Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin

Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D₁-class DA receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF81297","term_id":"1156277425","term_text":"SKF81297"}}SKF81297 induced pMeCP2 widely; however, coadministration of the D₂-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.     

Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature

We studied N-(2-aminoethyl)-N-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamide hydrochloride (M8-B), a selective and potent antagonist of the transient receptor potential melastatin-8 (TRPM8) channel. In vitro, M8-B blocked cold-induced and TRPM8-agonist-induced activation of rat, human, and murine TRPM8 channels, including those on primary sensory neurons. In vivo, M8-B decreased deep body temperature (T(b)) in Trpm8(+/+) mice and rats, but not in Trpm8(-/-) mice, thus suggesting an on-target action. Intravenous administration of M8-B was more effective in decreasing T(b) in rats than intrathecal or intracerebroventricular administration, indicating a peripheral action. M8-B attenuated cold-induced c-Fos expression in the lateral parabrachial nucleus, thus indicating a site of action within the cutaneous cooling neural pathway to thermoeffectors, presumably on sensory neurons. A low intravenous dose of M8-B did not affect T(b) at either a constantly high or a constantly low ambient temperature (T(a)), but the same dose readily decreased T(b) if rats were kept at a high T(a) during the M8-B infusion and transferred to a low T(a) immediately thereafter. These data suggest that both a successful delivery of M8-B to the skin (high cutaneous perfusion) and the activation of cutaneous TRPM8 channels (by cold) are required for the hypothermic action of M8-B. At tail-skin temperatures <23°C, the magnitude of the M8-B-induced decrease in T(b) was inversely related to skin temperature, thus suggesting that M8-B blocks thermal (cold) activation of TRPM8. M8-B affected all thermoeffectors studied (thermopreferendum, tail-skin vasoconstriction, and brown fat thermogenesis), thus suggesting that TRPM8 is a universal cold receptor in the thermoregulation system.     

Hotel NHS and the acute abdomen – admit first,investigate later

Aim: To determine the financial consequences of a policy of admission first, followed by definitive investigation for patients with an admission diagnosis of suspected acute abdomen. Results: Over a 1‐month period, 122 patients were admitted with a suspected surgical diagnosis of acute abdomen (55 men, 67 women); age range 16–95 years (median: 56.5). Based on surgical operation required (n = 36), death after admission (n = 6, three postoperative deaths) and/or severe surgical illness (n = 17), 56 required surgical inpatient admission, while 66 did not. The patients who did not require admission spent significantly shorter time in hospital than those who required admission (median: 5 days vs. 8.5 days; p = 0.0000). Total hospital hotel and investigation cost (not including ITU or theatre costs) for all 122 patients was £330,468. Overall, £205,468 was consumed by these 56 patients who required admission, while £125,000 was spent on 66 patients whose clinical course did not justify admission; 92% of which was spent on hospital hotel costs and 8% on the cost of imaging and/or endoscopy. Discussion and conclusion: On a national basis, emergency General Surgery admissions account for 1000 Finished Consultant Episodes per 100,000 population. The findings of this study suggest that this equates to a national NHS spend of £650 million each year, for the hotel costs of patients that could arguably avoid surgical admission altogether. Continuing to admit patients with a suspected acute abdomen first and then requesting definitive investigation makes neither clinical nor economic sense.