Pharmacology Biochemistry and Behavior最新文献

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.

Despite the rising prevalence of autism spectrum disorder (ASD), there remains a significant unmet need for pharmacotherapies addressing its core and associative symptoms. While some atypical antipsychotics have been approved for managing associated irritability and aggression, their use is constrained by substantial side effects. This study aimed firstly to develop behavioral measures to explore frustration, irritability and aggression phenotypes in the rat prenatal valproic acid (VPA) model of ASD. Additionally, we investigated the potential of two novel mechanisms, 5-HT_1B and TAAR1 agonism, to alleviate these behaviors. Male offspring exposed to prenatal VPA were trained to achieve stable performance on a cued operant task, followed by pharmacological assessment in an operant frustration test, bottle brush test and resident intruder test. VPA exposed rats demonstrated behaviors indicative of frustration and irritability, as well as increased aggression compared to controls. The irritability-like behavior and aggression were further exacerbated in animals previously experiencing a frustrative event during the operant test. Single administration of the 5-HT_1B agonist CP-94253 or TAAR1 agonist RO5263397 attenuated the frustration-like behavior compared to vehicle. Additionally, both agonists reduced irritability-like behavior under both normal and frustrative conditions. While CP-94253 reduced aggression in the resident intruder test under both conditions, RO5263397 only produced effects in rats that previously experienced a frustrative event. Our study describes previously uncharacterized phenotypes of frustration, irritability, and aggression in the rat prenatal VPA model of ASD. Administration of selective TAAR1 or 5-HT_1B receptor agonists alleviated these deficits, warranting further exploration of both targets in ASD treatment.

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 μg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation.

Anxiety is a part of the human condition and has been managed by psychoactive substances for centuries. The current medical need and societal demand for anxiolytic medicines has not abated. The present overview provides a brief historical introduction to the discovery of modern age anxiolytics that include the benzodiazepines together with a discussion of the continuing medical need for new antianxiety medications. The paper also discusses the use and impact of behavioral pharmacology in the preclinical development of anxiolytics. The review then highlights the diversity of mechanisms for creating a new generation of anxiolytics through mechanisms beyond the potentiation of GABA_A receptors and the blockade of monoamine uptake. A discussion then follows on the behavioral specificity of action of anxiolytics that includes the concept of creating an anxioselective drug, one that targets anxiety without producing untoward effects that include sedation and dependence. The use of anxiolytics in the treatment of other conditions such as substance use disorder is also briefly reviewed. Finally, a brief summary of the current status of anxiolytic drug development is provided. The review concludes with the idea that despite a host of anxiolytic drugs, the lack of efficacy in some patients and the side-effects and safety issues associated with some of these medications demands alternative medicines. Current preclinical and clinical research is ongoing with the goal of identifying such compounds.

Background

Tobacco-derived nicotine exposure is linked to depression. However, the associations of nicotine and its metabolites with symptoms of depression, particularly concerning gender differences, remain underexplored.

Methods

The characteristics and total nicotine equivalents (TNE) of 1001 subjects were determined. The association between the TNE and symptoms of depression, accounting for gender differences, was investigated using generalized linear models and subgroup analyses.

Results

Men exhibited significantly greater levels of the nicotine exposure indicators TNE2, TNE3, TNE6, and TNE7 (P < 0.005). A significantly greater percentage of women (23.45 %) than men (9.81 %) exhibited symptoms of depression (P < 0.0001). In women, the relationship between the TNE and depression was reflected by a U-shaped curve with significant inflection points, particularly for TNE3, TNE6, and TNE7. Furthermore, in women, concentrations above 48.98 nmol/mL for TNE3, 53.70 nmol/mL for TNE6, and 57.54 nmol/mL for TNE7 were associated with 154 %, 145 %, and 138 % increases in the risk of depression, respectively. In contrast, these associations did not reach significance among men.

Limitations

The cross-sectional design limits the ability to infer causality between nicotine exposure and depressive symptoms. Larger-scale studies are needed to confirm these findings.

Conclusions

Gender could be a significant factor influencing the relationship between nicotine exposure levels and symptoms of depression. The impact of nicotine exposure on symptoms of depression should be particularly considered among women.

Implications

This study revealed the complex relationship between tobacco-related nicotine exposure and depressive symptoms, with a particular focus on gender differences. Our results revealed a distinct U-shaped correlation between total nicotine equivalents and depression in women, which differed from that in men. These findings emphasize the importance of tailoring clinical approaches to address nicotine exposure and manage depressive symptoms based on gender.

Cannabis (CB) use and psychological stressors increase oxidative stress in the brain. Glutathione (GSH), the most abundant antioxidant in the brain, protects against oxidative stress. Furthermore, distress intolerance, the inability to tolerate psychological or physiological stress is a risk factor for CB use. The relationship between CB use, brain GSH levels and distress intolerance remains unknown. Therefore, we examined GSH levels in the anterior cingulate cortex (ACC), as a measure of oxidative stress, and its relationship with distress intolerance in adolescent CB users and healthy controls (HC).

Sixteen HC and 17 CB-using adolescents were included in the analysis. GSH levels were measured in the ACC using a metabolite-edited proton magnetic resonance spectroscopy sequence on a 3T scanner. Distress intolerance was assessed using the Distress Intolerance Index (DII) and CB use was evaluated using a structured clinical interview.

In the CB group, lower CSF-corrected GSH levels in the ACC were correlated with higher DII scores. However, no significant between group differences were observed for ACC CSF-corrected GSH levels or on DII scores. No significant correlations were observed in the HC group between GSH levels and DII.

Our findings suggests that the association between lower GSH levels and greater distress intolerance in CB users might reflect alterations in the balance between protective and oxidative stress conditions linked to the ability to tolerate distress. Further examination into this relationship can provide important insights into neurobiological correlates and risk factors associated with CB use to help inform preventive and treatment targets in the future.

Rationale

Although the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. Methods: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. Results: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. Conclusions: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed. To address this gap in the literature, this report utilized male and female Sprague Dawley rats to (1) evaluate the impact of the selective KOR agonist U50,488, on the performance of animals responding for sucrose pellets under a progressive ratio (PR) schedule and (2) determine the effects of the short-acting KOR antagonist LY2444296 alone and on U50,488 mediated reductions in PR performance. Overall, U50,488 5 mg/kg significantly reduced the breakpoint and number of rewards obtained by animals. This occurred in the absence of motor impairment and independent of evidence for satiation. LY2444296 did not alter PR performance when administered alone but effectively blocked the deficits induced by U50,488. To further delineate the behavioral alterations that underlie these reductions in responding, a more detailed analysis was conducted on PR performance in the first 15 min of the session, the period of time when animals obtained the most reinforcers. During this period, U50,488 increased the length of the post-reinforcement pause and reduced the running rate on PR schedules. These changes in behavior produced by acute activation of KORs are consistent with a reduction of effort-related motivation in rodents. These data contribute to the understanding of how KORs modulate motivation, which is critical to future efforts to evaluate performance in the context of stress and assess how KOR antagonists alleviate anhedonic behaviors associated with stress.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.