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Mechanism of acute tryptophan depletion: is it only serotonin?
The method of acute tryptophan depletion (ATD), which reduces the availability of the essential amino acid tryptophan (TRP), the dietary serotonin (5-hydroxytryptamine (5-HT)) precursor, has been applied in many experimental studies. ATD application leads to decreased availability of TRP in the brain and its synthesis into 5-HT. It is therefore assumed that a decrease in 5-HT release and subsequent blunted neurotransmission is the underlying mechanism for the behavioural effects of ATD. However, direct evidence that ATD decreases extracellular 5-HT concentrations is lacking. Furthermore, several studies provide support for alternative underlying mechanisms of ATD. This may question the utility of the method as a selective serotonergic challenge tool. As ATD is extensively used for investigating the role of 5-HT in cognitive functions and psychiatric disorders, the potential of alternative mechanisms and possible confounding factors should be taken into account. It is suggested that caution is required when interpreting ATD effects in terms of a selective serotonergic effect.
Journal Article
I have diabetes, now what?
\"Discusses diabetes, providing information on the symptoms, how it is diagnosed, how it is treated, and most importantly, how it can be prevented\"--Google.com
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DTC Advertising's Benefits Far Outweigh Its Imperfections
Direct-to-consumer (DTC) communication about pharmaceutical products enables consumers to take a hands-on interest in their own health care. A growing body of research and expert opinion supports the view that the information presented in DTC communications informs patients' decision making and leads to more productive physician/ patient encounters. Arguments that DTC advertising leads doctors to write unnecessary prescriptions and increases costs are unfounded. Criticism of the practice may also be shortsighted, because outpatient drug treatment can substitute for more costly therapies and hospitalizations. Public debate should focus on making information clear and comprehensible so that consumers can get maximum value.
Journal Article
Phosphodiesterase Inhibitors Enhance Object Memory Independent of Cerebral Blood Flow and Glucose Utilization in Rats
Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP), and are currently studied as possible targets for cognitive enhancement. Earlier studies indicated beneficial effects of PDE inhibitors in object recognition. In this study we tested the effects of three PDE inhibitors on spatial memory as assessed in a place and object recognition task. Furthermore, as both cAMP and cGMP are known vasodilators, the effects of PDE inhibition on cognitive functions could be explained by enhancement of cerebrovascular function. We examined this possibility by measuring the effects of PDE5 and PDE4 inhibitor treatment on local cerebral blood flow and glucose utilization in rats using [
14
C]-iodoantipyrine and [
14
C]-2-deoxyglucose quantitative autoradiography, respectively. In the spatial location task, PDE5 inhibition (cGMP) with vardenafil enhanced only early phase consolidation, PDE4 inhibition (cAMP) with rolipram enhanced only late phase consolidation, and PDE2 inhibition (cAMP and cGMP) with Bay 60–7550 enhanced both consolidation processes. Furthermore, PDE5 inhibition had no cerebrovascular effects in hippocampal or rhinal areas. PDE4 inhibition increased rhinal, but not hippocampal blood flow, whereas it decreased glucose utilization in both areas. In general, PDE5 inhibition decreased the ratio between blood flow and glucose utilization, indicative of general oligaemia; whereas PDE4 inhibition increased this ratio, indicative of general hyperemia. Both oligaemic and hyperemic conditions are detrimental for brain function and do not explain memory enhancement. These results underscore the specific effects of cAMP and cGMP on memory consolidation (object and spatial memory) and provide evidence that the underlying mechanisms of PDE inhibition on cognition are independent of cerebrovascular effects.
Journal Article
Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet
Aims/hypothesis
Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3.
Methods
Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (
Ucn3
+
) under control conditions and following an obesogenic high-fat diet (HFD) challenge.
Results
Ucn3
+
mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in
Crfr2
(also known as
Crhr2
)-null mice negated key aspects of the
Ucn3
+
phenotype.
Ucn3
+
mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in
Ucn3
+
muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in
Ucn3
+
muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed.
Conclusions/interpretation
Urocortin 3 acting on CRFR2 in skeletal muscle of
Ucn3
+
mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.
Journal Article
PERSPECTIVE: DTC Advertising's Benefits Far Outweigh Its Imperfections
Direct-to-consumer (DTC) communication about pharmaceutical products enables consumers to take a hands-on interest in their own health care. A growing body of research and expert opinion supports the view that the information presented in DTC communications informs patients' decision making and leads to more productive physician/patient encounters. Arguments that DTC advertising leads doctors to write unnecessary prescriptions and increases costs are unfounded. Criticism of the practice may also be shortsighted, because outpatient drug treatment can substitute for more costly therapies and hospitalizations. Public debate should focus on making information clear and comprehensible so that consumers can get maximum value. [PUBLICATION ABSTRACT]
Journal Article
Effects of a single dose of 3,4-methylenedioxymethamphetamine on circadian patterns, motor activity and sleep in drug-naive rats and rats previously exposed to MDMA
Despite the well documented neurochemical actions of 3,4-methylenedioxymethamphetamine (MDMA), acute effects in rats previously exposed to the drug have not been extensively explored.
