Explore the vast range of titles available.

This study investigated the effectiveness of ketamine, a noncompetitive N -methyl- d -aspartate (NMDA) receptor antagonist, in alleviating the enhanced anxiety and fear response in both a mouse model of PTSD induced by inescapable electric foot shocks and a rat model of PTSD induced by a time-dependent sensitization (TDS) procedure. First, we evaluated the effect of ketamine on behavioral deficits in a mouse model of PTSD that consisted of foot shocks followed by three situational reminders. Our results showed that the aversive procedure induced several behavioral deficiencies, such as increased freezing behavior and anxiety, as well as reduced time spent in an aversive-like context, which were reversed by repeated treatment with ketamine. The effect of ketamine on behavioral changes after exposure to TDS was also investigated, and the levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were measured. The results revealed that after TDS, the rats showed a significant increase in contextual freezing and a decrease in the percentage of time spent in and numbers of entries into open arms in the elevated plus maze test. As a positive control drug, sertraline (Ser, 15 mg/kg, i.g.), a selective serotonin reuptake inhibitor (SSRI) ameliorated these behavioral deficits. These behavioral effects were mimicked by chronic ketamine treatment. Furthermore, ketamine normalized the decreased BDNF level in the hippocampus in post-TDS rats. Taken together, these results suggest that ketamine exerts a therapeutic effect on PTSD that might be at least partially mediated by an influence on BDNF signaling in the hippocampus.

Methamphetamine (METH) is a popular but harmful psychostimulant. METH use disorder (MUD) is characterized by compulsive and continued use despite adverse life consequences. METH users experience impairments in learning and memory functions that are thought to be secondary to METH-induced abnormalities in the hippocampus. Recent studies have reported that about 50% of METH users develop MUD, suggesting that there may be differential molecular effects of METH between the brains of individuals who met criteria for addiction and those who did not after being exposed to the drug. The present study aimed at identifying potential transcriptional differences between compulsive and non-compulsive METH self-administering male rats by measuring global gene expression changes in the hippocampus using RNA sequencing. Herein, we used a model of METH self-administration (SA) accompanied by contingent foot-shock punishment. This approach led to the separation of animals into shock-resistant rats (compulsive) that continued to take METH and shock-sensitive rats (non-compulsive) that suppressed their METH intake in the presence of punished METH taking. Rats were euthanized 2 h after the last METH SA plus foot-shock session. Their hippocampi were immediately removed, frozen, and used later for RNA sequencing and qRT-PCR analyses. RNA sequencing analyses revealed differential expression of mRNAs encoding cell adhesion molecules (CAMs) between the two rat phenotypes. qRT-PCR analyses showed significant higher levels of Cdh1 , Glycam1 , and Mpzl2 mRNAs in the compulsive rats in comparison to non-compulsive rats. The present results implicate altered CAM expression in the hippocampus in the behavioral manifestations of continuous compulsive METH taking in the presence of adverse consequences. Our results raise the novel possibility that altered CAM expression might play a role in compulsive METH taking and the cognitive impairments observed in MUD patients.

Methamphetamine (METH) is an extremely addictive drug which continues to cause significant harm to individuals and communities. In the present study we trained male rats to self-administer METH for 20 days, followed by 9 days of foot shock exposure. All rats escalated their METH intake during the first 20 days. The rats that continued to self-administer METH in the presence of aversive stimuli were termed shock-resistant (SR), while those that reduced their intake were shock-sensitive (SS). RNA sequencing showed numerous differentially expressed genes (DEGs) in the prefrontal cortex, nucleus accumbens, dorsal striatum, and midbrain. Ingenuity pathway analysis linked DEGs to addiction-related mechanisms. We identified shared genes with similar expression patterns across four brain regions (SR: Fos and Ahsp; SS: Tet1, Cym, and Tmem30c). The identified genes play key roles in addiction-related brain functions, such as neuronal activity, stress response, and epigenetic regulation, and their importance in METH addiction is highlighted. These genes represent promising targets for developing new treatments aimed at reversing neuroadaptations caused by METH use.

