Background: Linagliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes, enhances glucagon-like peptide-1 (GLP-1) signaling. Because GLP-1 receptors are widely expressed in the brain, DPP-4 inhibitors have emerged as potential modulators of central nervous system function. The present study investigated the effects of linagliptin (10 and 20 mg/kg, i.p.) on ketamine- (10 mg/kg, i.p.) and diazepam-induced (2 mg/kg, i.p.) deficits in passive avoidance performance in mice. Behavioral effects were assessed using the passive avoidance test, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA). Linagliptin attenuated ketamine- and diazepam-induced deficits in passive avoidance performance. In addition, both acute and chronic administration of linagliptin increased BDNF levels in the prefrontal cortex but not in the hippocampus. These findings provide preliminary evidence that linagliptin modulates passive avoidance performance in mice and is associated with increased BDNF levels in the prefrontal cortex. Further studies employing complementary behavioral paradigms and additional molecular approaches are required to clarify the neuropharmacological mechanisms underlying these effects.

Persistent fear responses and impaired fear extinction are characteristic features of stress-related disorders. Dopaminergic signalling within amygdala-centred circuits contributes to fear extinction, but the associated molecular mechanisms remain unclear. Here, we investigated whether selective dopamine transporter (DAT) inhibition with CE-123 (10 mg/kg, intraperitoneally) facilitates fear extinction and induces region-specific molecular adaptations. Adolescent male rats were subjected to a modified stress-enhanced fear learning (SEFL)-like paradigm followed by extinction training. Rats exposed to high-intensity fear conditioning (STRESSED groups) displayed persistent freezing and increased anxiety-like behaviour compared with non-shocked controls (NON-STRESSED groups). Repeated CE-123 administration during extinction significantly reduced freezing in stressed rats without affecting non-stressed animals. Quantitative proteomic analyses of the basolateral amygdala (BLA) and hippocampus (HPC) revealed marked region-specific effects. Stress-related fear enhancement induced extensive proteomic remodelling in the BLA, involving proteins associated with glutamatergic signalling, synaptic plasticity, and axonal organization, whereas the hippocampal proteome was largely unaffected. CE-123 also produced BLA-specific molecular effects, reducing the abundance of proteins associated with mitochondrial ATP synthesis in non-stressed animals and with ribosomal, mitochondrial, and RNA-processing pathways in stressed rats. These findings identify the BLA as a key substrate of fear-related molecular adaptations and demonstrate that selective DAT inhibition modulates amygdala proteomic architecture during fear extinction. Overall, the results support further investigation of DAT modulation as a potential strategy for facilitating fear extinction in stress-related disorders.

Levetiracetam, a second-generation antiepileptic drug, is effective in therapy of various types of seizures. Its pharmacological properties are increasingly used in diversified clinical conditions such as anxiety and neuropathic pain. Levetiracetam has unique mechanism of action - it selectively binds to the synaptic vesicle protein 2A (SV2A), which stabilizes synaptic function and reduces neurotransmitter release, distinguishing it from traditional antiepileptics. The aim of the present paper was to investigate whether levetiracetam (31.25; 62.5 mg/kg, ip) may also be effective drug in reducing of symptoms in morphine dependence in mice. It was studied in three paradigms: 1) morphine tolerance to antinociceptive effect measured in the hot plate test; 2) naloxone-induced (2 mg/kg, ip) morphine withdrawal signs (manifested as jumpings); 3) morphine-induced behavioral sensitization to the locomotor activity of mice. Levetiracetam, at least in one of the doses used, was effective drug in reduction of all measured parameters. The study highlights the need for further research on levetiracetam properties, because it seems to be an innovative target in morphine dependence.

Levetiracetam (LEV) is an antiepileptic drug and is used in the management of various types of seizures and other clinical conditions, including anxiety and neuropathic pain. Its unique mechanism primarily involves selective interaction with synaptic vesicle protein 2A (SV2A), which stabilizes synaptic function and the release of neurotransmitters. The objective of the present study was to evaluate LEV activity in morphine (MPH) dependence. In mice, LEV was used at doses ranging from 31.25 to 125 mg/kg, depending on the experimental paradigm. It was studied in three schedules: (1) MPH tolerance to antinociceptive effects (the hot plate test—HPT); (2) MPH withdrawal signs, manifested as jumps, induced by naloxone (NAL)—2 mg/kg, i.p.; (3) MPH sensitization to locomotor activity. In this study, LEV reduced MPH tolerance to analgesic effects. Moreover, LEV diminished the intensity of NAL-precipitated MPH withdrawal signs. This drug was also effective in attenuating MPH-induced sensitization. These findings suggest that LEV may modulate behavioral adaptations associated with repeated MPH exposure. However, further mechanistic studies are required to identify the molecular and neurochemical pathways involved in these effects.