L-CCG-I activates group III metabotropic glutamate receptors in the hippocampal CA3 region

Specific agonists of metabotropic glutamate receptors (mGluRs) provide powerful tools to discriminate afferent fibers originating from different presynaptic neurons. The group II mGluR agonists L-CCG-I ((2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine) and DCG-IV ((2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine) are commonly used to distinguish between mossy fiber and associational-commissural (A/C) fiber input to the hippocampal CA3 region because only on the former group II mGluRs are expressed. Since previous reports indicated that L-CCG-I can activate group III mGluRs as well, we investigated whether L-CCG-I depresses A/C field potentials. L-CCG-I (10-300 microM) exhibited a significant dose-dependent and reversible reduction of A/C field potentials by 8 +/- 4% (10 microM), by 32 +/- 4% (100 microM, p < 0.001) and by 38 +/- 7% (300 microM, p < 0.05) that was accompanied by a concomitant increase in paired-pulse facilitation. Moreover, the selective group III antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP; 100 microM) significantly reduced the field potential inhibition by L-CCG-I (100 microM) to 9 +/- 4% (p < 0.05). In contrast, DCG-IV did not affect A/C field potentials. In conclusion, the purported group II mGluR agonist L-CCG-I depresses A/C synaptic transmission by activation of group III mGluRs. For this reason, DCG-IV should be the drug of choice when aiming to discriminate between mossy fiber and A/C input to CA3 pyramidal cells.     

Modulation of voltage-dependent sodium channels by the delta-agonist SNC80 in acutely isolated rat hippocampal neurons

Following activation, voltage-gated Na+ currents (I(Na)) inactivate on two different time scales: fast inactivation takes place on a time scale of milliseconds, while slow inactivation takes place on a time scale of seconds to minutes. Both fast and slow inactivation processes govern availability of Na+ channels. In this study, the effects of the delta-opioid receptor agonist SNC80 on slow and fast inactivation of I(Na) in rat hippocampal granule cells were analyzed in detail. Following application of SNC80, a block of the peak Na+ current amplitude (EC50: 50.6 microM, Hill coefficient: 0.518) was observed. Intriguingly, SNC80 (50 microM) also caused a selective effect on slow but not fast inactivation processes, with a notable increase in the fraction of Na+ channels undergoing slow inactivation during prolonged depolarization. In addition, recovery from slow inactivation was considerably slowed. At the same time, fast recovery processes were unaffected. The effects of SNC80 were not mimicked by the peptide delta-receptor agonist DPDPE (10 microM), and were not inhibited by the opioid receptor antagonists naloxone (50-300 microM) or naltrindole (10 and 100 microM), indicating an opioid receptor independent modulation of Na+ channels. These data suggest that SNC80 not only affects delta-opioid receptors, but also voltage-gated Na+ channels. SNC80 is to our knowledge hitherto the only substance that selectively influences slow but not fast inactivation processes and could provide an important tool in unraveling the mechanism underlying these distinct biophysical processes.     

Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics

Rationale Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior.Objectives Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients.Methods We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded.Results Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning.Conclusions This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.     

Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study

Rationale Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has medical indications but is also used as a recreational drug. Previous research has found persisting cognitive and psychotogenic effects of ketamine in chronic abusers of this drug 3 days after an acute dose.Objective The present study aimed to investigate the effects of ketamine on two processes related to drug abuse, response inhibition and reinforcement, and to examine whether an acute dose of ketamine produced residual cognitive effects in healthy volunteers.Methods Fifty-four healthy volunteers were given an 80-min infusion of one of two doses (0.4, 0.8 mg kg^–1) of ketamine or placebo. Subjects completed a battery of tests at three time points: pre-infusion, during the infusion and 3 days later at follow-up. The battery consisted of tests of episodic and semantic memory, schizophrenic-like and dissociative symptoms, response inhibition and measures of subjective effects, including mood, bodily symptoms and enjoyment of and desire for the drug.Results Ketamine acutely impaired response inhibition and had related biphasic effects on the subjective reinforcing effects of the drug. Ketamine also acutely impaired episodic but not semantic memory and increased schizophrenic-like and dissociative symptoms. No residual cognitive effects were observed 3 days following an acute dose.Conclusions The lack of residual effects in healthy volunteers on day 3 indicates that impairments found on day 3 in ketamine abusers are chronic effects. The abuse of ketamine may be related to its capacity both to reinforce and to decrease response inhibition.     