A combination of antidepressant drugs and psychotherapy exhibits more promising efficacy in treating fear disorders than either treatment alone, but underlying mechanisms of such treatments remain largely unknown. Here we investigated the role of DNA methylation of the brain-derived neurotrophic factor (Bdnf) gene in the therapeutic effects of ketamine in combination with extinction training in a mouse model of post-traumatic stress disorder (PTSD) induced by inescapable electric foot shocks (IFS). Male mice received ketamine for 22 consecutive days starting 1 h after the IFS (long-term ketamine treatment) or 2 h prior to the extinction training on days 15 and 16 after the IFS (short-term ketamine treatment). The Open Field (OF) and Elevated Plus Maze (EPM) tests were conducted on days 18 and 20. The spontaneous recovery and fear renewal tests were performed on day 23. Mice, subjected to IFS, exhibited anxiety-like behavior and fear relapse, accompanied by the increased levels of DNA methyltransferases, hyper-methylation of Bdnf gene, and decreased BDNF mRNA expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Long-term treatment with ketamine combined with extinction training alleviated the IFS-induced abnormalities. These results suggest that long-term ketamine treatment in combination with extinction training may ameliorate fear relapse in the murine model of PTSD, at least in part, by normalizing DNA methylation of Bdnf gene.

Glycine max Merr. (GM) is a functional food that provides many beneficial phytochemicals. However, scientific evidence of its antidepressive and sedative activities is scarce. The present study was designed to investigate the antidepressive and calmative effects of GM and its biologically active compound, genistein (GE), using electroencephalography (EEG) analysis in an electric foot shock (EFS)-stressed rat. The underlying neural mechanisms of their beneficial effects were determined by assessing corticotropin-releasing factor (CRF), serotonin (5-HT), and c-Fos immunoreactivity in the brain using immunohistochemical methods. In addition, the 5-HT2C receptor binding assay was performed because it is considered a major target of antidepressants and sleep aids. In the binding assay, GM displayed binding affinity to the 5-HT2C receptor (IC50 value of 14.25 ± 11.02 µg/mL). GE exhibited concentration-dependent binding affinity, resulting in the binding of GE to the 5-HT2C receptor (IC50, 77.28 ± 26.57 mg/mL). Administration of GM (400 mg/kg) increased non-rapid eye movement (NREM) sleep time. Administration of GE (30 mg/kg) decreased wake time and increased rapid eye movement (REM) and NREM sleep in EPS-stressed rats. In addition, treatment with GM and GE significantly decreased c-Fos and CRF expression in the paraventricular nucleus (PVN) and increased 5-HT levels in the dorsal raphe in the brain. Overall, these results suggest that GM and GE have antidepressant-like effects and are effective in sleep maintenance. These results will benefit researchers in developing alternatives to decrease depression and prevent sleep disorders.

Acute stress leads to sequential activation of functional brain networks. A biologically relevant question is exactly which (single) cells belonging to brain networks are changed in activity over time after acute stress across the entire brain. We developed a preprocessing and analytical pipeline to chart whole-brain immediate early genes’ expression—as proxy for cellular activity—after a single stressful foot shock in four dimensions: that is, from functional networks up to three-dimensional (3D) single-cell resolution and over time. The pipeline is available as an R package. Most brain areas (96%) showed increased numbers of c-fos+ cells after foot shock, yet hypothalamic areas stood out as being most active and prompt in their activation, followed by amygdalar, prefrontal, hippocampal, and finally, thalamic areas. At the cellular level, c-fos+ density clearly shifted over time across subareas, as illustrated for the basolateral amygdala. Moreover, some brain areas showed increased numbers of c-fos+ cells, while others—like the dentate gyrus—dramatically increased c-fos intensity in just a subset of cells, reminiscent of engrams; importantly, this “strategy” changed after foot shock in half of the brain areas. One of the strengths of our approach is that single-cell data were simultaneously examined across all of the 90 brain areas and can be visualized in 3D in our interactive web portal.

Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal “go” circuit and a decreased prelimbic cortex-ventrolateral striatal “stop” circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, “shock-resistant” rats showed strengthening of this negative connectivity after shock exposure. In contrast, “shock-sensitive” rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.

