Pharmacology Biochemistry and Behavior最新文献

Understanding the reasons why people consume alcohol is a critical health issue. Alcohol produces a variety of effects, including a reduction in stress or negative emotional states termed an anxiolytic effect. The anxiolytic effect of alcohol is an often-reported reason for why people begin consuming the drug. However, several factors concerning the stress-reducing effect of alcohol need to be investigated. For example, research has demonstrated that both age and sex are factors that impact alcohol's anxiolytic effect producing differential outcomes in aged female rats compared to aged male rats. In light of these findings, the current commentary highlights critical questions in need of research with the goal of better understanding how age and sex interact to influence the anxiolytic effect of alcohol. For example, the central nucleus of the amygdala has been identified as a critical brain region mediating the anxiolytic effect of drugs, but additional research is needed to understand how aging alters the neurological functioning of the central nucleus of the amygdala in both females and males. Furthermore, specific receptor isoforms, such as GABA_A receptor α2, have been shown to be critical for anxiolysis and understanding how aging and sex alter receptor isoform expression by brain region is needed. Finally, age and sex interact to alter allopregnanolone levels in brain and differential neurosteroid levels may mediate alcohol's unique anxiolytic effect in aged female rats compared to aged male rats. Given the increasing age of the population in most countries and the increasing alcohol consumption levels in females compared to males, investigating the interaction of sex and age on alcohol's anxiolytic effect has great promise to discover critical answers to what are currently unasked questions.

Anxiety disorders are characterized by intense feelings of worry and fear, which can significantly interfere with daily functioning. Current treatment options primarily include selective serotonin reuptake inhibitors, benzodiazepines, non-benzodiazepine anxiolytics, gabapentinoids, and beta-blockers. Neuropeptides have shown an important role in the regulation of complex behaviours, such as psychopathology and anxiety-related reactions. Neuropeptides have a great deal of promise to advance our understanding of and ability to help people with anxiety disorders. This review focuses on the expanding role of neuropeptides in anxiety management, particularly examining the impact of substance P, neuropeptide Y, corticotropin-releasing hormone, arginine-vasopressin, pituitary adenylate cyclase-activating polypeptide, and cholecystokinin. Furthermore, the paper discusses the neuropeptides that are becoming more and more recognized for their impact on anxiety-related reactions and their potential as therapeutic targets.

Anxiety disorders represent one of the most common and debilitating illnesses worldwide. However, the development of novel therapeutics for anxiety disorders has lagged compared to other mental illnesses. A growing body of research suggests the gut microbiota plays a role in the etiopathology of anxiety disorders and may, therefore, serve as a novel target for their treatment through the use of probiotics. The use of dietary supplements like probiotics is increasing and their interaction with pharmacotherapies is not well understood. Utilizing the chick social-separation stress test, the primary aim of this study was to evaluate the commercially-available multi-strain probiotic found in VSL#3 for potential anxiolytic-like and/or antidepressant-like effects in the stress-vulnerable Black Australorp genetic line. A secondary aim was to evaluate the interaction between probiotics and the SSRI fluoxetine. Animals were treated with either saline, probiotics, fluoxetine, or probiotics + fluoxetine for 8 days prior to exposure to a 90-min isolation stressor that produces both a panic-like (i.e., anxiety-like) state followed by a state of behavioral despair (i.e., depression-like). The 8-day probiotic regimen produced anxiolytic-like effects but did not attenuate behavioral despair. Fluoxetine failed to significantly alter behavior in either of the two phases. Moreover, the combination of fluoxetine with probiotics attenuated the anxiolytic-like effects of probiotics. The fluoxetine + probiotics combination had no effect on behavioral despair. The results of the current study align with other preclinical studies and some clinical trials suggesting probiotics may offer beneficial effects on anxiety. Investigations examining the anxiolytic-like mechanism of probiotics are needed before any conclusions can be made. Additionally, as the use of probiotics becomes more popular, research on the interactions between probiotic-microbiota and psychotropic medications is necessary.

Substance Use Disorder (SUD) has been conceptualized as an outcome of a dysregulated reward system. However, individuals with SUD suffer from anxiety with an intensity depending on the abstinence period length. This review discusses the role of anxiety as a major contributor to the initiation and perpetuation of SUD, and its dependence on an up-regulated defense-antireward system. In addition, it is discussed that sleep debt, and its psychosocial consequences, promote anxiety, contributing to SUD generation and maintenance. Healthy sleep patterns can be disrupted by diverse medical conditions and negative psychosocial interactions, resulting in accumulated sleep debt and anxiety. Within this narrative review, we discuss the interplay between the motivation-reward and defense-antireward systems, framing the progression from recreational drug use to addiction. This interplay is nuanced by sleep debt-induced anxiety and its psychosocial consequences as contributory vulnerability factors in the genesis of addiction.

