Role of CCK in anti-exploratory action of paroxetine, 5-HT reuptake inhibitor

The administration of paroxetine (0.5–8 mg/kg), a selective 5-HT reuptake inhibitor, induced a dose-dependent reduction of exploratory activity of rats in the motility test. In the elevated plus-maze paroxetine was less effective, only 8 mg/kg of paroxetine decreased the exploratory behaviour of rats. The doses of paroxetine (2–8 mg/kg) reducing the exploratory activity in the motility test increased the density of CCK receptors in the frontal cortex, but not in the hippocampus. The treatment of rats with the CCKB receptor antagonist LY288,513 (0.01–1 mg/kg) did not change the exploratory activity. However, the reduction of exploratory activity induced by the low dose of paroxetine (2 mg/kg), but not by the higher dose (8 mg/kg), was dose-dependently reversed by the administration of LY288,513. Moreover, LY288,513 did not affect the anti-exploratory action of paroxetine (8 mg/kg) in the elevated plus-maze. Diazepam at doses (0.5–1.0 mg/kg) not suppressing the locomotor activity did not change the anti-exploratory action of paroxetine in the motility test. It is likely that the anti-exploratory action of a low dose of paroxetine (2 mg/kg) is not related to the increase in anxiety, but rather to the reduction of exploratory drive. Evidence exists that this effect of paroxetine is mediated via the activation of CCK-ergic transmission

Non-equivalent stringency of ethical review in the Baltic States : A sign of a systematic problem in Europe?

We analyse the system of ethical review of human research in the Baltic States by introducing the principle of equivalent stringency of ethical review, that is, research projects imposing equal risks and inconveniences on research participants should be subjected to equally stringent review procedures. We examine several examples of non-equivalence or asymmetry in the system of ethical review of human research: (1) the asymmetry between rather strict regulations of clinical drug trials and relatively weaker regulations of other types of clinical biomedical research and (2) gaps in ethical review in the area of nonbiomedical human research where some sensitive research projects are not reviewed by research ethics committees at all. We conclude that non-equivalent stringency of ethical review is at least partly linked to the differences in scope and binding character of various international legal instruments that have been shaping the system of ethical review in the Baltic States. Therefore, the Baltic example could also serve as an object lesson to other European countries which might be experiencing similar problems.publishersversionPeer reviewe

Upwelling events, coastal offshore exchange, links to biogeochemical processes - Highlights from the Baltic Sea Sciences Congress at Rostock University, Germany, 19-22 March 2007

The Baltic Sea Science Congress was held at Rostock University, Germany, from 19 to 22 March 2007. In the session entitled"Upwelling events, coastal offshore exchange, links to biogeochemical processes" 20 presentations were given,including 7 talks and 13 posters related to the theme of the session.This paper summarises new findings of the upwelling-related studies reported in the session. It deals with investigationsbased on the use of in situ and remote sensing measurements as well as numerical modelling tools. The biogeochemicalimplications of upwelling are also discussed.Our knowledge of the fine structure and dynamic considerations of upwelling has increased in recent decades with the advent ofhigh-resolution modern measurement techniques and modelling studies. The forcing and the overall structure, duration and intensity ofupwelling events are understood quite well. However, the quantification of related transports and the contribution to the overall mixingof upwelling requires further research. Furthermore, our knowledge of the links between upwelling and biogeochemical processes is stillincomplete. Numerical modelling has advanced to the extent that horizontal resolutions of c. 0.5 nautical miles can now be applied,which allows the complete spectrum of meso-scale features to be described. Even the development of filaments can be describedrealistically in comparison with high-resolution satellite data.But the effect of upwelling at a basin scale and possible changes under changing climatic conditions remain open questions

Functional Diversity of Human Basic Helix-Loop-Helix Transcription Factor TCF4 Isoforms Generated by Alternative 5′ Exon Usage and Splicing

BACKGROUND: Transcription factor 4 (TCF4 alias ITF2, E2-2, ME2 or SEF2) is a ubiquitous class A basic helix-loop-helix protein that binds to E-box DNA sequences (CANNTG). While involved in the development and functioning of many different cell types, recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and TCF4 haploinsufficiency is the cause of the Pitt-Hopkins mental retardation syndrome. However, the structure, expression and coding potential of the human TCF4 gene have not been described in detail. PRINCIPAL FINDINGS: In the present study we used human tissue samples to characterize human TCF4 gene structure and TCF4 expression at mRNA and protein level. We report that although widely expressed, human TCF4 mRNA expression is particularly high in the brain. We demonstrate that usage of numerous 5' exons of the human TCF4 gene potentially yields in TCF4 protein isoforms with 18 different N-termini. In addition, the diversity of isoforms is increased by alternative splicing of several internal exons. For functional characterization of TCF4 isoforms, we overexpressed individual isoforms in cultured human cells. Our analysis revealed that subcellular distribution of TCF4 isoforms is differentially regulated: Some isoforms contain a bipartite nuclear localization signal and are exclusively nuclear, whereas distribution of other isoforms relies on heterodimerization partners. Furthermore, the ability of different TCF4 isoforms to regulate E-box controlled reporter gene transcription is varied depending on whether one or both of the two TCF4 transcription activation domains are present in the protein. Both TCF4 activation domains are able to activate transcription independently, but act synergistically in combination. CONCLUSIONS: Altogether, in this study we have described the inter-tissue variability of TCF4 expression in human and provided evidence about the functional diversity of the alternative TCF4 protein isoforms

l-Arginine abolishes the anxiolytic-like effect of diazepam in the elevated plus-maze test in rats