Electric foot shock is a complex stressor with both physical and emotional components. It has been employed as an important tool to develop diverse animal models in the field of psychopharmacology. The electric foot shock paradigm includes acute or chronic exposures of shocks of varying intensity and duration on an electrified grid floor in an electric foot shock apparatus. Research evidence reveals that foot shocks of varying intensity produce behavioral and neurochemical changes reflecting depression, anxiety, and post-traumatic stress disorder (PTSD) in humans. Animals generally do not habituate to foot shocks in comparison to other stressors, including loud noise, bright light, and hot and cold temperatures. Additionally, it offers an experimental advantage of control over intensity and duration; therefore, by varying its application parameters, different disorder models have been created. Electric foot shock fear conditioning-induced ultrasonic vocalization and fear-potentiated startle have been explored to develop models of anxiety and panic. Similarly, fear conditioning in the form of foot shock exposure followed by situational reminders has been used to develop a model of PTSD. Electric foot shock-induced conflict has been explored to develop operant conflict models (Geller-Seifter and Vogel tests), which in turn are pharmacologically validated to screen potential anti-anxiety agents. Inescapable electric shock-induced ‘learned helplessness’ mimics the symptomology of depression, and this phenomenon has been employed to develop the model of depression. The present review describes the pharmacologically validated models of anxiety, depression, and PTSD involving electric foot shock as an aversive stimulus.

Neurons in the ventral tegmental area (VTA) are sensitive to stress and their maladaptation have been implicated in the psychiatric disorders such as anxiety and addiction, . The cellular properties of the VTA neurons in response to different stressors related to different emotional processing remain to be investigated. By combining immediate early gene (IEG)-dependent labeling, rabies virus tracing, ensemble-specific transcriptomic analysis and fiber photometry recording in the VTA of male mice, the spatial distribution, brain-wide connectivity and cellular signaling pathways in the VTA neuronal ensembles in response to morphine (Mor-Ens) or foot shock (Shock-Ens) stimuli were investigated. Optogenetic activation of the Mor-Ens drove approach behavior, whereas chemogenetic activation of the Shock-Ens increased the anxiety level in mice. Mor-Ens were clustered and enriched in the ventral VTA, contained a higher proportion of dopaminergic neurons, received more inputs from the dorsal medial striatum and the medial hypothalamic zone, and exhibited greater axonal arborization in the zona incerta and ventral pallidum. Whereas Shock-Ens were more dispersed, contained a higher proportion of GABAergic neurons, and received more inputs from the ventral pallidum and the lateral hypothalamic area. The downstream targets of the G protein and β-arrestin pathways, PLCβ3 and phosphorylated AKT1 , were relatively enriched in the Mor-Ens and Shock-Ens, respectively. Cariprazine, the G-protein-biased agonist for the dopamine D2 receptor, increased the response of Mor-Ens to sucrose water and decreased the anxiety-like behavior during morphine withdrawal, whereas the β-arrestin-biased agonist UNC9994 decreased the response of Shock-Ens to tail suspension. Taken together, these findings reveal the heterogeneous connectivity and signaling pathways of the VTA neurons in response to morphine and foot shock, providing new insights for development of specific interventions for psychiatric disorders caused by various stressors associated with different VTA neuronal functions.

Continued alcohol use despite negative consequences is a defining feature of alcohol use disorder (AUD). It remains poorly understood whether individual variability in drinking despite negative consequences is due to inherent differences or emerges after prolonged alcohol use. The goal of the present study was to use a rat model of drinking despite negative consequences to assess individual differences in foot shock-punished alcohol self-administration prior to and following alcohol vapor exposure in male Wistar rats. After baseline operant self-administration was established, rats underwent additional self-administration sessions in which random, response-contingent foot shock punishment was introduced. Average percent change from baseline was calculated for each rat during punished sessions and rats were classified into shock-sensitive (SS) and shock-resistant (SR) subgroups using the top and bottom thirds. Rats then underwent 3 cycles of air or alcohol vapor exposure every other week, with unpunished self-administration sessions occurring during the intervening weeks. Following the last vapor cycle, rats were re-assessed for resistance to foot shock during punished self-administration sessions. Alcohol vapor exposure had no effect on punished self-administration overall, nor by subgroup. Examination of individual differences showed that rats classified as SR showed increased unpunished self-administration relative to baseline regardless of air vs. vapor condition. These data suggest that alcohol history has a minimal effect on individual differences in foot shock-punished self-administration. •Alcohol vapor exposure did not alter punished drinking.•Rats classified as punishment-resistant escalated unpunished drinking.•Individual differences in punished drinking are unaffected by vapor exposure.