Psychopharmacology最新文献

The present study has investigated whether circulating estrogen level variations in the pro-estrus and estrus phases of the intact rats and estrogen depletion in the ovariectomized animals (OVX) adjust the formalin-induced nociceptive behaviors. During the pro-estrus and estrus phases of rats' estrus cycle and in the OVX rats, 17β-estradiol and ICI 182,780 (estrogen receptor antagonist) were administered into the right paragigantocellularis lateralis (LPGi) nucleus. Then, the formalin-induced flexing and licking responses were recorded for 60 min. The findings of this study revealed that intra-LPGi administration of 17β-estradiol (0.8 μmol) reduced the formalin-induced flexing and licking duration in pro-estrus and estrus rats (P < 0.001), suggesting an analgesic effect. 17β-Estradiol injection into the LPGi nucleus of OVX rats increased the flexing duration (P < 0.05) while decreasing the licking duration (P < 0.05) of the formalin test. The pain modulatory effect of 17β-estradiol on the flexing response was reversed by ICI 182,780 (15 nmol) in the pro-estrus (P < 0.001) and estrus rats (P < 0.001) but not in the OVX rats. Also, pretreatment of LPGi nucleus with ICI 182,780 reversed the analgesic effect of 17β-estradiol on the licking response in the pro-estrus (P < 0.05), estrus (P < 0.001), and OVX rats (P < 0.001). These results suggest that the pain threshold in intact female rats is modulated independently of the estrus state. Still, the basal level of plasma estrogen and the activation of its receptors are necessary for pain modulation.

Rationale: Despite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible.

Objective: To examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine.

Methods and results: Newly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6-7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine.

Conclusion: Usefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested.

Rationale: A recent study by our group found that women displayed greater attentional bias to alcohol-related cues during the late versus early follicular phase in both sober and intoxicated states, suggesting a greater risk of excessive drinking among women during this phase. Changes in attentional bias as a function of menstrual cycle phase raise questions about potential sex differences in the relative consistency by which women and men display attentional bias to alcohol over time.

Objectives: The present study tested sex differences in attentional bias to alcohol by comparing the change in women's attentional bias from early to late follicular phase to that observed in men over the same period.

Methods: Twenty-five men and 25 women aged 21-32 participated in a placebo-controlled study examining sex differences in the rewarding properties of alcohol. Participants completed measures of attentional bias to alcohol-related cues during two sessions following both 0.6 g/kg alcohol and placebo. Test sessions occurred one week apart, and for female participants coincided with the early and late follicular phases.

Results: Men consistently displayed attentional bias to alcohol-related cues across sessions under both doses. By contrast, women showed attentional bias only during the late follicular phase, at a magnitude greater than that observed in men, and persistent under both doses.

Conclusions: These findings highlight the potential role of sex and menstrual cycle phase in sensitizing drinkers to rewarding properties of alcohol-related cues. Men's motivation to drink may remain relatively consistent, whereas women may be most motivated during the late follicular phase.

Objectives: Substance use disorders (SUDs) represent a significant global health concern, demanding the development of effective pharmacological treatments. To address this, an investigation was conducted to examine the anti-addictive properties of two compounds, (S)-T1 and (S)-T2, which specifically target the α3β4 nicotinic acetylcholine receptor (nAChR).

Methods: The effects of (S)-T1 and (S)-T2 on nicotine-induced conditioned place preference (CPP), locomotor activity and dopamine levels in particular brain regions associated to addiction were investigated and compared in male C57BL/6N mice.

Results: The results demonstrate that neither (S)-T1 nor (S)-T2 induced place conditioning or conditioned place aversion (CPA), suggesting the absence of rewarding or aversive effects. Both compounds significantly attenuated nicotine-induced CPP, with (S)-T1 exhibiting a dose-dependent effect. Furthermore, the co-administration of (S)-T2 (10 mg/kg) with nicotine markedly reduced locomotor activity compared to nicotine treatment alone. Additionally, dopamine analysis revealed that nicotine increased dopamine levels in the nucleus accumbens (NAc) and dorsal striatum, whereas the co-administration of (S)-T1 (1, 3, and 10 mg/kg) and (S)-T2 (10 mg/kg) significantly decreased dopamine levels in these brain regions. No significant effects were observed in the prefrontal cortex (PFC).

Conclusions: These findings suggest that (S)-T1 and (S)-T2 hold promise for treating nicotine addiction by attenuating nicotine-induced CPP and modulating dopamine release in key reward-related brain regions. Further research is needed to gain insights into the underlying mechanisms behind their anti-addictive effects and substantiate their potential for treating nicotine addiction.

