Psychopharmacology最新文献

Rationale: In previous work, a convergent transcriptomic approach strongly suggested a role for retinoic acid (RA) in controlling the emotion- and reward-related functions of the nucleus accumbens shell (NAcSh).

Objective: Here, we causally assess the role of NAcSh RA in controlling anxiety-, emotion-, and reward-related behavior in rats and explore cellular mechanisms that may underlie this phenotype.

Methods: Rats underwent bilateral knockdown of the retinoic acid synthesis enzyme Aldh1a1 in the NAcSh. Anxiety-related behavior was assessed using open-field exploration, elevated plus maze, and sucrose neophobia tests. Emotion-related behavior was assessed via sucrose preference, post-isolation social contact, and forced swim tests. Animals were subsequently allowed to self-administer fentanyl to assess reward- and frustration-related behavior. In parallel, electrophysiological testing of medium spiny neurons (MSNs) in the NAcSh was used to explore the role of RA in NAcSh cellular function.

Results: We observed an anxiety-vulnerable, depression-resilient phenotype in knockdown animals compared to controls. During operant tasks, knockdown animals took fewer fentanyl infusions during FR5 maintenance and showed decreased demand intensity in behavioral economics sessions. Finally, electrophysiological assessment of NAcSh MSNs revealed attenuated excitability following Aldh1a1 knockdown. Altogether, our findings reveal a key role for NAcSh RA signaling in determining emotional resilience and drug-taking, likely via decreased MSN excitability.

Conclusions: Our results posit the RA synthesis enzyme Aldh1a1 as a promising therapeutic target for depression-, frustration-, and addiction-associated disorders. This is the first report linking RA to frustrative nonreward, the NAcSh to operant frustration, and RA to fentanyl drug-taking behavior.

Background: Methamphetamine is a psychostimulant with significant public health implications. Chronic methamphetamine use is linked to profound dysregulation of the dopaminergic system, cognitive deficits, and psychiatric symptoms. While traditional experimenter administered "binge" dosing models reliably produce dopaminergic neurotoxicity, they fail to capture the volitional, drug intake characteristic of human methamphetamine use. Although self-administration paradigms better reflect human drug-taking behavior, they have yet to consistently reproduce the neurochemical deficits seen in the non-contingent models.

Methods: In this study, we employed a very long-access (96-h) methamphetamine self-administration model over eight weeks to evaluate whether contingent, volitional drug intake produces dopaminergic neurotoxicity. Male and female rats were given extended access to methamphetamine (0.06 mg/kg/infusion) for 96-h sessions weekly, with saline-yoked controls. Neurochemical analysis focused on striatal dopamine and metabolites to assess drug-induced alterations.

Results: Rats exhibited significant escalation in methamphetamine intake over eight weeks, with no sex differences in total intake. Importantly, striatal dopamine levels were significantly reduced in both male and female methamphetamine self-administering rats compared to saline-yoked controls, representing the first demonstration of dopamine depletion following voluntary administration methamphetamine self-administration. Dopamine depletion was significantly correlated with total methamphetamine intake. Interestingly, no significant changes were observed in dopamine metabolites (DOPAC, HVA).

Conclusions: These findings demonstrate that volitional methamphetamine intake under a 96-h access model induces robust dopaminergic deficits, paralleling those seen in non-contingent binge dosing. This model provides a translationally relevant paradigm, capturing both the behavioral and neurobiological aspects of human methamphetamine use, supporting its utility for investigating neurotoxicity and potential treatments.

Quercetin, a naturally occurring flavonoid, has been found to be a potential agent for the treatment of major depressive disorder (MDD), given the complexity of its interaction with the serotonin transporter (SERT). Clinically, quercetin has direct and indirect modulatory effects as opposed to conventional selective serotonin reuptake inhibitors (SSRI), which act mainly by inhibiting SERT after a time delay and communicate with SERT through possible binding location preferences and allosteric processing, while simultaneously controlling its definite expression through anti-inflammatory and antioxidant pathways, such as the NF-kB, AMPK/SIRT-1, and Nrf2-ARE cascades. These processes assist in modifying serotonergic neurotransmission and minimizing oxidative and inflammatory strains, which are the major contributors to the pathophysiology of depression. Quercetin positively affects neuroplasticity and regulates the gut-to-brain axis, which affirms its antidepressant effects. Preclinical evidence indicates that quercetin can cause more rapid and extensive effects than SSRIs. However, translation issues include poor bioavailability and interindividual variation. Future trials should focus on inflammatory markers and individual quercetin formulations to maximize therapeutic effects in the depressed state.

Rationale: Adolescent depression is often linked to biological changes associated with stress. However, new approaches and treatment strategies for early intervention and prevention of depression in children and adolescents are still limited. Ashwagandha is an Ayurvedic herb widely used in the management of anxiety and stress. However, there is no information in the current literature on its potential effect on adolescent depression.

Objectives: This study aimed to investigate the effects of depression on proapoptotic proteins and neuroinflammation and the antidepressant effect of Ashwagandha on depression-like symptoms in adolescent rats exposed to the Chronic Unpredictable Mild Stress (CUMS) model.

