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.

FIG. 1.

Hypothetical mechanisms of actions of glutamate and dopamine release by paraxanthine in the striatal spine module II, which includes a striatal spine from a medium spiny neuron (MSN) receiving glutamatergic, dopaminergic, and GABAergic terminals (from GABA interneurons). NO is produced by GABAergic interneurons and induces glutamate release by acting on soluble guanylyl cyclase (NO receptor or sGC), which converts GMP into cGMP. Phosphodiesterase 9 (PDE9) terminates NO-cGMP signaling by metabolizing cGMP back to GMP. NO produces dopamine release secondarily to glutamate release (that activates ionotropic glutamate receptors localized in dopaminergic terminals) and by directly blocking dopamine transporter (DAT) function. Paraxanthine potentially increases glutamate and dopamine release by blocking A₁ receptors (which tonically inhibit glutamate and dopamine release) and by inhibiting PDE9 function, which potentiates NO signaling at the glutamatergic terminal. NO, nitric oxide.

FIG. 2.

Effect of paraxanthine (PARAX) (30 mg/kg, i.p.), caffeine (CAFF) (30 mg/kg, i.p.) and the PDE9 inhibitor BAY 73-6691 (BAY) (3 mg/kg, i.p.) on locomotor activation and striatal cGMP accumulation. Paraxanthine produces stronger locomotor activation than caffeine and the same cGMP accumulation than BAY. Bars represent locomotor activity (mean±SEM) of the 10-min period transformed values during the first 60 min of recording. ## and ###p<0.01 and p<0.001 compared to vehicle, respectively; ^&p<0.05 compared to CAFF; analysis of variance (ANOVA) with Neuwman-Keuls post hoc test. Symbols represent cGMP accumulation (mean±SEM) from striatal homogenates after 30 min of systemic administration of compounds expressed in % of the vehicle (VEH). **p<0.01 compared to vehicle; ^§p<0.05 compared to CAFF; ANOVA with Neuwman-Keuls post hoc test.