Effects of sleep deprivation on neural functioning: an integrative review

Sleep deprivation has a broad variety of effects on human performance and neural functioning that manifest themselves at different levels of description. On a macroscopic level, sleep deprivation mainly affects executive functions, especially in novel tasks. Macroscopic and mesoscopic effects of sleep deprivation on brain activity include reduced cortical responsiveness to incoming stimuli, reflecting reduced attention. On a microscopic level, sleep deprivation is associated with increased levels of adenosine, a neuromodulator that has a general inhibitory effect on neural activity. The inhibition of cholinergic nuclei appears particularly relevant, as the associated decrease in cortical acetylcholine seems to cause effects of sleep deprivation on macroscopic brain activity. In general, however, the relationships between the neural effects of sleep deprivation across observation scales are poorly understood and uncovering these relationships should be a primary target in future research

PROMISCUOS COUPLING AND INVOLVEMENT OF PROTEIN KINASE C AND EXTRACELLULAR SIGNAL-REGULATED KINASE 1/2 IN THE ADENOSINE A(1) RECEPTOR SIGNALLING IN MAMMALIAN SPERMATOZOA

Mammalian spermatozoa require a maturational event after ejaculation that allows them to acquire the capacity for fertilisation. This process occurs spontaneously during the transit through the female reproductive tract where spermatozoa are in contact with micromolar concentrations of adenosine that might act as a capacitative effector. This study shows that the adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, can induce capacitation, i.e., the ability to undergo the acrosome reaction and to become fertile. This receptor, already known to be bound to Galpha(i2), is also bound to G(q/11). These G proteins are functional in the signalling pathway elicited by the A1 receptor and correlate with the multiple intracellular events that follow its activation. The use of protein kinase C isoform inhibitors and MEK inhibitors, resulting in the abolition of the biological response to the selective agonist, indicates the involvement of protein kinase C and MEK in its signalling. In agonist-treated spermatozoa an extracellular calcium influx, involvement of alpha and gamma PKC isoforms and transient phosphorylation of ERK1/2 have been observed. Our results, besides showing that adenosine A1 receptor prompts mammalian spermatozoa to undergo the acrosome reaction hence supporting a role for adenosine as agent for fertilisation, show that 2-chloro-N6-cyclopentyladenosine triggers signalling mechanisms that involve both Galpha(i2) and G(q/11), extracellular calcium influx, modulation of classical Ca2+-dependent PCK isoforms and up-regulation of the ERK1/2 phosphorylation

Comparison of CGS 15943, ZM 241385 and SCH 58261 as antagonists at human adenosine receptors

Three structurally related non-xanthine compounds, CGS 15943, ZM 241385 and SCH 58261, are potent A2A adenosine receptor antagonists and have been used as tools in many pharmacological studies. We have now characterized their affinity and selectivity profile on human adenosine receptors stably transfected into either CHO cells (A1 and A2B receptors) or HEK-293 cells (A2A and A3 receptors). In binding studies using [3H]SCH 58261 as a radioligand, the three compounds were equally potent at A2A receptors, their K(i) value being less than 1 nM. Affinity for A1 and A3 receptors was measured using [3H]DPCPX and [125I]AB-MECA as radioligands. Given the lack of selective ligands, interaction with A2B receptors was assessed using the cAMP accumulation assay following stimulation by the adenosine receptor agonist N-ethylcarboxamidoadenosine (NECA). CGS 15943 was almost as potent at A1 receptors (K(i)3.5 nM) as at A2A receptors, showed moderate affinity for A3 receptors (K(i) 95 nM) and also interacted with A2B receptors (K(i) 44 nM; pA2 7.5). ZM 241385 showed little affinity for A1 receptors (K(i) 255 nM), and did not interact with A3 receptors (K(i)>10 microM); however, it displayed moderate affinity for A2B receptors (K(i) 50 nM; pA2 7.3). SCH 58261 had weak affinity for A1 receptors (K(i) 287 nM), no interaction with A3 receptors (K(i)>10 microM), and showed negligible interaction with A2B receptors (K(i) 5 microM; pA2 6.0). These data indicate that SCH 58261 is the most selective A2A antagonist currently available. Moreover, the different receptor selectivity of these three chemically related compounds provides useful information to progress with structure-activity relationship studies