Background: Previous studies have reported conflicting findings regarding the efficacy of esketamine in managing postoperative depression. While the positive effects of subanesthetic doses esketamine have been observed in treatment-resistant depression, the response to this medication in patients experiencing depression following surgery has not been consistent. Building upon the known impact of anesthesia on brain function, we have formulated a hypothesis suggesting that the timing of esketamine administration in relation to anesthesia may significantly affect its efficacy in managing postoperative depression. The aim of this study was to investigate the effect of esketamine administered at different time points before and after anesthesia.

Methods: Our randomized, double-blind, controlled study involved 120 patients undergoing laparoscopic bariatric surgery, randomly divided into three groups. Group Post- ESK received an intravenous injection of esketamine at a dose of 0.2 mg/kg after anesthesia induction. Group Pre- ESK received the same esketamine dosage 2 h prior to anesthesia induction. Group Placebo served as the control group and received a 0.9% saline solution after induction. The primary outcome measures of the study were depression scores as measured by Patient Health Questionnaire-9 (PHQ-9) and plasma brain-derived neurotrophic factor (BDNF) levels.

Results: On the first postoperative day, the PHQ-9 scores, incidence and severity of postoperative depression in the Pre-ESK group were significantly lower than those in the Post-ESK and placebo groups (P < 0.05). Additionally, plasma BDNF levels in the Pre-ESK group were significantly higher than those in the Post-ESK and placebo groups (P < 0.05). Notably, there was a negative correlation between PHQ-9 scores and plasma BDNF levels.

Conclusions: Our study supports the potential for subanesthetic dose esketamine to alleviate postoperative depression symptoms following laparoscopic bariatric surgery, and anesthetic drugs have a significant effect on its efficacy. The use of subanesthetic dose esketamine after anesthesia does not improve postoperative depression symptoms in patients undergoing laparoscopic bariatric surgery, while the use of sub-anesthetic dose esketamine before anesthesia can improve postoperative depression symptoms.

Rationale: Depression is a serious psychiatric disease, which is diagnosed twice as frequently in women than men. We have recently shown that lesioning or inactivation of the nucleus reuniens (RE), which interconnects the prefrontal cortex (PFC) and hippocampus, promoted resilience to stress in males, exerts an antidepressant effect in the Forced Swim Test (FST) and prevents the development of behavioral and neurobiological alterations induced by the chronic mild stress model of depression.

Objectives: In this study, we expand our findings on the FST in female rats and we investigate whether RE lesion presents sex differences following treatment with two distinct antidepressants, a selective serotonin reuptake inhibitor, i.e. sertraline and a tricyclic antidepressant, i.e. clomipramine.

Methods: Male and female rats received either a surgical lesion of the RE or sham operation, then treated with vehicle, sertraline (10mg/kg) or clomipramine (10mg/kg) and were subjected to the FST. Activation of key brain areas of interest (PFC, Hippocampus and RE) were measured by c-Fos immunoreactivity.

Results: RE lesion induced an antidepressant-like phenotype in both female and male rats, confirming its crucial role in the stress response. Similarly to RE lesion, sertraline treatment resulted in increased swimming and decreased immobility duration, as well as enhanced head shake frequency, in both sexes. Notably, climbing behavior was increased only following clomipramine treatment. RE area was less active in females compared to male rats and in clomipramine-treated males compared to their corresponding vehicle-group. Activation of the PFC and the CA1 hippocampal area was reduced in clomipramine-treated females, in comparison to vehicle-treated female rats. This effect was not evident in males, which exhibited less activation in the PFC and the hippocampus than females.

Conclusion: Re lesion proves equally effective in female and male rats, but sex is highlighted as a pivotal factor in behavioral and treatment response in FST, as well as in related circuit connectivity and activation.

Rationale: Major depression has been an area of extensive research during the last decades, for it represents a leading cause of disability and suicide. The stark rise of depression rates influenced by life stressors, economic threats, pandemic era, and resistance to classical treatments, has made the disorder rather challenging. Adult hippocampal neurogenesis and plasticity are particularly sensitive to the dynamic interplay between autophagy and inflammation. In fact, the intricate balance between the two processes contributes to neuronal homeostasis and survival.

Objectives: Having demonstrated promising potentials in AMPK activation, a major metabolic sensor and autophagy regulator, empagliflozin (Empa) was investigated for possible antidepressant properties in the reserpine rat model of depression.