The involvement of nitrergic mechanisms in the behavioural effects of diazepam in rats was studied in the elevated plus-maze, open-field and rotarod tests. Administration of the nitric oxide (NO) precursor l-arginine (100 mg/kg, i.p.), assumed to increase the synthesis of NO, abolished the anxiolytic-like effect of diazepam (2 mg/kg, i.p.) in the elevated plus-maze, whereas the inactive enantiomer d-arginine (100 mg/kg) did not. Neither diazepam alone nor in combination with l- or d-arginine affected the exploratory activity of animals in the open field. Pretreatment with l-arginine (100 and 200 mg/kg) did not modify the motor impairment of rats after diazepam (3 mg/kg) in the rotarod test. Diazepam (2 mg/kg i.p.) did not inhibit the cortical or hippocampal cytosolic NO synthase activity measured ex vivo by [3H]l-arginine assay. Diazepam was similarly ineffective in in vitro studies at concentrations up to 10 μM. We conclude that a suppression of NO synthase activity may be important in the anxiolytic-like effect of benzodiazepines. However, diazepam does not inhibit NO synthase directly, but may affect NO synthase activity indirectly via some unknown mechanism

BOC-CCK-4, CCKB receptor agonist, antagonizes anxiolytic-like action of morphine in elevated plus-maze

This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like action of morphine, an agonist of μ-opioid receptors, in the rat plus-maze model of anxiety. The acute administration of morphine (1 mg/kg) induced a significant increase of exploratory activity in the plus-maze, but did not affect the locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg) tended to decrease the locomotor activity and, therefore, did not cause the anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L-365,260) and their combinations with morphine (0.5–1 mg/kg) did not affect the locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity in the plus-maze, but potently antagonized the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCKBreceptors BOC-CCK-4 (1–50 μg/kg) induced a dose-dependent anxiogenic-like action in the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 μg/kg) completely reversed the action of morphine. Also, one dose of CCKBreceptor antagonist L-365,260 (10 μg/kg) was effective to modify the behaviour of rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the ratio between open and total arm entries, a behavioural measure believed to reflect the anxiolytic-like action in the elevated plus-maze. The combination of L-365,260 (100 μg/kg) with the sub-effective dose of morphine (0.5 mg/kg) caused the anxiolytic-like action in the plus-maze not seen if the drugs were given alone. In conclusion, morphine induces a potent anxiolytic-like action in the elevated plus-maze and CCK is acting as an endogenous antagonist of this effect of morphine

Nitric oxide mediates caeruleininduced suppression of locomotor activity

Caerulein, a non-selective agonist of cholecystokinin (CCK) receptors, is shown to suppress locomotor activity in rodents via stimulation of CCKA receptors. In the present study we examined the possible involvement of nitric oxide (NO) in caerulein-induced hypolocomotion in rats. Caerulein (10 μg/kg) markedly decreased the horizontal and vertical components of locomotor activity in rats measured in dark motility boxes. Pretreatment with a nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME), at 5 mg/kg i.p., abolished the inhibiting action of caerulein on the horizontal activity, but did not affect the reduced frequency of rearing. The other doses of l-NAME (1, 10 and 20 mg/kg) were ineffective against caerulein. As L-NAME at this dose range does not stimulate locomotor activity, it is likely that NO is involved in the motor suppressant effect of systemically administered caerulein

Apomorphine-induced behavioural sensitization in rats: Individual differences, role of dopamine and NMDA receptors

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED50 values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D2 antagonist), 0.023 mg/kg for SCH 23390 (dopamine D1 antagonist), 6.42 mg/kg for clozapine (dopamine D4 antagonist). This supports the involvement of D1 and D2 receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D1 and D2, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization

Pharmacological comparison of antipsychotic drugs and σ-Antagonists in rodents

We compared antipsychotic drugs (haloperidol, chlorpromazine and clozapine) and σ antagonists (remoxipride, cinuperone, α‐(4‐fluorophenyl)‐4‐(‐fluoro‐2‐pyrimidinyl)‐1‐piperazine butanol (BMY 14802) and rimcazole) in the radioligand binding and behavioural experiments in rodents. A good correlation was established between the affinity of compounds at dopamine2‐receptors in the striatum and their ability to block apomorphine‐, amphetamine‐ and quipazine‐induced behavioural effects in rodents. By contrast, no correlation was found between the behavioural effects of these drugs and their affinity at dopamine1‐, 5‐HT2‐ and a receptors. The rank order of potency among the studied antipsychotic drugs in the behavioural tests and at dopamine2‐receptors was following: haloperidol≫chlorpromazine≥clozapine. The effectiveness of chlorpromazine and clozapine was nearly similar against apomorphine‐induced aggressiveness and yawning, whereas at 5‐HT2‐receptors clozapine was more active than chlorpromazine. The weak activity of σ antagonists at dopamine2 receptors could be a possible reason why these compounds were less effective in the behavioural studies compared to antipsychotic drugs. However, the antagonism of remoxipride against apomorphine‐induced stereotypy and aggressiveness is not related to its activity at σ receptors, because the other σ antagonists did not block these effects of apomorphine. It is probable that remoxipride exerts its action through blocking of dopamine2 receptors. In conclusion, the present study revealed only weak activity of σ antagonists in the behavioural models widely used to study the antipsychotic drugs. Therefore, the antipsychotic activity of σ antagonists is doubtful