Pharmacology Biochemistry and Behavior最新文献

mGlu2/3 Receptors (LY354740) in Anxiety mGlu2/3 receptors when activated decrease glutamate excitation on limbic synapses involved in anxiety. The orally active agonist compound LY354740 (or prodrug LY544344) was active in animal and human models of stress/anxiety. Later clinical studies showed efficacy in generalized anxiety in patients, validating this mechanism clinically. However, the compound was terminated due to rodent seizures in long-term toxicology studies.

Current medications for panic disorder each carry significant limitations that indicate the need for novel anxiolytics. The high costs and low success rates of drug development demand that testing trials be efficient. Lab panicogenic challenges in humans allow for the rapid biochemical induction of panic symptoms and hence an efficient means of testing potential anti-panic drugs. This paper describes ideal characteristics of lab panicogens, reviews the validity and utility of various biochemical panicogenic agents, identifies key outcome measures for studies of novel anti-panic drugs, and makes broad recommendations for labs wishing to perform such studies. We conclude by presenting a four-tiered hierarchy of panicogens that matches each against ideal characteristics and reflects our recommendations for their laboratory use.

Most cases of anxiety are currently treated with either benzodiazepines or serotonin reuptake inhibitors. These drugs carry with them risks for a multitude of side effects, and patient compliance suffers for this reason. There is thus a need for novel anxiolytics, and among the most compelling prospects in this vein is the study of the TAARs. The anxiolytic potential of ulotaront, a full agonist at the human TAAR1, is currently being investigated in patients with generalized anxiety disorder. Irrespective of whether this compound succeeds in clinical trials, a growing body of preclinical literature underscores the relevance of modulating the TAARs in anxiety. Multiple behavioral paradigms show anxiolytic-like effects in rodents, possibly due to increased neurogenesis and plasticity, in addition to a panoply of interactions between the TAARs and other systems. Crucially, multiple lines of evidence suggest that the TAARs, particularly TAAR1, TAAR2, and TAAR5, are expressed in the extended amygdala and hippocampus. These regions are central in the actuation of anxiety, and are particularly susceptible to neurogenic and neuroplastic effects which the TAARs are now known to regulate. The TAARs also regulate the dopamine and serotonin systems, both of which are implicated in anxiety. Ligands of the TAARs may thus constitute a new class of anxiolytics.

Purpose

For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT_2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT_2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat.

Methods

Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography.

Results

DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP.

Conclusions

DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.

Adolescence is a critical period for social experience-dependent oligodendrocyte maturation and myelination. Adolescent stress predisposes to cause irreversible changes in brain structure and function with lasting effects on adulthood or beyond. However, the molecular mechanisms linking adolescent social isolation stress with emotional and social competence remain largely unknown. In our study, we found that social isolation during adolescence leads to anxiety-like behaviors, depression-like behaviors, impaired social memory and altered patterns of social ultrasonic vocalizations in mice. In addition, adolescent social isolation stress induces demyelination in the prefrontal cortex and hippocampus of mice, with decreased myelin-related gene expression and disrupted myelin structure. More importantly, clemastine was sufficient to rescue the impairment of emotional and social memory by promoting remyelination. These findings reveal the demyelination mechanism of emotional and social deficits caused by social isolation stress in adolescence, and provides potential therapeutic targets for treating stress-related mental disorders.

Schizophrenia impacts about 1 % of the global population, with clozapine (CLZ) being a critical treatment for refractory cases despite its limitations in effectiveness and adverse effects. Therefore, the search for more effective treatments remains urgent. Light treatment (LT) recognized for enhancing cognition and mood, presents a promising complementary approach. This study investigated the effects of CLZ and LT on cognitive impairments in a sub-chronic MK-801 induced schizophrenia mouse model. Results showed that both CLZ and CLZ + LT treatment elevate cognitive performance of sub-chronic MK-801 treated mice in serial behavioral tests over two months. Histological analysis revealed increased dendritic spine density and branching, and synaptic repair in the hippocampus with CLZ and CLZ + LT interventions. Furthermore, both treatments increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus, likely contributing to cognitive amelioration in MK-801 treated mice. Additionally, BrdU labeling revealed that CLZ + LT further enhances neurogenesis in the dentate gyrus (DG) and lateral ventricle (LV) of sub-chronic MK-801 treated mice. These findings may have implications for the development of noninvasive and adjunctive treatment strategies aimed at alleviating cognitive impairments and improving functional outcomes in individuals with schizophrenia.

Abstract

The volatile compound 2,4,5-trimethylthiazoline (TMT, a synthetic predator scent) triggers fear, anxiety, and defensive responses in rodents that can outlast the encounter. The receptor systems underlying the development and persistence of TMT-induced behavioral changes remain poorly characterized, especially in females. Kappa opioid receptors regulate threat generalization and fear conditioning and alter basal anxiety, but their role in unconditioned fear responses in females has not been examined. Here, we investigated the effects of the long-lasting kappa opioid receptor antagonist, nor-binalthorphinmine dihydrochloride (nor-BNI; 10 mg/kg), on TMT-induced freezing and conditioned place aversion in female mice. We also measured anxiety-like behavior in the elevated plus maze three days after TMT and freezing behavior when returned to the TMT-paired context ten days after the single exposure. We found that 35$\mathrm{\mu l}$ of 10 % TMT elicited a robust freezing response during a five-minute exposure in female mice. TMT evoked persistent fear as measured by conditioned place aversion, reduced entries into the open arm of the elevated plus maze, and increased general freezing behavior long after TMT exposure. In line with the known role of kappa-opioid receptors in threat generalization, we found that kappa-opioid receptor antagonism increased basal freezing but reduced freezing during TMT presentation. Together, these findings indicate that a single exposure to TMT causes long-lasting changes in fear-related behavioral responses in female mice and highlights the modulatory role of kappa-opioid receptor signaling on fear-related behavioral patterns in females.

This report evaluates the effects of chlordiazepoxide, a benzodiazepine commonly prescribed to manage anxiety-related disorders in adolescent/pediatric populations, on elevated plus maze (EPM) performance in juvenile mice. This approach was taken because chlordiazepoxide produces anxiolytic-like effects in multiple models in adult rodents, however, less is known about the behavioral effects of this benzodiazepine in juveniles. Thus, we administered a single intraperitoneal injection of chlordiazepoxide (0, 5, or 10 mg/kg) to postnatal day 35 male C57BL/6 mice. Thirty minutes later, mice were allowed to explore the EPM for 5-min. We found that chlordiazepoxide-treated mice (5 and 10 mg/kg) spent more time exploring the open arms of the EPM. No differences in velocity (cm/s) or distance traveled (cm) were observed between the groups. These results indicate that chlordiazepoxide induces anxiolytic-related behavior in adolescent male mice.

Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in stress-induced sensitization (SIS) of behavioral responses, in which a particular stressor triggers a state of hyper-responsiveness to other stressors after an incubation period, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents SIS; blocking NOS-2 90 min after stress also prevents stress-induced sensitization, as does blocking calcium-activated potassium channels in this latter time window. Stress-induced sensitization is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce stress-induced sensitization.