Potentiation of latent inhibition by haloperidol and clozapine is attenuated in Dopamine D2 receptor (Drd-2) deficient mice: Do antipsychotics influence learning to ignore irrelevant stimuli via both Drd-2 and non-Drd-2 mechanisms?

Whether the dopamine Drd-2 receptor is necessary for the behavioural action of antipsychotic drugs is an important question, as Drd-2 antagonism is responsible for their debilitating motor side effects. Using Drd-2 null mice (Drd2 -/-) it has previously been shown that Drd-2 is not necessary for antipsychotic drugs to reverse D-amphetamine disruption of latent inhibition (LI), a behavioural measure of learning to ignore irrelevant stimuli. Weiner's 'two-headed' model indicates that antipsychotics not only reverse LI disruption, 'disrupted LI', but also potentiate LI when low/absent in controls, 'persistent' LI. We investigated whether antipsychotic drugs haloperidol or clozapine potentiated LI in wild-type controls or Drd2 -/-. Both drugs potentiated LI in wild-type but not in Drd2 -/- mice, suggesting moderation of this effect of antipsychotics in the absence of Drd-2. Haloperidol potentiated LI similarly in both Drd1 -/- and wild-type mice, indicating no such moderation in Drd1 -/-. These data suggest that antipsychotic drugs can have either Drd-2 or non-Drd-2 effects on learning to ignore irrelevant stimuli, depending on how the abnormality is produced. Identification of the non-Drd-2 mechanism may help to identify novel non-Drd2 based therapeutic strategies for psychosis

The Role of Dopamine D2 adn D1 Receptor Subtypes in Latent Inhibition : Behavioural Studies in Gene Knockout Mice

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Changes in behaviour and cytokine expression upon a peripheral immune challenge

Depression is frequently associated with inflammation. Animal studies have shown that peripheral inflammation induces depressive-like behaviour, but the underlying mechanisms remain unclear. A distinction between sickness- and depressive-like behaviour has been proposed. We hypothesize that the behavioural distinction is due to changes in the central production of immune mediators. As a model of peripheral inflammation, we administered lipopolysaccharide (LPS) intraperitoneally daily for 4 days in rats. The effect of LPS on sickness- and depressive-like behaviour was assessed. We examined protein levels and mRNA expression of cytokines and cyclooxygenase (COX) enzymes in serum, cerebrospinal fluid (CSF) and specific brain regions. Two hours post-LPS, the rats displayed sickness behaviour and cytokine levels were elevated in both serum and CSF. This was paralleled by specific alterations of mRNA transcription of IL-1β, IL-6 and TNF-α in frontal cortex, hippocampus and striatum. Twenty-four hours post-LPS the rats showed depressive-like behaviour and peripheral cytokine levels were back close to baseline. In contrast, the central transcription of IL-1β mRNA had increased even further, as well as IL-1β CSF levels. IL-6 and TNF-α transcription was unaltered compared to controls. COX enzymes were downregulated in the hippocampus during sickness behaviour and unaltered during depressive-like behaviour. Our results show for the first time that a peripheral immune challenge induces a region specific transcription of cytokines and COX-enzymes in the brain, at time-points corresponding to behavioural sickness and depression. When the peripheral inflammation and sickness behaviour had ceased, a production of proinflammatory cytokines remained within the brain parenchyma

Pro-inflammatory cytokines reduce the proliferation of NG2 cells and increase shedding of NG2 in vivo and in vitro.

Neuron glial 2 (NG2) cells become strongly activated in injured brain areas. The activation is characterized by increased proliferation as well as increased expression and shedding of the proteoglycan NG2 expressed on their cell surface. It is currently not known how these cells respond to low-grade neuroinflammation provoked by systemic inflammation. To investigate this, we analyzed NG2 cell proliferation as well as soluble NG2 (sNG2) in cerebrospinal fluid (CSF) from rats treated with an acute intraperitoneal (i.p) injection of lipopolysaccharides (LPS) or saline and sacrificed after 2 or 24 hours. The systemically induced neuroinflammation was confirmed as elevated levels of cytokines, including interleukin (IL)-6 and IL-1β, and MHCII expressing microglia were found 24 h after LPS treatment. At this time point NG2 cell proliferation was significantly decreased in both amygdala and hippocampus and sNG2 levels in CSF were increased twofold. We also exposed human NG2 cells in culture to IL-6 and IL-1β for 24 h and found, in line with our in vivo study, a direct impact of these cytokines reducing cell proliferation and increasing shedding of NG2. We conclude that LPS induced systemic inflammation significantly affects NG2 cell proliferation and shedding and that these two events at least in in part are mediated by IL-6 and IL-1β

Aldosterone synergizes with peripheral inflammation to induce brain IL-1β expression and depressive-like effects.