Ornithine alpha-ketoglutarate supplementation influences motor activity in healthy rats

Background: Ornithine alpha-ketoglutarate (OKG) improves nutritional status in malnourished patients. Published and unpublished data suggest OKG may have effects on the central nervous system that may contribute to its action. Objective: We investigated the effect of an OKG-enriched diet on behaviour in healthy rats. Design: Thirty male Wistar rats were randomised in three groups: the OKG group was fed for 5 days (D0-D5) at 90% of spontaneous food intake with an OKG-enriched diet (5 g/kg/d). The non-essential amino acids (NEAA) group was fed similarly with a regimen enriched with NEAA (glycine, alanine, histidine and serine) to be isonitrogenous to OKG group. The ad libitum (AL) group had no treatment and was fed ad libitum with a standard regimen throughout. Rats were tested at D4 for motor activity by actimetry, and at D5 first for spontaneous alternation behaviour measured in the Y-maze, and then for exploratory behaviour measured using the open-field test (stressful environment). Results: We found that OKG supplementation enhanced global motricity by actimetry (AL 772 +/- 55, NEAA 811 +/- 54 vs. OKG 966 +/- 24 arbitrary units, P < 0.05) and total numbers of arms visited in the Y-maze (AL 26 +/- 2, NEAA 30 +/- 3 vs. OKG 38 +/- 3, P < 0.05). The lack of any effect of the OKG-enriched diet in the open-field test shows that the enhancement of locomotion activity was most probably not due to an increase in anxiety or fear in the rats. Conclusion: An OKG-enriched diet can induce beneficial stimulant effects that may be involved in the mechanism of action of OKG.     

Mercury accumulation and loss in mallard eggs

Female mallards (Anas platyrhynchos) were fed diets containing 5, 10, or 20 ppm mercury as methylmercury chloride. One egg was collected from each bird before the start of the mercury diets and 15 eggs were collected from each bird while it was being fed mercury. The mercury diets were then replaced by uncontaminated diets, and each female was allowed to lay 29 more eggs. Mercury levels in eggs rose to about 7, 18, and 35 ppm wet-weight in females fed 5, 10, or 20 ppm mercury, respectively. Mercury levels fell to about 0.16, 0.80, and 1.7 ppm in the last egg laid by birds that had earlier been fed 5, 10, or 20 ppm mercury, respectively. Higher concentrations of mercury were found in egg albumen than in yolk, and between 95 and 100% of the mercury in the eggs was in the form of methylmercury.     

The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients

The European Cancer Anaemia Survey (ECAS) was conducted to prospectively evaluate the prevalence, incidence and treatment of anaemia (haemoglobin <12.0 g/dL) in European cancer patients, including the relationship of mild, moderate and severe anaemia to performance status. Patients were evaluated for up to 6 months. Data (N=15367) included demographics, tumour type, performance status, haemoglobin levels, cancer treatments and anaemia treatments. Prevalence of anaemia at enrollment was 39.3% (haemoglobin <10.0 g/dL, 10%), and 67.0% during the survey (haemoglobin <10.0 g/dL, 39.3%). Low haemoglobin levels correlated significantly with poor performance status. Incidence of anaemia was 53.7% (haemoglobin <10.0 g/dL, 15.2%). Anaemia was treated in 38.9% of patients (epoetin, 17.4%; transfusion, 14.9%; and iron, 6.5%). Mean haemoglobin to initiate anaemia treatment was 9.7 g/dL. Anaemia prevalence and incidence in cancer patients are high. Anaemia significantly correlates with poor performance status and many anaemic patients are not treated.     

Long-term prognostic significance of HER-2/<Emphasis Type="Italic">neu</Emphasis> in untreated node-negative breast cancer depends on the method of testing

Introduction  

The prognostic significance of HER-2/neu in breast cancer is a matter of controversy. We have performed a study in 101 node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting, and analysed the prognostic significance of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), both separately and in combination, in comparison with traditional prognostic factors.