To examine motor activity and vigilance effects of MDMA in drug-naive rats and in rats exposed to the drug 3 weeks earlier.
MDMA (15 mg/kg, i.p.) was administered to Dark Agouti rats. Motor activity, wakefulness, light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2) and paradoxical sleep (PS), sleep and PS latencies were measured. Acrophases and amplitudes of the 24 h cycles were calculated by cosinor analysis. In parallel groups, local cerebral glucose utilization (lCMRglu) and (3H)-paroxetine binding were measured in motor areas of the brain.
In drug-naive rats MDMA caused marked increases in motor activity and wakefulness for at least 5-6 h. Circadian patterns of motor activity and sleep/vigilance parameters were altered up to 5 days after treatment. Despite most parameters tending to return to normal, there were still significant effects of MDMA on motor activity, wakefulness, and SWS-2 28 days later. Acute MDMA administration caused significant increases in lCMRglu, but after 3 weeks lCMRglu was decreased in the same brain areas. No significant change in [3H]paroxetine binding was observed in motor areas, although significant reductions were seen elsewhere (neocortex -81%). In rats exposed to MDMA 3 weeks earlier, most acute effects induced by MDMA administration were similar to those in drug-naive rats, but shorter duration of the acute effects were found in motor activity and vigilance.
Our findings provide evidence that MDMA use can lead to long-term changes in regulation of circadian rhythms, motor activity and sleep generation.
Journal Article
Acute methylenedioxymethamphetamine administration: effects on local cerebral blood flow and glucose utilization in the dark agouti rat
Clinical reports indicate that acute exposure to 3,4-methylenedioxymethamphetamine (MDMA; \"Ecstasy\") may induce pathological cerebrovascular responses in human users of the drug, however, the mechanism by which MDMA might effect these pathological changes is not clear.
To examine the effects of acute MDMA administration on the relationship between local cerebral blood flow (LCBF) and local cerebral glucose utilisation (LCMRglu); to determine the effect, if any, acute exposure to MDMA has on the cerebral circulation, independently of alterations in cerebral metabolic demand.
Dark Agouti rats were injected with 15 mg.kg(-1) i.p. MDMA or saline equivalent. LCBF and LCMRglu were measured in 50 brain areas using the fully quantitative [14C]iodoantipyrine and [14C]2-deoxyglucose autoradiographic techniques, respectively.
MDMA produced significant increases in LCMRglu in 23 brain areas, most markedly in the motor system (globus pallidus; +82%; medial striatum; +71%). In contrast, significant decreases in LCBF were observed in 28 brain areas, most markedly in primary sensory nuclei (superior colliculus; -32%) and limbic areas (anterior thalamus; -34%). Global analysis revealed a close correlation (r=0.87) between LCMRglu and LCBF with a ratio of 1.53 in controls. Despite the divergence of LCMRglu (increases) and LCBF (decreases) in MDMA-treated groups, there was a similar close correlation (r=0.84), but the ratio was decreased to 1.22.
This study provides clear evidence that acute exposure to MDMA results in cerebrovascular dysfunction. The uncoupling of LCBF from underlying metabolic demand, possibly due to the vasoconstrictor action of 5-HT, could provide the basis for oligaemia-induced pathological changes in the brain.
Journal Article
Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats
MDMA causes selective depletion of serotonergic terminals in experimental animals and the consequent decrease in synaptic 5-HT may, inter alia, increase impulsivity. To study the effects of MDMA upon brain function, the behaviour of male Dark Agouti rats exposed to MDMA (15 mg/kg i.p.), two 5-HT1B agonists (CGS-12066A and CP-94,253, both 5 mg/kg i.p.) or saline were investigated in the resident-intruder test. Studies were performed in drug-naive rats and also in rats exposed to MDMA (15 mg/kg i.p.) 21 d earlier. In parallel experiments the functional neuroanatomy of MDMA effects were assessed using 2-deoxyglucose imaging of local cerebral metabolic rate of glucose utilization (LCMRGlu) and neurotoxicity was assessed by measuring [3H]paroxetine binding. There was no significant difference in aggressive behaviour (biting, boxing, wrestling and their latencies) between drug-naive rats and rats previously exposed to MDMA 21 d earlier, despite reduced social behaviour, decreased LCMRGlu in several brain areas involved in aggression, and reductions in paroxetine binding by 30–60% in the forebrain. CGS-12066A, CP-94,253 and acute MDMA produced marked decreases in aggressive behaviours, especially in biting, boxing and kicking found in drug-naive rats. In animals previously exposed to the drug, acute anti-aggressive effects of MDMA were, in general, preserved as were MDMA-induced increases in LCMRGlu. Our studies provide evidence that in the resident-intruder test, where social isolation is a requirement, aggressive behaviour and acute anti-aggressive effects of MDMA and 5-HT1B receptor agonists remain intact 3 wk after a single dose of the drug despite significant damage to the serotonergic system.
Journal Article