Recent findings have shown that the physiological functions of the hormone aldosterone go far beyond its well-known role in blood-pressure regulation and salt/water homeostasis. Aldosterone is for example involved in the regulation of inflammation, and also binds directly to mineralocorticoid receptors in specific brain regions. Interestingly, depressive symptoms appear to correlate with alterations of the aldosterone system but the underlying mechanisms have not been elucidated. In this study aldosterone (2μg/100g body weight/day) was continuously administered via osmotic minipumps for 5days. Lipopolysaccharide (LPS) was administered once a day for 5days in a dose of 1mg/kg ip. The rats were tested for depressive-like behavior 24h after the last LPS injection. Protein levels of cytokines were measured in serum and cerebrospinal fluid (CSF). mRNA expression of interleukin (IL)-1β and IL-6 in the prefrontal cortex (PFC) was analyzed using reverse transcriptase qPCR. We found that aldosterone treatment increased LPS-induced IL-1β mRNA expression in the PFC and CSF. Moreover, there was a positive correlation between IL-1β in CSF and depressive-like behaviors. These findings suggest that IL-1β is affected by the renin-aldosterone-angiotensin system (RAAS) activity and connected to symptoms of depression

Maternal stress and placental function; ex vivo placental perfusion studying cortisol, cortisone, tryptophan and serotonin.

BACKGROUND:Exposure to maternal stress during pregnancy can have adverse effects on the fetus, which has potential long-term effects on offspring´s development and health. We investigated the kinetics and metabolism of the hormones and amino acids: cortisol, cortisone, tryptophan and serotonin in the term placenta in an ex vivo human placental perfusion model. The placentas used in the experiments were donated from families participating in the Maternal Stress and Placental Function project with a known maternal stress background. METHOD:Cortisol, cortisone, tryptophan and serotonin were added simultaneously to the maternal side in the 6 hour ex vivo term human recirculating placental perfusion model, in four experimental set-ups: without inhibitors, with carbenoxolone -that inhibits cortisol metabolism into cortisone, with fluoxetine that inhibits the serotonin transporter, and with PCPA that inhibits metabolism of tryptophan into serotonin. The concentration of cortisol and cortisone, and tryptophan and serotonin were quantified using UPLC and HPLC-MS respectively. RESULTS:Cortisol was rapidly metabolized into cortisone in the placenta, to a somewhat lesser degree when adding the inhibitor carbenoxolone, resulting in higher fetal exposure to cortisol. Serotonin was also rapidly metabolized in the placenta. When adding fluoxetine a peak of fetal serotonin levels was seen in the first hour of the perfusion. No effect was seen of the maternal stress levels on placental transport kinetics in this study. CONCLUSION:Inhibiting the metabolism of cortisol in the placenta increased fetal exposure to cortisol as expected. Unexpectedly we saw an increased fetal exposure to serotonin when inhibiting the serotonin transporter, which may be related to the increased serotonin concentration on the maternal side of the placenta. No effect on placental kinetics were evident on maternal stress levels during the pregnancy as the majority of participating mothers had normal stress levels

Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice.

Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome

Systematic evaluation of skeletal fractures caused by induction of electroconvulsive seizures in rat state a need for attention and refinement of the procedure

Objective: Electroconvulsive therapy (ECT) is one of the most efficient treatments for major depression. Electroconvulsive seizures (ECS), the animal model of ECT, is widely used to study both mechanisms of action and adverse effects of ECT. As the treatment itself serves as an instant anaesthetic and anaesthetic agents may affect memory functions and behaviour, ECS is traditionally administered without muscle relaxation and anaesthesia. A major problem of unmodified ECS, which has only been addressed peripherally in the literature, is that some animals sustain spinal fractures and subsequent hind leg paralysis (paraplegia). This phenomenon leads to a higher degree of suffering and these animals need to be excluded from the studies. To reach sufficient statistical power, the group sizes are therefore often increased and this may lead to a pre-selected study group in risk of skewing the results. Moreover, the study design of the experiments do not comply with the 3R principles, which advocate for both refinement and reduction of animal experiments. The objective of this study is to systematically evaluate injuries caused by ECS. Methods: We summarise the incidence of spinal fractures from 24 studies conducted during 2009–2015 in six different rat strains and report preliminary findings on scapular fractures following auricular ECS. Results: In total, 12.8% of all tested animals suffered from spinal fractures and we find an increase in spinal fracture incidence over time. Furthermore, X-ray analyses revealed that some animals displayed scapular fractures. Conclusion: We discuss consequences of and possible explanations for ECS-induced fractures. Modifications of the method are highly warranted and we furthermore suggest that all animals are thoroughly examined for discrete fractures

Serum cytokine levels (pg/ml) 2 h and 24 h after LPS and saline treatment.

<p>Values represent means ± SEM * p = 0.01, ** p = 0.001 and *** p = 0.001 indicates a significant difference compared to controls. ^aindicate values set that were to detection limit.</p><p>Serum cytokine levels (pg/ml) 2 h and 24 h after LPS and saline treatment.</p