Results: While the reserpine protocol elicited behavioral, biochemical, and histopathological changes relevant to depression, Empa outstandingly hindered these pathological perturbations. Importantly, hippocampal autophagic response markedly declined with reserpine which disrupted the AMPK/mTOR/Beclin1/LC3B machinery and, conversely, neuro-inflammation prevailed under the influence of the NLRP3 inflammasome together with oxidative/nitrative stress. Consequently, AMPK-mediated neurotrophins secretion obviously deteriorated through PKCζ/NF-κB/BDNF/CREB signal restriction. Empa restored hippocampal monoamines and autophagy/inflammation balance, driven by AMPK activation. By promoting the atypical PKCζ phosphorylation (Thr403) which subsequently phosphorylates NF-κB at Ser311, AMPK successfully reinforced BDNF/CREB signal and hippocampal neuroplasticity. The latter finding was supported by hippocampal CA3 toluidine blue staining to reveal intact neurons.

Conclusion: The current study highlights an interesting role for Empa as a regulator of autophagic and inflammatory responses in the pathology of depression. The study also pinpoints an unusual contribution for NF-κB in neurotrophins secretion via AMPK/PKCζ/NF-κB/BDNF/CREB signal transduction. Accordingly, Empa can have special benefits in diabetic patients with depressive symptoms.

Limitations: The influence of p-NF-κB (Ser311) on NLRP3 inflammasome assembly and activation has not been investigated, which can represent an interesting point for further research.

Rationale and objective: Rodents acquire food information from their conspecifics and display a preference for the conspecifics' consumed food. This social learning of food information from others promotes the survival of a species, and it is introduced as the socially transmitted food preference (STFP) task. The cholinergic system in the basal forebrain plays a role in the acquisition of STFP. Cannabidiol (CBD), one of the most abundant phytocannabinoids, exerts its therapeutic potential for cognitive deficits through versatile mechanisms of action, including its interaction with the cholinergic system. We hypothesize a positive relationship between CBD and STFP because acetylcholine (ACh) is involved in STFP, and CBD increases the ACh levels in the basal forebrain.

Materials and methods: Male C57BL/6J mice were trained to acquire the STFP task. We examined whether CBD affects STFP memory by administering CBD (20 mg/kg, i.p.) before the STFP social training. The involvement of cholinergic system in CBD's effect on STFP was examined by knockdown of brain acetylcholinesterase (AChE), applying a nonselective muscarinic antagonist SCO (3 mg/kg, i.p.) before CBD treatment, and measuring the basal forebrain ACh levels in the CBD-treated mice.

Results: We first showed that CBD enhanced STFP memory. Knockdown of brain AChE also enhanced STFP memory, which mimicked CBD's effect on STFP. SCO blocked CBD's memory-enhancing effect on STFP. Our most significant finding is that the basal forebrain ACh levels in the CBD-treated mice, but not their control counterparts, were positively correlated with mice's STFP memory performance.

Conclusion: This study indicates that CBD enhances STFP memory in mice. Specifically, those which respond to CBD by increasing the muscarinic-mediated ACh signaling perform better in their STFP memory.

Rationale: Cannabidiol (CBD) is increasingly used as a sleep aid for insomnia; yet neurocognitive and subjective state effects following daily therapeutic use are unclear.

Objectives: To measure the effect of daily CBD use on neurocognitive performance and daily subjective mood in a population with primary insomnia.

Methods: This study used a randomized, placebo-controlled, parallel design incorporating a single-blind placebo run-in week followed by a two-week double-blind dosing period, during which participants consumed 150 mg CBD (N = 15) or placebo (N = 15) sublingually 60-minutes daily before bed. Attention, executive function, reasoning, information processing, working and episodic memory were assessed using the CogPro system at the beginning of the placebo run-in, after 1-week and 2-weeks of dosing. Subjective states using visual analogue scales and side effects were recorded daily.

Results: Cognitive performance was unaffected by nightly CBD supplementation (all p > 0.05). From baseline to trial conclusion, those receiving CBD reported greater experience of calmness, clear-headedness, coordination and were more likely to report side-effects of dry mouth relative to placebo (all p < 0.05).

Conclusions: Relative to placebo, daytime cognitive functioning following nightly supplementation as a therapeutic aid for primary insomnia was preserved under trial conditions. Results suggested an overall favourable safety profile, with larger controlled trials and thorough analyses of varying insomnia phenotypes necessary to corroborate these findings.

Rationale: The accumulation of beta-amyloid peptide (Aβ) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer's disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aβ toxicity. Recent research has demonstrated that intrahippocampal Aβ can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer's disease.

Objectives: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus.

Methods: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ_1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice.

Results: The mice that received Aβ_1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ_1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ_1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups.

Conclusions: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ_1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.