The Modulatory Role of Caffeine and Other Adenosine Receptor Antagonists onto Spinal Locomotor Circuits: Evidence for its Dependence on Adenosine A1- Dopamine D1 Receptor Heteromers in Spinal Motoneurons.
MetadataShow full item record
Locomotion is generally defined as any type of motor activity that animals use, including humans, to produce activity such as walking, running, swimming, jumping, flying, and gliding. In vertebrates, these activities are controlled by a complex neural network located in the spinal cord referred to as the central pattern generator (CPG) for locomotion. Spinal CPG adjustments, rely mostly on sensory motor stretch reflexes, which provides direct excitatory feedback to the motoneurons (MNs) innervating the muscle which has been stretched, and thus sending that information to the spinal interneurons for readjustments on movements or posture. After the loss of supraspinal brain/brainstem) inputs to the spinal cord via injury or disease, locomotion is entirely directed by the CPG and the sensory information coming from periphery. Within motor control systems, neuromodulators are necessary for proper and efficient CPG function because they induce or regulate essential components of spinal network activity, including firing parameters of CPG neurons and network synaptic strength, allowing the network to change/adapt and sometimes to even become functional. Caffeine modulates adenosine receptors, which can regulate dopaminergic and glutamatergic neurotransmission, among others. Recent studies showed that caffeine stimulates spinal lumbar circuits controlling mammalian locomotion through an A1R-D1R interaction suggesting the existence of A1R-D1R heteromeric complexes within yet unidentified spinal neurons. This study assessed the specific cellular target for the neuromodulatory effects of caffeine within the lumbar spinal cord. Patch recordings from mouse lumbar cord slices showed that caffeine and DPCPX (an A1 receptor antagonist) produced an excitatory effect on spinal MNs with no significant effects on interneurons (INs). The effects of both caffeine and DPCPX were abolished in the absence of dopamine and in the presence of a D1R antagonist (SKF81297), suggesting an A1R-D1R dependent mechanism. The application of an A1R-D1R heteromer disrupting peptide (TM5), blocked the effects of caffeine and DPCPX onto MNs. Furthermore, antibodies against A1Rs and D1Rs and a proximity ligation assay confirmed A1R-D1R colocalization principally within MNs. This study confirms the existence of A1R-D1R heteromeric complexes within MNs of the mammalian spinal cord. These results have significant clinical implications in the design of specific drugs that could preferentially target these A1-D1 heteromers within MNs of the spinal networks for the treatment of MN-related neurodegenerative diseases.