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Rationale Selective serotonin reuptake inhibitors (SSRIs) are the first choice of treatment for anxiety-like disorders. However, which aspects of anxiety are affected by SSRIs is not yet fully understood. Objective We aimed to systematically review the effect of six clinically effective SSRIs on four aspects of unconditioned anxiety: approach-avoidance behaviour (elevated plus maze), repetitive behaviour (marble burying), distress behaviour (ultrasonic vocalization), and activation of the autonomous nervous system (stress-induced hyperthermia). Methods We identified publications by searching Medline and Embase databases and assessed the risk of bias. A random effects meta-analysis was performed and moderator effects were analysed with Bayesian penalized meta-regression. Results Our search yielded 105 elevated plus maze, 63 marble burying, 11 ultrasonic vocalization, and 7 stress-induced hyperthermia articles. Meta-analysis suggested that SSRIs reduce anxiety-like behaviour in the elevated plus maze, marble burying and ultrasonic vocalization test and that effects are moderated by pre-existing stress conditions (elevated plus maze) and dose dependency (marble burying) but not by duration of treatment or type of SSRI. The reporting quality was low, publication bias was likely, and heterogeneity was high. Conclusion SSRIs seem to reduce a broad range of unconditioned anxiety-associated behaviours. These results should be interpreted with caution due to a high risk of bias, likely occurrence of publication bias, substantial heterogeneity and limited moderator data availability. Our review demonstrates the importance of including bias assessments when interpreting meta-analysis results. We further recommend improving the reporting quality, the conduct of animal research, and the publication of all results regardless of significance.

Contains fulltext : 300200.pdf (Publisher’s version ) (Open Access), RATIONALE: Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. OBJECTIVE: We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. METHODS: We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. RESULTS: Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. CONCLUSIONS: This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs., 01 november 2023

Contains fulltext : 300201.pdf (Publisher’s version ) (Open Access), RATIONALE AND OBJECTIVES: Fear conditioning is an important aspect in the pathophysiology of anxiety disorders. The fear-potentiated startle test is based on classical fear conditioning and over the years, a broad range of drugs have been tested in this test. Synthesis of the available data may further our understanding of the neurotransmitter systems that are involved in the expression of conditioned fear. METHODS: Following a comprehensive search in Medline and Embase, we included 68 research articles that reported on 103 drugs, covering 56 different drug classes. The systematic review was limited to studies using acute, systemic drug administration in naive animals. RESULTS: Qualitative data synthesis showed that most clinically active anxiolytics, but not serotonin-reuptake inhibitors, reduced cued fear. Anxiogenic drugs increased fear potentiation in 35% of the experiments, reduced fear potentiation in 29% of the experiments, and were without effect in 29% of the experiments. Meta-analyses could be performed for five drug classes and showed that benzodiazepines, buspirone, 5-HT(1A) agonists, 5-HT(1A) antagonists, and mGluR2,3 agonists reduced cued conditioned fear. The non-cued baseline startle response, which may reflect contextual anxiety, was only significantly reduced by benzodiazepines and 5-HT(1A) antagonists. No associations were found between drug effects and methodological characteristics, except for strain. CONCLUSIONS: The fear-potentiated startle test appears to have moderate to high predictive validity and may serve as a valuable tool for the development of novel anxiolytics. Given the limited available data, the generally low study quality and high heterogeneity additional studies are warranted to corroborate the findings of this review., 01 november 2023

Psychiatric disorders are known for their high disease burden, even though it is still uncertain what exactly causes these disorders. However, it is known that environmental factors such as infections can largely influence the developing brain. Previous studies have shown that maternal infections during pregnancy increase the risk of psychiatric disorders in offspring, but many specifics still remain to be unravelled. It is important to gain more knowledge about this subject in order to improve treatment and prevention of psychiatric disorders. In the current paper, the influence of polyI:C injections in pregnant rats on the development of psychiatric disorders in offspring is assessed. We compare two different stages of pregnancy; gestational day (GD) 9 - corresponding to the first trimester in humans - and GD15 - corresponding to the second trimester. The offspring is analysed based on heart rate variability (HRV) and ultrasonic vocalizations (USV) on postnatal days 7 and 14. The difference in bandwidth of USV’s, as a measure for the complexity of USV’s, showed a significant interaction between the treatment day of the pregnant rat and the sex of the offspring. Specifically, there was a difference between males and females for treatment at GD9, with a p-value of 0,004. Other than that, no significance was found in any variables in both the HRV and the USV measurements. However, non-significant correlations in mainly the USV data suggested a difference for the interaction of sex and treatment day. Possibly polyI:C at GD9 affects males more, while polyI:C at GD15 affects females more. Possibly there are differences between male and female rat pups regarding HRV and USV’s. No significance could be found in the current research to support this idea, but slight differences have been observed. Combined with previous research this does indicate that differences could be present. Further research is warranted to establish the relationship between the sex of the offspring

