Psychopharmacology最新文献

Rationale: That exaggerated production of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia is well-documented. Therefore, compounds that can adjust nitrergic activity such as NO synthase (NOS) inhibitors might be useful for the treatment of schizophrenia.

Objectives: The purpose of the current study was to investigate in the rat the ability of the neuronal NOS (nNOS) inhibitor 7-nitroindazole (7-NI) in counteracting schizophrenia-like-deficits caused by blockade of the N-methyl-D-aspartate (NMDA) receptor.

Methods: 7NI's capacity to attenuate social withdrawal, disruption of emotional and recognition memory induced by NMDA receptor antagonists, namely ketamine and MK-801, were evaluated using the social interaction, the step-through passive avoidance, the object recognition and the object location tests. The efficacy of the joint administration of sub-threshold doses of 7-NI with those of the atypical neuroleptics clozapine and risperidone in attenuating recognition memory deficits induced by ketamine was also tested.

Results: 7-NI (1 and 3 mg/kg) alleviated social withdrawal caused by ketamine (8 mg/kg), abolished emotional memory impairments caused by MK-801 (0.1 mg/kg) and counteracted ketamine (3 mg/kg)-induced recognition memory deficits. Finally, co-administration of inactive doses of 7-NI (0.1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) reduced the detrimental effects of ketamine (3 mg/kg) on recognition memory.

Conclusions: The present results indicate that 7-NI is sensitive to glutamate blockade since it decreased behavioural impairments resembling the negative symptoms and cognitive deficits of schizophrenia. Moreover, these findings corroborate the potential of 7-NI as an adjunctive molecule for the medication of schizophrenia.

Rational: Rodent EEGs display 7-12 Hz oscillations called spike-wave discharges (SWDs) that are more abundant with age, and some data suggest that they might interfere with hippocampus-dependent memory processing.

Objective: To test whether SWD activity contributes to the memory decline reported in aged rats.

Methods: Spatial learning was assessed in young and aged Long-Evans (LE) rats using a water maze protocol where aged rats display substantial interindividual variability in hippocampus-dependent memory. We then collected 24 h EEG data to quantify SWD incidence and duration among young and aged animals. Lastly, we took a pharmacological approach to test the efficacy of two antiepileptic drugs-levetiracetam and ethosuximide-at reducing SWD activity.

Results: We found that SWDs were significantly more frequent in aged rats than young, but entirely unrelated to between-subject differences in cognitive outcome. Age-dependent increases in SWD frequency were also insensitive to levetiracetam at doses known to reverse memory impairment in aged rats, but potently inhibited by the other antiepileptic drug, ethosuximide, that functions through a different mechanism of action.

Conclusion: Together these findings provide evidence that the disrupted excitatory/inhibitory balance associated with individual differences in cognitive aging is unrelated to the SWD increase seen in aged rats.

Rationale: High levels of stress and acute stress responses are significant predictors of chronic illnesses; however, specific stress response components of resilience and healthy coping are not well understood.

Objectives: To develop and assess a pain stress test (Yale Pain Stress Test - YPST) involving three uncontrollable and unpredictable consecutive 3-minute trials of pain-stress (0 °C ice + water) or no pain-stress control (37 °C warm water) hand immersion conditions, adapted from the Cold Pressor Task (CPT).

Methods: Fifty men and women participated in a within-subjects experiment. Repeated autonomic [pulse, systolic and diastolic blood pressure (SBP/DBP)], hypothalamic pituitary adrenal (HPA) axis (cortisol, ACTH) and subjective stress (self-reported pain, anxiety) measures during the pre-stress baseline, acute reactivity and return to homeostasis/recovery time periods were collected. Behavioral pain tolerance per trial (in seconds) was also assessed.

Results: Robust multi-level stress responses were observed (p's < 0.009), with sex-specific interactions only for SBP, DBP and pain ratings. Greater reactivity in SBP, DBP, cortisol, and Cortisol/ACTH ratio predicted higher behavioral pain tolerance (p's < 0.038), and higher DBP predicted lower pain during recovery in the pain-stress condition (p < .028). Higher SBP, DBP, Cortisol, and ACTH reactivity in pain-stress but not control predicted lower basal anxiety during recovery (p's < 0.004).

Conclusion: These findings indicate robust multi-level stress responses with YPST provocation, that were also significantly related to behavioral pain tolerance and subjective distress and recovery. The results suggest that acute physiological stress responses play a role in stress adaptability and resilient coping, but replication in larger samples and in individuals suffering from stress-related illnesses is warranted.

