Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms.
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 A(2A) 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.
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
JeanMarie
J
Acevedo
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
Alexandra
A
Santana-Almansa
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
Nikol
N
Matos-Vergara
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
Luis René
LR
Marrero-Cordero
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA.
Ernesto
E
Cabezas-Bou
Department of Anatomy and Neurobiology and Institute of Neurobiology, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA. Electronic address: manuel.diaz6@upr.edu.
Manuel
M
Díaz-Ríos
D000818:Animals; D000831:Animals, Newborn; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D058905:Purinergic Agents / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology
D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D058905:Purinergic Agents; D043682:Receptor, Adenosine A1; D017447:Receptors, Dopamine D1; D014970:Xanthines; D012701:Serotonin; D002110:Caffeine; D016202:N-Methylaspartate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D017868:Cyclic AMP-Dependent Protein Kinases
Adenosine; Caffeine; Dopamine; Locomotion; Mouse; Spinal cord