Background: Benzodiazepines have long held a leading position in medical therapeutics, known for their multiple common therapeutic properties and primarily being prescribed for anxiety and insomnia. However, their lack of specificity and various side effects have led to a reevaluation of their long-term use, resulting in a rapid growth in the literature focusing on targeted therapies. Areas of Uncertainty: Despite many efforts, uncertainties persist and there are heterogeneous findings across studies regarding the pharmacological effects attributed to gamma-aminobutyric acid type A (GABAA) receptor subunits. Selective compounds targeting GABAA receptor alpha subunits are currently under active research and definitive conclusions have not been reached yet. Some compounds have not progressed to clinical trials, while others, if advanced, have been halted. These challenges emphasize the difficulty in translating preclinical findings into clinical use. Data Sources: A literature review was conducted using the PubMed database, searching for articles discussing GABAA receptor subunits. The search was refined by including only selective compounds with potential anxiolytic and cognitive enhancement properties. Results: Findings reveal compounds with promising anxiolytic and antidepressant effects with minimal sedation and absence of tolerance development. Moreover, some compounds show potential in alleviating cognitive dysfunction. There is a broad spectrum of potential therapeutic applications for selective compounds, ranging from neurological disorders such as epilepsy and neuropathic pain to cognitive dysfunction–related conditions. Currently, the leading selective compounds with the most promising results in ongoing clinical trials are basmisanil and darigabat. Basmisanil holds further exploration potential in the treatment of cognitive impairment and related conditions, while darigabat shows progress in the advancement of adjunctive therapy of focal onset seizures and for the treatment of panic disorder, respectively. Conclusions: Future drug discovery efforts are encouraged to focus on positive allosteric modulators that selectively target the α2, α3 subunits and negative/positive allosteric modulators that target the α5 subunit of the GABAA receptor. The pursuit of ligands possessing only anxiolytic effects or those enhancing cognition continues to be an important focus for future research, with promising advancements depicted in recent studies.

Amyloidosis is a group of diseases characterized by the extracellular deposition of abnormally folded, insoluble proteins that lead to organ dysfunction. While it commonly affects the cardiovascular system, gastrointestinal (GI) tract involvement is undetermined. Recent research has focused on understanding the pathophysiology, diagnostic challenges, and therapeutic approaches to GI amyloidosis, particularly in systemic amyloid light-chain (AL) and amyloid A (AA) forms. GI manifestations can include motility disorders, bleeding, and, in severe cases, bowel obstruction. This review highlights the importance of the early recognition of digestive symptoms and associated imagistic findings in GI amyloidosis by analyzing the research that included clinical, pathological, and endoscopic approaches to amyloidosis. A systematic search of the PubMed and Scopus databases identified 19 relevant studies. Our findings showed that amyloid deposits commonly affect the entire GI tract, with AL amyloidosis being the most predominant form. Endoscopic evaluations and biopsy remain key diagnostic tools, with Congo Red staining and mass spectrometry being used to confirm amyloid type. Although progress has been made in diagnosis, the absence of targeted therapies and the indistinct nature of GI symptoms continue to be challenging.

Cholinesterase inhibitors with distinct pharmacological profiles may influence exploratory behavior, yet their effects on recall-related exploration in physiologically intact animals remain insufficiently characterized. The present study aimed to directly compare the effects of donepezil, a relatively selective acetylcholinesterase inhibitor, and tacrine, a cholinesterase inhibitor with broader enzymatic and pharmacological activity, on exploratory allocation during memory recall in healthy rats. Male Wistar rats were assigned to five groups (n = 8/group): control, donepezil 1 mg/kg, donepezil 3 mg/kg, tacrine 3 mg/kg, and tacrine 5 mg/kg. Treatments were administered intraperitoneally 50 min before the acquisition trial, while recall performance was evaluated 24 h later without additional treatment using a two-trial Y-maze paradigm. Time spent and entries into the familiar and novel arms, novel-to-familiar ratios, and mean time per entry were analyzed. Control animals showed no marked preference for the novel arm, whereas donepezil produced only limited, non-significant behavioral changes. Tacrine 5 mg/kg significantly increased the U/K time ratio compared with controls (p = 0.0006) and the U/K entry ratio (p = 0.001), primarily through reduced time spent in the familiar arm (p = 0.0004) and fewer familiar-arm entries (p = 0.025). Absolute time spent in, and entries into, the novel arm did not differ significantly among groups (p = 0.689 and p = 0.883, respectively). Overall, these findings suggest that tacrine, but not donepezil, modified recall-phase exploratory preference in healthy rats, predominantly by reducing persistence in the familiar arm.