This study describes efforts to create a cell culture-based in vitro model of epilepsy, based on E18 rat cortex material. To study this model, two assays are used. The calcium-6 assay is used to measure network activity in vitro. Immunofluorescent staining is performed against a variety of cell types commonly found in the central nervous system and the cortex in efforts to characterize and quantify cells in culture. This report describes comparisons and choices made for cell seeding density, medium change protocols, culture plate coatings, medium choices, the effects of medium changes on network development, and long-term culture as part of optimization of the culturing conditions. Additionally, it compares epilepsy models commonly used in vitro including addition of convulsant drugs like 4-Aminopyridine as well as incubation of cells in low magnesium conditions. The final part of the report describes preliminary efforts to determine the effects of nutritional supplementation and ketosis inducing conditions in culture.

Bipolar disorder (BD) is a prevalent psychiatric disorder affecting about 1% of the world’s population. However, there is still a lack of adequate treatment for BD. Mania state, the defining feature of BD, manifests insomnia, aggression, and motor hyperactivity, possibly due to dysregulation of the dopaminergic system. In BD lower dopamine transporter (DAT) expression and function are observed which leads to decreased dopamine metabolism which may cause elevated dopamine transmission during mania state. Cannabis is used in higher rates in people with BD than in the general population. THC, a psychoactive compound present in cannabis, decreases dopamine levels over time, and therefore, with the elevated dopamine levels observed in bipolar mania, may be able to treat the mania-like symptoms of BD. DAT knockdown (KD) mice reconstruct BD-related behaviors such as hyperexploratory and risky decision- making behavior in the behavioral pattern monitor (BPM) and may be useful to develop newer treatment strategies for BD mania. We investigated if hyperexploratory behavior of DAT KD mice would decrease after chronically administering THC (14 days) in the behavioral pattern monitor (BPM). 45 mice (51% DAT KD, 22% female) were intraperitoneal injected of either THC (3mg/kg) or saline for 14 consecutive days and then tested in the BPM. Another cohort of DAT KD mice in the BPM, other cohort DAT KD mice were tested in the temporal discrimination task (TDT). The TDT measures temporal perception which altered in BD and by THC. Therefore, we used the TDT to investigate the effect of THC on temporal perception of these subjects. The data we provide is data from during the training phase. 45 mice (54% DAT KD, 56% female) were trained in the TDT task, with each session duration being 30 minutes. The 19 sessions were insufficient for all mice to attain criterion in the TDT (> 85% correct), although current training revealed no sex or genotype differences in training to-date. Chronic THC

Contains fulltext : 220922.pdf (publisher's version ) (Open Access), Various animal models are used to study pharmacokinetics (PK) of drugs in development. Human renal clearance (CLr) should be predictable through interpolation from animal data by allometric scaling. Based on this premise, we quantified interspecies differences in CLr, and related them to drug properties. Using PubMed and EMBASE, we systematically reviewed literature on human and animal CLr measures for 20 renally excreted drugs, calculated average fold errors, and quantified mean differences between animals and humans. Our results show that animal models are generally good predictors for human drug clearance using simple allometry, except for rats, with which human CLr is significantly overestimated.

Contains fulltext : 220922.pdf (publisher's version ) (Open Access), Various animal models are used to study pharmacokinetics (PK) of drugs in development. Human renal clearance (CLr) should be predictable through interpolation from animal data by allometric scaling. Based on this premise, we quantified interspecies differences in CLr, and related them to drug properties. Using PubMed and EMBASE, we systematically reviewed literature on human and animal CLr measures for 20 renally excreted drugs, calculated average fold errors, and quantified mean differences between animals and humans. Our results show that animal models are generally good predictors for human drug clearance using simple allometry, except for rats, with which human CLr is significantly overestimated.

Contains fulltext : 220922.pdf (publisher's version ) (Open Access), Various animal models are used to study pharmacokinetics (PK) of drugs in development. Human renal clearance (CLr) should be predictable through interpolation from animal data by allometric scaling. Based on this premise, we quantified interspecies differences in CLr, and related them to drug properties. Using PubMed and EMBASE, we systematically reviewed literature on human and animal CLr measures for 20 renally excreted drugs, calculated average fold errors, and quantified mean differences between animals and humans. Our results show that animal models are generally good predictors for human drug clearance using simple allometry, except for rats, with which human CLr is significantly overestimated.

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin releasing hormone receptor 1 (CRHR1) is associated with reduced fear conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear conditioning procedure as in Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear conditioned responses compared to C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin releasing hormone plays a role in the acquisition of fears.

