Synergistic antidepressant- and anxiolytic-like effects of harmaline along with cinanserin in acute restraint stress-treated mice

Psychopharmacology - Acute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety....     

Morphine-induced behavioral sensitization increased the mRNA expression of NMDA receptor subunits in the rat amygdala

This study was designed to evaluate the effect of repeated morphine treatment on rat behavioral responses. In the genetic section, the mRNA expression of NMDA receptor subunits (NR1 and NR2A) was measured in certain areas of the male rat brain (striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala). In the behavioral section, the effect of repeated morphine treatment on animal models such as locomotion, oral stereotypy, and state-dependent memory in a passive avoidance test was evaluated in the presence or absence of MK801 (NMDA receptor antagonist). Our results showed that chronic morphine treatment, followed by a 7-day (but not 24-hour) washout period, potentiated the effect of test doses of morphine, which is referred to as behavioral sensitization. Meanwhile, pretreatment of animals with MK801 (0.1 and 0.25 mg/kg), 30 min before a test dose of morphine (5 mg/kg), failed to attenuate the locomotion and oral stereotypy in the behavioral sensitization state. Interestingly, a higher dose of MK801 (0.25 mg/kg) decreased memory retrieval induced by morphine (2.5 mg/kg) in state-dependent memory. This effect may be due to the intrinsic motor enhancer property of higher doses of MK801, rather than the blockade of NMDA receptors. It can be concluded that MK801 does not affect morphine-induced behavioral sensitization in the expression phase. In the genetic section of the study, results of quantitative real-time RT-PCR clearly indicated that morphine sensitization increased the expression of NMDA receptor subunits mRNA in the amygdala (NR1 by 104% and NR2A by 85%), while the other areas of the brain were unaffected. Maenwhile, no change in the mRNA levels was observed in non-sensitized animals (chronic morphine treatment followed by a 24-hour washout period). In summary, the present study indicates that repeated morphine treatment followed by long-term (7-day washout) induces behavioral sensitization and causes a delayed increase in mRNA levels of NMDA receptor subunits in the rat amygdala. Meanwhile, it has previously been reported that the amygdala is involved in behavioral sensitization. Thus, it can be concluded that the increase in NMDA receptor expression is associated with morphine-induced behavioral sensitization.     

Involvement of dorsal hippocampal nicotinic receptors in the effect of morphine on memory retrieval in passive avoidance task

The present study evaluated the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulas in the CA1 regions of the dorsal hippocampi, trained in a step-through type passive avoidance task, and tested 24 h after training to measure step-through latency. Results indicate that post-training subcutaneous (s.c.) administration of morphine (2.5-7.5 mg/kg) dose-dependently reduced the step-through latency, showing an amnestic response. Post-training intra-CA1 microinjection of nicotine (0.5-1 microg/rat) decreased significantly the amnesia induced by post-training morphine (7.5 mg/kg). Moreover, co-treatment of mecamylamine (0.5 and 1 microg/rat, intra-CA1) with an ineffective dose of morphine (2.5 mg/kg), immediately after training, caused inhibition of memory retrieval. On the other hand, amnesia produced by post-training morphine (7.5 mg/kg) was reversed by pre-test administration of the opioid that is due to a state-dependent effect. Interestingly, pre-test intra-CA1 microinjection of nicotine (0.25 and 0.5 microg/rat) improved post-training morphine (7.5 mg/kg)-induced retrieval impairment. Moreover, pre-test administration of the same doses of nicotine in combination with a lower dose of morphine (0.5 mg/kg), which had no effects alone, synergistically improved memory performance impaired by post-training morphine. Pre-test injection of mecamylamine (0.5-2 microg/rat) prevented the restoration of memory by pre-test morphine. It is important to note that post-training or pre-test intra-CA1 administration of the same doses of nicotine or mecamylamine, alone did not affect memory retrieval. These results suggest that nicotinic acetylcholine receptors of the hippocampal CA1 regions may play an important role in morphine-induced amnesia and morphine state-dependent memory.     

Structural features of guinea pig aldehyde oxidase inhibitory activities of flavonoids explored using QSAR and molecular modeling studies

In this study, guinea pig aldehyde oxidase inhibitory activities of flavonoids were investigated using in silico, quantitative structure–activity relationships, molecular modeling, and experimental techniques, in order to understand more about their mode of interactions. The aldehyde oxidase inhibitory activity values determined experimentally in this work or collected from our previous report were used to derive mathematical models for the prediction purposes employing combined genetic algorithm and partial least square method, as well as multiple linear regression analysis. The statistical parameters for the developed models and the results of leave-one-out internal cross-validation were indicative of the validity of the models. To further investigate the mechanism of interaction between flavonoid inhibitors and guinea pig aldehyde oxidase enzyme, the structural model of the enzyme was built and the inhibitors were docked manually into the binding site. The model for quercetin-aldehyde oxidase complex was validated based on its appropriate stability during 10?ns molecular dynamics simulation, and hence the positioning procedure for the rest of flavonoids was guided based on the manually docked position of quercetin. The identified interactions were compared with those of flavonoids previously reported for rat aldehyde oxidase and the results showed a substantial commonality between the modes of interactions predicted for flavonoids positioned into the binding site of aldehyde oxidase from guinea pig and rat. This commonality is also reflected by the quantitative structure–activity relationships models. The results presented in this work may provide useful information where the structural requirements for aldehyde oxidase inhibition are sought, such as designing novel aldehyde oxidase inhibitors or investigating drug interaction involving aldehyde oxidase mediated biotransformation.     

