotor activity in the absence of dopamine or in the presence of a D1 receptor antagonist supporting A1/D1 receptor-dependent mechanism of action. The use of caffeine or an A1 receptor blocker failed to stimulate an ongoing locomotor rhythm in the presence of a blocker of the cAMP-dependent protein kinase (PKA) supporting the need of this intracellular pathway for the modulatory effects of caffeine to occur. These results support a stimulant effect of caffeine on the lumbar spinal network controlling hindlimb locomotion through the inhibition of A1 receptors and subsequent activation of D1 receptors via a PKA-dependent intracellular mechanism.
Motor patterns driving rhythmic movements of our lower limbs during walking are generated by groups of neurons within the spinal cord, called central pattern generators (CPGs). After suffering a spinal cord injury (SCI), many descending fibers from our brain are severed or become nonfunctional which leaves the spinal CPG network without its initiating drive. Recent studies are focusing on the importance of maintaining sensory stimulation to the legs on SCI patients as a way to initiate and control the CPG locomotor network. We began assessing the role of sensory feedback to the locomotor CPG network by using a neonatal mouse spinal cord preparation were the lower limbs are still attached. Removing sensory feedback coming from the hindlimbs by way of a lower lumbar transection or by ventral root denervation revealed a positive correlation in the ability of sensory input deprivation to disrupt ongoing locomotor activity on older versus younger animals. The differences in the motor responses as a function of age could be correlated with the loss of excitatory activity from sensory afferents. Continued studies on this field could eventually provide key information that translates in the design of novel therapeutic strategies to treat patients that have suffered a SCI.
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