Rationale: Preclinical and clinical findings support the potential for GLP-1 receptor activation to reduce alcohol consumption and reward. Human experimental studies are needed to clarify whether acute changes in endogenous GLP-1 influence alcohol craving and responses to alcohol. Dietary stimulation may present a method to study the effects of endogenous GLP-1 on responses to alcohol.

Objectives: Assess the effects of a dietary manipulation on acute changes in GLP-1 and laboratory responses to alcohol.

Methods: Healthy young adult heavy drinkers (N = 40) were recruited to participate in two study visits where they received a dietary supplement designed to increase endogenous GLP-1 or a calorically matched placebo in counterbalanced order. Blood was sampled before and 40 min after supplement or placebo administration to measure changes in plasma GLP-1. Subjective effects, craving, and alcohol attentional bias were measured in response to a priming drink of alcohol (target BAC 30 mg%).

Results: Compared to placebo, dietary supplement preload significantly increased blood GLP-1 concentration, β = 0.79, p < 0.001, and significantly reduced alcohol attentional bias, β = -0.56, p = 0.010. Blood GLP-1 concentration correlated with the magnitude of alcohol attentional bias reduction after supplement preload (r = -0.30). There were no significant effects of the manipulation on subjective responses or craving.

Conclusions: Results suggest that dietary stimulation may reduce the incentive motivational properties of alcohol-related cues, potentially through increases in endogenous GLP-1, absent effects on self-report measures of alcohol subjective response or craving. Acute changes in circulating GLP-1 may influence implicit motivation for alcohol.

Rationale and objective: Buprenorphine is an FDA-approved medication for opioid addiction, but the brain regions underlying its therapeutic effects remain unknown. We previously found that chronic buprenorphine treatment decreases several relapse-related behaviors in rats. Here, we tested whether chronic buprenorphine decreases the time-dependent increase (incubation) in heroin seeking during abstinence. We also used the activity marker Fos to test whether buprenorphine's inhibition of incubation of heroin seeking is associated with decreased activation of cortical and striatal regions.

Methods: We trained Oprm1-Cre rats and their wild-type littermates to self-administer heroin for 12 days (6 h/day). On abstinence Day 1, we tested for heroin seeking under extinction conditions. On Day 14, we implanted osmotic minipumps containing saline or buprenorphine (6 mg/kg/day). On abstinence Days 21-22, we tested the rats (or not tested, baseline condition) for incubation of heroin seeking, after which brains were collected for Fos immunohistochemistry.

Results: Oprm1-Cre rats did not differ from wild-type littermates in heroin self-administration or 'non-incubated' heroin seeking on abstinence Day 1. In both genotypes, chronic buprenorphine decreased incubated heroin seeking on Days 21-22. Buprenorphine also decreased incubation-related neuronal activation in several cortical areas (cingulate cortex 1 and dorsal peduncular, but not prelimbic, infralimbic, or orbitofrontal cortex) and striatal areas (dorsolateral and dorsomedial striosomes and nucleus accumbens core, but not shell).

Conclusions: Chronic buprenorphine decreased incubation of heroin seeking, supporting the predictive validity of the rat model. This effect was associated with decreased neuronal activity in specific subregions of the medial prefrontal cortex and striatum.

Rationale: Binge drinking during adolescence is associated with a higher risk of developing Alcohol Use Disorders and impaired stress reactivity in adulthood. The hypothalamic-pituitary-adrenal axis matures during adolescence and is under strict GABAergic control. Yet, how early binge drinking alters GABAergic signaling in this region, and whether these changes contribute to later-life disruptions in stress reactivity, remain unknown.

Objectives: Our goal with these set of experiments was to test the hypothesis that adolescent binge drinking would impair maturation of GABAergic signaling in the paraventricular nucleus (PVN) and lead to aberrant behavioral and neuroendocrine stress reactivity.

Methods: Adolescent male and female C57BL/6J mice were given access to 20% ethanol or tap water under Drinking in the Dark-Multiple Scheduled Access paradigm from PD28 to PD42 and went through abstinence until adulthood. At adulthood (PD60+), the behavioral and endocrine response to two stressors, forced swim stress and social defeat stress, were evaluated.

Results: Only females with a history of adolescent drinking showed abnormal behavioral reactivity to stress, with increased immobility in the forced swim stressor task. Females with a history of adolescent binge drinking displayed a hypo-corticosterone response after social stress and males showed delayed negative feedback to the forced swim stressor. PVN-enriched tissue from these mice showed no changes in transcription of Gabrg2, but males showed a significant increase in expression of Slc12a5, which encodes for the chloride potassium co-transporter, KCC2. These males showed no change in KCC2 protein when evaluated by immunohistochemistry.