The sex of the patient often affects the prevalence, progression, and severity of many psychiatric disorders. The incidence, progression, and severity of Parkinson's disease and Alzheimer's disease, the most common neurodegenerative diseases, also differ between the sexes. Sex differences in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and anxiety are also observed in tuberous sclerosis complex (TSC). Neuropsychiatric symptoms are one of the most important manifestations of TSC, and the multiple neuropsychiatric symptoms are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). We created TSC model mice (Tsc2 conditional knockout [cKO] mice) that developed epilepsy and TAND. Sex-based differences were observed for hyperactivity and cognitive dysfunctions in Tsc2 cKO mice with TAND, indicating more severe symptoms in female mice than in male mice. TSC is thought to be caused by the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), and mTORC1 inhibitors improve almost all TSC symptoms. Treatment with sirolimus, an mTORC1 inhibitor, improved TAND in Tsc2 cKO mice. We aimed to elucidate the mechanism underlying sex-based differences in TAND using Tsc2 cKO mice and sirolimus. We found that estradiol (E2) and estrogen receptor (ER)α are involved in sex differences in neuropsychiatric symptoms, and discovered a novel function of sirolimus. We showed that sirolimus ameliorated TAND by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. This indicates sirolimus may be beneficial for the treatment of TAND as well as diseases caused by sex-based differences and steroid levels.

Second-generation antipsychotics are frequently prescribed to adolescents, but the long-term consequences of their use remain understudied. These medications work via monoamine neurotransmitter systems, especially dopamine and serotonin, which undergo considerable development and pruning during adolescence. Dopamine and serotonin are linked to a wide host of behaviors, including impulsive choice and behavioral plasticity. In a murine model of adolescent antipsychotic use, male C57BL/6 mice were exposed to either 2.5 mg/kg/day risperidone or 5 mg/kg/day olanzapine via drinking water from postnatal days 22–60. To determine whether the adolescent period was uniquely sensitive to antipsychotic exposure, long-term effects on behavior were compared to an equivalently exposed group of adults where mice were exposed to 2.5 mg/kg risperidone from postnatal days 101–138. Motor activity and body weight in adolescent animals were assessed. Thirty days after exposure terminated animal's behavioral flexibility and impulsive choice were assessed using spatial discrimination reversal and delay discounting. Antipsychotic exposure produced a modest change in behavior flexibility during the second reversal. There was a robust and reproducible difference in impulsive choice: exposed animals devalued the delayed alternative reward substantially more than controls. This effect was observed both following adolescent and adult exposure, indicating that an irreversible change in impulsive choice occurs regardless of the age of exposure.

Background

One of the reasons for tolerance to morphine is increased oxidative stress and dysfunction of cell mitochondria in the hippocampus. Venlafaxine and calcium channel blockers can protect mitochondrial function. The investigation of the role of mitochondrial damage and oxidative stress in the simultaneous use of venlafaxine and calcium channel blockers on the acute analgesic effects of morphine and the induction of tolerance to its effects in mice was assessed.

Method

In this experimental study, to induce tolerance to morphine, NMRI mice were treated with 50 mg/kg morphine for three consecutive days and 5 mg/kg morphine on the fourth day. Venlafaxine (20 mg/kg) alone or in combination with calcium channel blockers, nimodipine (10 mg/kg), and diltiazem (40 mg/kg) was administered 30 min before morphine, and the hot plate test was used. Then, hippocampal mitochondria were isolated by differential centrifugation method, and the levels of mitochondrial dehydrogenase activity, mitochondrial membrane potential, mitochondrial ROS production rate, as well as the content of glutathione and malondialdehyde in hippocampal mitochondria, were measured.

Results

The administration of venlafaxine-nimodipine and venlafaxine-diltiazem increased morphine's acute analgesic effects (P < 0.05) and reduced the induction and expression of tolerance to the analgesic effects of morphine (P < 0.05). Morphine significantly decreased MTT and GSH and increased MDA, mitochondrial membrane damage, and ROS compared to the control group (P < 0.01). Injection of venlafaxine-nimodipine and also venlafaxine-diltiazem 30 min before morphine can improve these alterations (P < 0.05).

Discussion and conclusion

Our data showed that the simultaneous use of venlafaxine with calcium channel blockers could increase the acute analgesic effects of morphine and reduce the induction and expression of tolerance to it. Also, the preventive and protective roles of simultaneous administration of venlafaxine and calcium channel blockers on morphine-induced mitochondrial oxidative stress and damage during the tolerance test were achieved.