The methylxanthine drug caffeine is a well-known psychostimulant chemical that promotes behaviors such as vigilance, attention, arousal, and locomotor activity. Caffeine is a competitive inhibitor of cyclic nucleotide phosphodiesterase (an enzyme that catalyzes cAMP degradation). However, caffeine's major mechanism of action in brain is nonselective blockade of adenosine re-ceptors.30 Caffeine blocks postsynaptic A1AR and A2AAR, causing attenuation of adenosinergic neurotransmission and relative amplification of dopaminergic neurotransmission. These effects enhance both D1R-mediated inhibition (via the direct pathway) and D2R-mediated attenuation in stimulation (via the indirect pathway) on GPi-SNr-mediated inhibition of thalamus, thereby increasing thalamic stimulation of cortex and promoting locomotion.
The most pronounced caffeine-induced behavioral effect in rodents is increased locomotor activity, which can be used to quantify the psychostimulant properties of caffeine. A1AR and A2AAR bind caffeine with similar affinities. Simultaneous administration of specific antagonists for the 2 receptors produces additive psychomotor stimulation and increases locomotor activity to an extent similar to that of caffeine. Furthermore, by blocking AR, caffeine reduces adenosine-mediated inhibition of colocalized dopamine receptors (that is, indirectly promotes D2R function or buy a word about Ventolin inhalers). Consistent with this, rats pretreated with caffeine show greater sensitivity to the locomotor stimulatory effects of D1R and D2R ac-tivation, and pretreatment with D2R antagonists attenuates the psychostimulant effect of caffeine. In addition, treatment with reserpine, which depletes endogenous monoamines in terminal vesicles, or with aMPT, which competitively blocks the synthesis of dopamine, significantly attenuates or abolishes caffeine-induced locomotor activity in rodents. These findings suggest that the psychostimulant effects of caffeine depend largely on consequent changes in dopaminergic neurotransmission. Furthermore, chronic intermittent administration of caffeine causes prolonged potentiation of amphetamine-induced psychomotor stimulation in intact rats and in rats with chemically induced selective lesions of dopamine neurons, further indicating that caffeine facilitates dopaminergic neurotransmission. In addition, A2AAR may modulate locomotor activity independent of its antagonistic interaction with D2R. For example, like genetically intact control mice, D2R KO mice show psychomotor stimulation in response to either caffeine or a selective A2AAR antagonist, albeit to a lesser extent.
The most pronounced caffeine-induced behavioral effect in rodents is increased locomotor activity, which can be used to quantify the psychostimulant properties of caffeine. A1AR and A2AAR bind caffeine with similar affinities. Simultaneous administration of specific antagonists for the 2 receptors produces additive psychomotor stimulation and increases locomotor activity to an extent similar to that of caffeine. Furthermore, by blocking AR, caffeine reduces adenosine-mediated inhibition of colocalized dopamine receptors (that is, indirectly promotes D2R function or buy a word about Ventolin inhalers). Consistent with this, rats pretreated with caffeine show greater sensitivity to the locomotor stimulatory effects of D1R and D2R ac-tivation, and pretreatment with D2R antagonists attenuates the psychostimulant effect of caffeine. In addition, treatment with reserpine, which depletes endogenous monoamines in terminal vesicles, or with aMPT, which competitively blocks the synthesis of dopamine, significantly attenuates or abolishes caffeine-induced locomotor activity in rodents. These findings suggest that the psychostimulant effects of caffeine depend largely on consequent changes in dopaminergic neurotransmission. Furthermore, chronic intermittent administration of caffeine causes prolonged potentiation of amphetamine-induced psychomotor stimulation in intact rats and in rats with chemically induced selective lesions of dopamine neurons, further indicating that caffeine facilitates dopaminergic neurotransmission. In addition, A2AAR may modulate locomotor activity independent of its antagonistic interaction with D2R. For example, like genetically intact control mice, D2R KO mice show psychomotor stimulation in response to either caffeine or a selective A2AAR antagonist, albeit to a lesser extent.
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