Contains fulltext : 153647.pdf (Publisher’s version ) (Open Access), The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups. Electronic databases were searched for original research articles, yielding 32 studies that met inclusion criteria. We extracted data on pharmacological intervention, animal and methodological characteristics, and study quality indicators. Meta-analysis showed that the different drug classes in clinical use for the treatment of anxiety disorders, have comparable effects on vocalization behaviour, irrespective of their mechanism of action. Of the experimental drugs, nociception (NOP) receptor agonists proved very effective in this test. Analysis further indicated that the commonly used read-outs total number and total duration of vocalizations are equally valid. With regard to methodological characteristics, repeated testing of pups as well as selecting pups with moderate or high levels of vocalization were associated with larger treatment effects. Finally, reporting of study methodology, randomization and blinding was poor and Egger's test for small study effects showed that publication bias likely occurred. This review illustrates the value of systematic reviews and meta-analyses in improving translational value and methodological aspects of animal models. It further shows the urgent need to implement existing publication guidelines to maximize the output and impact of experimental animal studies.

Contains fulltext : 153647.pdf (Publisher’s version ) (Open Access), The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups. Electronic databases were searched for original research articles, yielding 32 studies that met inclusion criteria. We extracted data on pharmacological intervention, animal and methodological characteristics, and study quality indicators. Meta-analysis showed that the different drug classes in clinical use for the treatment of anxiety disorders, have comparable effects on vocalization behaviour, irrespective of their mechanism of action. Of the experimental drugs, nociception (NOP) receptor agonists proved very effective in this test. Analysis further indicated that the commonly used read-outs total number and total duration of vocalizations are equally valid. With regard to methodological characteristics, repeated testing of pups as well as selecting pups with moderate or high levels of vocalization were associated with larger treatment effects. Finally, reporting of study methodology, randomization and blinding was poor and Egger's test for small study effects showed that publication bias likely occurred. This review illustrates the value of systematic reviews and meta-analyses in improving translational value and methodological aspects of animal models. It further shows the urgent need to implement existing publication guidelines to maximize the output and impact of experimental animal studies.

Contains fulltext : 153647.pdf (Publisher’s version ) (Open Access), The separation-induced vocalization test in guinea pig pups is one of many that has been used to screen for anxiolytic-like properties of drugs. The test is based on the cross-species phenomenon that infants emit distress calls when placed in social isolation. Here we report a systematic review and meta-analysis of pharmacological intervention in the separation-induced vocalization test in guinea pig pups. Electronic databases were searched for original research articles, yielding 32 studies that met inclusion criteria. We extracted data on pharmacological intervention, animal and methodological characteristics, and study quality indicators. Meta-analysis showed that the different drug classes in clinical use for the treatment of anxiety disorders, have comparable effects on vocalization behaviour, irrespective of their mechanism of action. Of the experimental drugs, nociception (NOP) receptor agonists proved very effective in this test. Analysis further indicated that the commonly used read-outs total number and total duration of vocalizations are equally valid. With regard to methodological characteristics, repeated testing of pups as well as selecting pups with moderate or high levels of vocalization were associated with larger treatment effects. Finally, reporting of study methodology, randomization and blinding was poor and Egger's test for small study effects showed that publication bias likely occurred. This review illustrates the value of systematic reviews and meta-analyses in improving translational value and methodological aspects of animal models. It further shows the urgent need to implement existing publication guidelines to maximize the output and impact of experimental animal studies.

Contains fulltext : 233028.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 87611.pdf (publisher's version ) (Closed access), BACKGROUND: The amygdala is involved in the coordination of stress but is also an important gatekeeper involved in the regulation of vigilance. The amygdala is structurally complex, consisting of several nuclei with specific functions in the affective response to environmental stimuli. There are indications that the medial amygdaloid nucleus may be a pivotal player in acute responses to emotional environmental stimuli. METHODS: The present study therefore aimed to study the effects of bilateral electrolytic lesions of the medial amygdala on unconditioned anxiety-related behavior as well as a sensorimotor gating parameter (prepulse inhibition, PPI) in rats. Anxiety-related behavior was assessed with the use of stress-induced hyperthermia (SIH), light-enhanced startle (LES) and open field behavior. RESULTS: Bilateral electrolytic lesions of the medial amygdala decreased the SIH response and anxiety-related open field behavior. In contrast, lesioned animals displayed augmented LES and disrupted PPI. No changes in basal locomotor activity, body temperature and acoustic startle were found between lesioned and sham animals. CONCLUSIONS: The present study suggests that the medial amygdala is an important player in response to acute environmental stimuli. Decreased unconditioned psychological stress responses were found, whereas LES was enhanced and sensorimotor processing was disrupted. However, considering the existing data on basolateral amygdala involvement in PPI and bed nucleus of the stria terminalis involvement in LES, local infusion studies into the MeA should be performed to further substantiate these findings.