Methods: In the study, CUMS model was used to induce depression in adolescent rats. Rats were treated with Ashwagandha or Sertraline. To evaluate the antidepressant effects, behavioral tests as well as biochemical and histological analyses were performed. Forced Swim Test (FST), Sucrose Test and Elevated Plus Maze Test were performed as behavioral tests. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured by the ELISA method in the fronto-parietal cortex. Proapoptotic proteins (Bax and Caspase-3) and inflammatory markers (TNF-α and IL-1β), as well as glial fibrillary acidic protein (GFAP), were evaluated immunohistochemically in the fronto-parietal cortex.

Results: Proapoptotic proteins (Bax and Caspase-3) and inflammatory markers (TNF-α and IL-1β) were increased in the CUMS group. BDNF and GFAP levels were decreased. Ashwagandha treatment was more effective than Sertraline in reducing the levels of these proteins and markers. Additionally, Ashwagandha prevented weight loss.

Conclusions: Ashwagandha showed antidepressant-like effects in adolescent rats, reducing apoptosis, inflammation, and neuroinflammation, suggesting potential for treating adolescent depression.

Rationale: A growing body of evidence suggests that the N/OFQ-NOP receptor system modulates learning and memory in rodents, with NOP receptor agonists impairing memory and antagonists reversing this effect. Moreover, previous studies on transgenic mice showed that genetic deletion of the NOP receptor enhances spatial and aversive memory.

Objectives: To further investigate the role of the NOP receptor system in learning and memory, we used a rat model to assess how genetic deletion of NOP receptors affects spatial and associative memory, comparing it with a wild-type (WT) control group.

Methods: Male Wistar Han and NOP^(-/-) rats were tested for spatial memory using the classical Morris Water Maze (MWM) test. A modified MWM was then used to assess cued learning and associative memory. Conditioned place aversion (CPA) further evaluated associative memory. Anxiety-like behavior and motor skills were tested using the Elevated Plus Maze (EPM), Open Field, and Rotarod tests.

Results: NOP^(-/-) rats displayed impaired acquisition in the spatial and cued MWM tasks but performed comparably to controls in CPA and spatial MWM retrieval. Notably, NOP^(-/-) rats exhibited an anxiogenic-like phenotype in the MWM, EPM, and OF tests, without showing any motor impairment.

Conclusions: Deletion of NOP receptors impairs spatial and associative memory acquisition in the MWM, but this is likely not due to a direct cognitive deficit. Instead, our data suggest that these impairments depend on the anxiogenic-like phenotype observed in NOP^(-/-) rats. These findings highlight the complex interplay between anxiety and memory processes in the context of NOP receptor signaling.

Rationale: While medications such as acamprosate, baclofen, or naltrexone have shown promising effects in the treatment of alcohol use disorder (AUD), meta-analyses have yielded conflicting findings regarding their efficacy. This retrospective study examined whether alcohol cue reactivity and its neural correlates could serve as protective factors against relapse in AUD inpatients receiving pharmacological treatment during a three-week detoxification program.

Method: Fifty-eight inpatients diagnosed with AUD undergoing a three-weeks detoxification program were selected. These patients received either acamprosate (n = 21), naltrexone (n = 21), or baclofen (n = 16) during their stay. They completed an event-related potential cue-reactivity task at the beginning (T0) and end (T1) of the program. Follow-up data on relapse were collected up to two months post- discharge.

Results: The Log-Rank (Mantel-Cox) test ([Formula: see text] (2) = 5.84; p =.059) revealed a marginally significant difference in survival distributions between medications. A significant difference emerged between baclofen and acamprosate groups ([Formula: see text] (1) = 4.73; p =.030), with slower return to alcohol use in the baclofen group. No other significant difference emerged between the acamprosate and naltrexone groups or between the naltrexone and baclofen groups (p >.05). Only the baclofen group showed a significant reduction in oddball P3 amplitude between T0 and T1 (p =.002), suggesting decreased neural cue reactivity.

Conclusion: A reduction in neural cue reactivity, observed exclusively in the baclofen group, may act as a protective factor against early relapse in AUD. However, this study was underpowered, and findings should be interpreted cautiously until confirmed in larger prospective investigations.

Rationale: The sense of smell plays a key role in guiding motivated behavior, and olfactory function is impaired in clinical populations with dysfunctional approach-avoidance behavior, including major depressive and alcohol use disorder (AUD). However, whether olfactory impairments are also observed in individuals with substance use disorders (SUDs) other than AUD is currently unknown.

Objectives: This study aimed to evaluate the relationship between olfactory function and SUDs.

Methods: We tested olfaction in 40 individuals with substance use disorders (SUDs) other than AUD using the Sniffin' Sticks odor identification and olfactory threshold tests, versus 112 controls. Group differences were assessed with linear regression models, with diagnosis (SUD vs. controls) as a predictor, controlling for age, sex and smoking.

Results: Across a diverse range of substances used, individuals with SUDs had significantly lower identification scores than those in the control group. In contrast, olfactory thresholds did not differ significantly by diagnosis overall. However, exploratory analyses showed that men with SUDs had lower olfactory threshold scores (i.e., higher thresholds) than men in the control group, a difference that was absent in women.

Conclusions: These results suggest that olfactory function is impaired in individuals with SUDs relative to controls. There are several plausible pathways by which differences in olfaction could be related to differences in hedonic processing, but longitudinal studies are needed to clarify the timing of olfactory impairment relative to substance use or SUD symptomatology.