Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission

Abstract

Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine. Nitric Oxide Neurotransmission S ince nitric oxide (NO) was first identified as an endothelial-derived relaxation factor in peripheral blood vessels, 1 its role as a biological messenger, and particularly as a neurotransmitter has been well established. Thus, NO fits within the broad definition of neurotransmitter coined by Snyder and Ferris 2-that is, ''a molecule, released by neu-rons or glia, which physiologically influences the electro-chemical state of adjacent cells''. Because NO cannot be stored in cells, it depends on new synthesis to exert its functional properties. NO is produced by NO synthase (NOS), which generates NO from the amino acid L-arginine. NOS is a complex heterodimeric protein that is found constitu-tively in two isoforms, neuronal, and endothelial NO (nNOS and eNOS, respectively). A third inducible form (iNOS) can be expressed by macrophages and microglia upon immunological challenge. 3 nNOS is the most abundant isoform found in the brain and the one responsible for NO production in neurons and its enzyme activity is regulated by Ca 2+ and calmodulin. 4 The subcellular localization of nNOS is mediated by its ability to bind to adapter proteins. For instance, through its PDZ domain it binds to PSD95 (post-synaptic density protein 95), which links nNOS to the N-methyl-D-aspartate (NMDA) receptor and accounts for the efficient activation of nNOS by NMDA receptor stimulation. 5 In the central nervous system, nNOS is synthesized by specific populations of neurons (NO neurons). In the cerebellum, nNOS is expressed by local stellate, basket and granule, but not Purkinje cells, although Purkinje are abundant in NO receptors. 6 In the brainstem, nNOS is produced by cholinergic neurons of the ascending reticular activating system. 6 These cells originate in the latero-dorsal and pedunculo-pontine nu-clei (LDT and PPT nuclei), which through a dorsal tegmental pathway project heavily to the thalamus, to the midline-intralaminar and reticular nuclei, which transmit the activity of the ascending reticular activating system to extensive areas of the cerebral cortex (for a recent review see ref. 7). Through a ventral tegmental pathway the cholinergic cells of the LDT and P...

Caffeine and Substance Use Disorders

“…The hallmark of that profile is a significant increase in the striatal extracellular concentration of dopamine, and this has only been clearly seen in a distinct region of the ventral striatum. 1 In this issue, Ferre et al 2 review recent results that indicate that paraxanthine, the main metabolite of caffeine in man, produces stronger motor activating effects and a more significant striatal dopamine-releasing effect than caffeine. This unique pharmacological profile of paraxanthine depends on an additional selective mechanism, other than adenosine receptor antagonism: inhibition of cGMP-preferring phosphodiesterases.…”

Coffee Drinking and Adverse Physical Outcomes in the Aging Adult Population: A Systematic Review

“…Despite the fact that further trials are needed to corroborate the causal path, caffeine and some of its metabolites, including the main one, paraxanthine, show notable potential pharmacological interests, sometimes different from caffeine, for example on nitric oxide (NO) neurotransmission [ 44 , 45 ]. Jäger and colleagues showed interesting results of paraxanthine supplementation on grip strength, muscle mass, treadmill performance and NO in mice, all with seemingly less toxicity compared to caffeine [ 45 , 46 ].…”

Paraxanthine Supplementation Increases Muscle Mass, Strength, and Endurance in Mice

“…Nutrients 2022, 14, 893 2 of 13 In addition to being an adenosine receptor antagonist, paraxanthine, and not caffeine, has been shown to potentiate nitric oxide (NO) neurotransmission [7]. NO is produced in the brain by GABAergic interneurons and induces glutamate release by converting guanosine-3 ,5 -monophosphate (GMP) into cyclic GMP (cGMP).…”

“…NO is produced in the brain by GABAergic interneurons and induces glutamate release by converting guanosine-3 ,5 -monophosphate (GMP) into cyclic GMP (cGMP). The enzyme phosphodiesterase 9 (PDE9) terminates NO-cGMP signaling by metabolizing cGMP back to GMP [7]. PDE9 is a specific target of paraxanthine and is not influenced by caffeine, or the other methylxanthine metabolites theophylline and theobromine [7].…”