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sws 1

Figure 3. Effect of hcrt1/OxA (1-30|g ICV), administered to rats at the beginning of the sleep phase, on the proportion of time spent in arousal, slow wave sleep (SWS) 1 and 2 and PS. aP<0.05 and bP<0.01 compared to vehicle-treated controls. Data are adapted from ref 50.

Figure 3. Effect of hcrt1/OxA (1-30|g ICV), administered to rats at the beginning of the sleep phase, on the proportion of time spent in arousal, slow wave sleep (SWS) 1 and 2 and PS. aP<0.05 and bP<0.01 compared to vehicle-treated controls. Data are adapted from ref 50.

completely inhibited by both SB-334867 (1-10mg/kg IP);14 and SB-408124 (1-10mg/kg PO)17 indicating sole mediation by OX1R. In contrast, SB-334867 (10-30mg/kg IP) and SB-408124 (10mg/kg PO) have either no effect or only partially inhibit the hyperactivity produced by OxA (3^g ICV), OxB (10^g ICV) and [A11]OxB (10^g ICV) (Table 4) implicating a role for OX1R and, by inference, OX2R in modulating behavioural arousal. Studies have now been undertaken to elucidate the neurotransmitter pathways involved in OxA-induced grooming and hyperlocomotion, downstream from orexin receptors. Monoaminergic systems appear to be particularly important with both dopamine (D1 & D2;)56,57 and serotonin receptor (5HT2;)14,57 antagonists found to attenuate the grooming and/or locomotor response to ICV OxA.

Thus, there is now an impressive body of data supporting a key role of OX1R and OX2R in controlling arousal under normal and/or pathophysiological conditions. As described above, there is already direct evidence that OX1R within the LC are involved in this respect.52,53 It is highly likely that excitation of orexin receptors localized in regions such as tuberomammillary nucleus, lateral preoptic area and basal forebrain cholinergic area are equally important given that all of these brain centres are exquisitely sensitive to the wake-promoting action of hcrt1/OxA in conscious animals.58,59,60

Table 4. Effect of OX1R antagonists on the hyperlocomotor responses to hcrt1/OxA, OxB and [A11]OxB in rats

% Increase in Locomotor Activity '

Table 4. Effect of OX1R antagonists on the hyperlocomotor responses to hcrt1/OxA, OxB and [A11]OxB in rats

% Increase in Locomotor Activity '

Pretreatment b

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