Background: Benzodiazepines and non-benzodiazepine hypnotics (Z-drugs) act at the benzodiazepine binding site of GABA_A receptors but differ in their receptor subtype selectivity and behavioural profiles. Diazepam acts as a non-selective positive allosteric modulator of benzodiazepine-sensitive GABA_A receptors, whereas zolpidem and indiplon display preferential affinity for α1-containing receptor subtypes. Although these compounds have been investigated individually in experimental models of exploratory behaviour and cognition, comparative behavioural data obtained using the same experimental protocol remain limited. Methods: This study evaluated the behavioural effects of diazepam, zolpidem and indiplon in male Wistar rats using a two-trial Y-maze paradigm with a 24 h retention interval. Animals received one of three dose levels of each compound before the acquisition trial. Recall-phase behaviour was evaluated using conventional exploration measures together with time- and entry-based preference indices for the previously inaccessible arm. Primary analyses were performed separately for each compound using one-way ANOVA with appropriate post hoc comparisons. Complementary exploratory factorial analyses were subsequently conducted to examine overall behavioural patterns across drug and nominal dose categories. Results: Diazepam produced marked dose-dependent reductions in recall-phase exploration of the previously inaccessible arm and in both exploratory preference indices. In contrast, zolpidem and indiplon reduced exploratory activity during the acquisition phase without significantly affecting recall-phase exploratory behaviour. The complementary factorial analyses identified significant Drug × Nominal Dose Categories interactions across all recall-related endpoints, indicating that behavioural responses across the nominal dose categories differed among the three compound-specific experimental series. The strongest interaction effects were observed for Time Index % (F(6,72) = 10.522, p < 0.001, ηp² = 0.467) and Entries Index % (F(6,72) = 6.870, p < 0.001, ηp² = 0.364). Conclusions: Diazepam produced more pronounced dose-dependent alterations in recall-phase exploratory behaviour than zolpidem or indiplon in the experimental conditions employed. The complementary factorial analyses support the interpretation that the three compounds exhibited different behavioural patterns across the nominal dose categories evaluated, while these exploratory comparisons should be interpreted within the constraints of the study design. Overall, the findings contribute to the comparative behavioural characterization of benzodiazepine-site modulators in the two-trial Y-maze paradigm.

Cognitive impairment may arise through multiple pathophysiological mechanisms, including altered GABAergic neurotransmission, cholinergic dysfunction, and neuroinflammation. This study investigated whether basmisanil, a selective negative allosteric modulator of α5-containing GABA_A receptors, attenuates spatial memory impairment induced by diazepam, trihexyphenidyl (THP), or lipopolysaccharide (LPS). Adult male Wistar rats were assigned to three experimental models of memory impairment, each comprising four treatment groups (control, inducing agent, basmisanil, and inducing agent plus basmisanil; n = 7/group). Spatial memory was assessed using the two-trial Y-maze paradigm. The primary outcome (Time Index U) was analyzed using two-way factorial general linear models with sensitivity analyses. Significant interactions between the inducing agent and basmisanil were observed in the diazepam and LPS models, indicating attenuation of memory impairment following basmisanil coadministration, whereas no significant interaction was detected in the THP model. The largest estimated recovery effect was observed in the diazepam model, followed by the LPS model and the THP model, although cross-model comparisons were not statistically significant. Basmisanil alone did not enhance baseline memory performance. These findings indicate that the behavioral effects of α5-containing GABA_A receptor modulation are mechanism-dependent and support further investigation of selective α5 negative allosteric modulators for benzodiazepine-associated memory impairment.