Molecular epidemiology of Escherichia coli diarrhoea in children in Tehran

From July to December 2003, four categories of diarrhoeagenic Escherichia coli were investigated in Tehranian children with acute diarrhoea. Stool specimens of children under 5 years of age with diarrhoea (n=200) and matched controls (n=200) without diarrhoea were studied for the presence of entero-aggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC) and Shiga toxin-producing (STEC) E. coli by PCR identification of six different genes of diarrhoeagenic E. coli. STEC isolates were typed by O157 and H7 antisera. EAEC was the most prevalent category and was found in 24% of patients with diarrhoea and 8% of controls (p<0.0001). ETEC was isolated in 15.5% of patients with diarrhoea but not in any controls ( p<0.0001), STEC in 15% of patients and 2% of controls (p<0.0001) and EPEC in 6% of patients and 5% of controls. Of 30 STEC isolates from patients with diarrhoea, seven were O157:H7 and 23 were non-O157:H7.     

The effect of morphine sensitization on extracellular concentrations of GABA in dorsal hippocampus of male rats

Repeated, intermittent exposure to drugs of abuse, such as morphine results in response enhancements to subsequent drug treatments, a phenomenon referred to as behavioral sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neurochemical mechanisms of sensitization is providing insights into addiction. Although it has been shown that GABAergic systems in the CA1 region of dorsal hippocampus are involved in morphine sensitization, the alteration of extracellular level of GABA in this area in morphine sensitization has not been investigated. In the present study, using the in vivo microdialysis technique, we investigated the effect of morphine sensitization on extracellular GABA concentration in CA1 region of dorsal hippocampus of freely moving rats. Sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days free of the opioid treatment. The results showed that extracellular GABA concentration in CA1 was decreased following acute administration of morphine in non-sensitized rats. However, morphine-induced behavioral sensitization significantly increased the extracellular GABA concentration in this area. The enhancement of GABA in morphine sensitized rats was inhibited by administration of naloxone 30 min before each of three daily doses of morphine. These results suggest an adaptation of the GABAergic neuronal transmission in dorsal hippocampus induced by morphine sensitization and it is implied that opioid receptors may play an important role in this effect.     

High prevalence of metallo-beta-lactamase-producing acinetobacter baumannii in a teaching hospital in Tabriz, Iran

Metallo-beta-lactamase (MBL)-producing Acinetobacter baumannii has become a growing therapeutic concern worldwide. The aims of this study were to evaluate the antimicrobial susceptibility of A. baumannii isolates and to determine the prevalence of MBL genes among carbapenem non-susceptible isolates. During a period of 16 months (March 2008-June 2009), 100 isolates of A. baumannii were collected from different clinical specimens of inpatients admitted to the largest teaching hospital in the northwest of Iran. All isolates were tested for antimicrobial susceptibility by Kirby-Bauer disk diffusion method. Carbapenem non-susceptible isolates were further screened for production of MBL by Etest and were then subjected to PCR for detection of MBL genes of types bla(IMP) and bla(VIM). Among 63 carbapenem (imipenem and meropenem) non-susceptible isolates of A. baumannii, 31 (49%) were found to be MBL producers. Of 31 MBL-producing isolates, 19 (61%) carried the bla(IMP) gene and 9 (29%) carried the bla(VIM) gene. All MBL-producing isolates were multidrug resistant. This is the first report of IMP and VIM types among MBL-producing A. baumannii in Iran.     

Dorsal hippocampal opioidergic system modulates anxiety-like behaviors in adult male Wistar rats

Aims: In the present study, we investigated the possible influence of the opioidergic system of the dorsal hippocampus on anxiety‐like behaviors. Methods: Elevated plus‐maze, which is one of the methods used for testing anxiety, was used in the present study. Rats were anesthetized with ketamine and xylazine and special cannulas were inserted stereotaxically into the CA1 region of the dorsal hippocampus. After 1 week of recovery, the effects of intra‐CA1 administration of morphine (0.25, 0.5, 1 and 2 µg/rat; 1 µl/rat; 0.5 µl/in each side), naloxone (2, 4, 6 and 8 µg/rat), enkephalin (1, 2, 5 and 10 µg/rat) and naltrindole (0.25, 0.5, 1 and 2 µg/rat) on percentage open arm time (%OAT) and percentage open arm entries (%OAE) were determined. Results: Bilateral administration of morphine into CA1 decreases %OAT and %OAE, indicating an anxiogenic‐like effect. Intra‐CA1 injection of naloxone, an opioid receptor antagonist, increased both %OAT and %OAE, parameters of anxiolytic‐like behavior. Bilateral administration of δ‐opioid receptor agonist, [D‐Pen^2,5]‐enkephalin acetate hydrate into the CA1, induced an anxiolytic‐like effect. Furthermore, intra‐CA1 injection of δ‐opioid receptor antagonist, naltrindole hydrochloride, increased anxiety‐related behaviors. Conclusions: The results of the present study demonstrate that activation of μ‐opioid receptors in this area produce an anxiogenic response while activation of δ‐opioid receptors produces an anxiolytic response.