Conclusions: Taken together, these data show that adolescent binge drinking in pair-housed mice is associated with male-specific potential vulnerability in hypothalamic inhibitory signaling and disrupted adult stress reactivity in a sex- and stressor- dependent manner.

Rationale: Tobacco dependence is characterized by a high relapse rate. It is thus important to obtain a better understanding of the cognitive precipitants of smoking relapses, and how these are changed under tobacco deprivation. Here, we provide evidence that tobacco deprivation impairs two cognitive processes important for successful smoking cessation: metacognition and cognitive flexibility.

Methods: In a pre-registered study following a within-subject design, persons who regularly smoke performed behavioral tasks measuring metacognition, motivation for mental effort, cognitive flexibility, and smoking lapses either in saturated or deprived states.

Results: We found that tobacco deprivation not only increased the preference for immediate rewards but also impaired metacognitive knowledge about these preferences; strikingly, these metacognitive skills were moreover related to individual lapse behavior. While there was no evidence for deprivation effects on mental effort, tobacco deprivation also impaired the ability to overcome dysfunctional cue-reward associations, indicating deficits in cognitive flexibility.

Conclusions: Taken together, the current findings deepen our understanding of how tobacco deprivation alters cognitive processes contributing to addictive behaviors in tobacco dependence, which may lead to improved interventions for smoking cessation.

Background: The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders.

Objectives: This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice.

Methods: Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated.

Results: Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB.

Conclusion: 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.

Background: Childhood trauma is associated with positive subjective responses to acute opioids in the laboratory. Yet, its impact on behavioural economic demand for opioids remains unclear. Because demand can predict future use and misuse, we investigated whether individuals with childhood trauma also display greater demand for opioids in the laboratory.

Methods: This secondary analysis used data from a double-blind, randomised, controlled, counterbalanced trial. Across two sessions, individuals with (n = 26) and without (n = 21) childhood trauma received a high (0.15 mg/kg) and low (0.01 mg/kg) dose of intramuscular morphine 120 min before a hypothetical purchase task. Participants also regularly reported their subjective desire for the study drug. Area under the consumption and expenditure curves, and specific demand indices (O_max, P_max, breakpoint, intensity, elasticity), were analysed with non-parametric mixed models.

Results: Consumption and expenditure for low dose morphine was lower in the childhood trauma group when compared to high dose morphine in this group, and low dose morphine in the control group (ps ≤ 0.03). Consistent results were obtained for specific demand indices O_max, P_max, and breakpoint, but not intensity or elasticity. Positive correlations between subjective desire and consumption and expenditure were only observed in the childhood trauma group (Tau-c = 0.24-0.34, ps ≤ 0.03).

Conclusion: Under laboratory conditions, desires to use opioids among individuals with childhood traumas may not manifest in strong intentions to acquire these drugs. Diverging results from psychometric measures of subjective and economic opioid value highlight the need for future research to explore contextual and resilience factors to understand how problematic opioid use emerges after childhood traumas.

Rationale: Psychiatric disorders are a largely elusive aspect of obesity, representing a growing public health concern. In this regard, a large body of evidence indicates a pivotal role of disturbed autophagic flux in the pathogenesis of obesity-associated neuropsychiatric deficits.

Objectives: This work was designed to evaluate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, which is increasingly utilized for the management of chronic obesity, on the depressive/cognitive deficits in the high-fat diet (HFD) rat model of obesity with an emphasis on its hippocampal mechanistic backgrounds.

Methods: The effects of chronic liraglutide administration (subcutaneous; 300 µg/kg/day for 28 days) were investigated on depressive-like phenotypes, cognitive deficits, and hippocampal phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)-regulated autophagy.

Results: Chronic liraglutide treatment amended the HFD-induced depressive-like phenotype (in the sucrose preference and the forced swimming tests) and cognitive deficits (in the Morris water maze test). Moreover, liraglutide enhanced the hippocampal expression of brain-derived neurotrophic factor (BDNF), PI3K, Akt, p-Akt, and p-mTOR and downregulated the expression of the autophagic markers (Beclin-1, LC3) and the inflammatory markers (TNF-α, IL-6) with amelioration of HFD-induced hippocampal neurodegeneration.

Conclusions: This work highlights the antidepressant and pro-cognitive properties of liraglutide in HFD-exposed rats, which could be mediated through amelioration of the disrupted PI3K/Akt/mTOR signaling activity with a possible impedance of the exaggerated autophagy-mediated neurodegenerative cascades. Indeed, this study highlights that liraglutide is not only effective in weight control, but its effects also extend to managing obesity-related psychiatric disorders.