Contains fulltext : 233028.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 87611.pdf (publisher's version ) (Closed access), BACKGROUND: The amygdala is involved in the coordination of stress but is also an important gatekeeper involved in the regulation of vigilance. The amygdala is structurally complex, consisting of several nuclei with specific functions in the affective response to environmental stimuli. There are indications that the medial amygdaloid nucleus may be a pivotal player in acute responses to emotional environmental stimuli. METHODS: The present study therefore aimed to study the effects of bilateral electrolytic lesions of the medial amygdala on unconditioned anxiety-related behavior as well as a sensorimotor gating parameter (prepulse inhibition, PPI) in rats. Anxiety-related behavior was assessed with the use of stress-induced hyperthermia (SIH), light-enhanced startle (LES) and open field behavior. RESULTS: Bilateral electrolytic lesions of the medial amygdala decreased the SIH response and anxiety-related open field behavior. In contrast, lesioned animals displayed augmented LES and disrupted PPI. No changes in basal locomotor activity, body temperature and acoustic startle were found between lesioned and sham animals. CONCLUSIONS: The present study suggests that the medial amygdala is an important player in response to acute environmental stimuli. Decreased unconditioned psychological stress responses were found, whereas LES was enhanced and sensorimotor processing was disrupted. However, considering the existing data on basolateral amygdala involvement in PPI and bed nucleus of the stria terminalis involvement in LES, local infusion studies into the MeA should be performed to further substantiate these findings.

Contains fulltext : 233028.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 87611.pdf (publisher's version ) (Closed access), BACKGROUND: The amygdala is involved in the coordination of stress but is also an important gatekeeper involved in the regulation of vigilance. The amygdala is structurally complex, consisting of several nuclei with specific functions in the affective response to environmental stimuli. There are indications that the medial amygdaloid nucleus may be a pivotal player in acute responses to emotional environmental stimuli. METHODS: The present study therefore aimed to study the effects of bilateral electrolytic lesions of the medial amygdala on unconditioned anxiety-related behavior as well as a sensorimotor gating parameter (prepulse inhibition, PPI) in rats. Anxiety-related behavior was assessed with the use of stress-induced hyperthermia (SIH), light-enhanced startle (LES) and open field behavior. RESULTS: Bilateral electrolytic lesions of the medial amygdala decreased the SIH response and anxiety-related open field behavior. In contrast, lesioned animals displayed augmented LES and disrupted PPI. No changes in basal locomotor activity, body temperature and acoustic startle were found between lesioned and sham animals. CONCLUSIONS: The present study suggests that the medial amygdala is an important player in response to acute environmental stimuli. Decreased unconditioned psychological stress responses were found, whereas LES was enhanced and sensorimotor processing was disrupted. However, considering the existing data on basolateral amygdala involvement in PPI and bed nucleus of the stria terminalis involvement in LES, local infusion studies into the MeA should be performed to further substantiate these findings.

Contains fulltext : 79534.pdf (publisher's version ) (Closed access)

Contains fulltext : 79534.pdf (publisher's version ) (Closed access)

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Contains fulltext : 35942.pdf (publisher's version ) (Closed access), Corticotropin-releasing factor (CRF) acts through CRF 1 and CRF 2 receptors (CRF1, CRF2). To test the hypothesis that CRF controls the expression of these receptors in a brain site- and receptor-type specific manner, we studied CRF1 mRNA and CRF2 mRNA expressions in mice with central CRF over-expression (CRF-OE) and using in situ hybridization. CRF1 and CRF2 mRNAs appear to be differentially distributed across the brain. The brain structures expressing the receptors are the same in wild-type (WT) and in CRF-OE mice. We therefore conclude that chronically elevated CRF does not induce or inhibit expression of these receptors in structures that normally do not or do, respectively, show these receptors. However, from counting cell body profiles positive for CRF1 and CRF2 mRNAs, clear differences appear in receptor expression between CRF-OE and WT mice, in a brain-structure-specific fashion. Whereas some structures do not differ, CRF-OE mice exhibit remarkably lower numbers of CRF1 mRNA-positive profiles in the subthalamic nucleus (-38.6%), globus pallidus (-31.5%), dorsal part of the lateral septum (-23.5%), substantia nigra (-22,8%), primary somatosensory cortex (-18.9%) and principal sensory nucleus V (-18.4%). Furthermore, a higher number of CRF2 mRNA-positive profiles are observed in the dorsal raphe nucleus (+32.2%). These data strongly indicate that central CRF over-expression in the mouse brain is associated with down-regulation of CRF1 mRNA and up-regulation of CRF2 mRNA in a brain-structure-specific way. On the basis of these results and the fact that CRF-OE mice reveal a number of physiological and autonomic symptoms that may be related to chronic stress, we suggest that CRF1 in the basal nuclei may be involved in disturbed information processing and that CRF2 in the dorsal raphe nucleus may play a role in mediating stress-induced release of serotonin by CRF.