Monoamine Reuptake Inhibitors Research Articles

Pramipexole, a D3 receptor agonist, increases cortical gamma power and biochemical correlates of cortical excitation; implications for mood disorders.

Major depressive disorder (MDD) has been associated with deficits in working memory as well as underlying gamma oscillation power. Consistent with this, overall reductions in cortical excitation have also been described with MDD. In previous work, we have demonstrated that the monoamine reuptake inhibitor venlafaxine increases gamma oscillation power in ex vivo hippocampal slices and that this is associated with concomitant increases in pyramidal arbour and reduced levels of plasticity-restricting perineuronal nets (PNNs). In the present study, we have examined the effects of chronic treatment with pramipexole (PPX), a D3 dopamine receptor agonist, for its effects on gamma oscillation power as measured by in vivo electroencephalography (EEG) recordings in female BALB/c and C57Bl6 mice. We observe a modest but significant increase in 20-50 Hz gamma power with PPX in both strains. Additionally, biochemical analysis of prefrontal cortex lysates from PPX-treated BALB/c mice shows a number of changes that could contribute to, or follow from, increased pyramidal excitability and/or gamma power. PPX-associated changes include reduced levels of specific PNN components as well as tissue inhibitor of matrix metalloproteases-1 (TIMP-1), which inhibits long-term potentiation of synaptic transmission. Consistent with its effects on gamma power, PNN proteins and TIMP-1, chronic PPX treatment also improves working memory and reduces anhedonia. Together these results add to an emerging literature linking extracellular matrix and/or gamma oscillation power to both mood and cognition.

Association between antidepressant use and delirium in older adults: an analysis of the World Health Organization’s global pharmacovigilance database

BackgroundPsychoactive drugs frequently cause delirium adverse events in older adults. However, few data on the relationship between antidepressants and delirium are available. Here, we investigated the association between antidepressant prescription and pharmacovigilance reports of delirium in older adults.MethodsUsing the World Health Organization’s VigiBase® global pharmacovigilance database from 1967 to 2022, we performed a disproportionality analysis in order to probe the putative associations between each antidepressant class (non-selective monoamine reuptake inhibitors (NSMRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), alpha-2-adrenergic receptor antagonists, and other antidepressants) and reports of delirium in people aged 65 or over. We calculated the reporting odds ratios (r-OR) and their 95% confidence interval ([95%CI]) with logistic regression models before and after adjustment for confounding factors. Secondary analyses were performed for each drug and within each class by age group (65-74, and 75 and over). We also studied the reports of concomitant delirium and hyponatremia.ResultsOur main analysis included 87,524 cases of delirium. After adjustment for confounders, a significant association was found between delirium and all antidepressant classes other than SNRIs. Intraclass disparities were found for the association between the most frequently prescribed antidepressants and reports of delirium. An elevated risk of reports of concomitant delirium and hyponatremia was found for SSRIs (4.46 [4.01-4.96]), SNRIs (1.25 [1.07-1.46]), MAOIs (1.72 [1.41-2.09]), and the “other antidepressants” class (1.47 [1.30-1.65]).ConclusionsThere was a significant association between reports of delirium and antidepressant classes (other than SNRIs). However, this association varied from one drug to another within a given antidepressant class. Moreover, this association could not always be explained by antidepressant-induced hyponatremia.

Thirst and drugs: A study in the World Health Organization's pharmacovigilance database.

Thirst is a complex physiological compensatory mechanism but could also be associated with drugs. This association was poorly investigated previously. Using the WHO global pharmacovigilance database, Vigibase®, disproportionality analyses potential associations between exposure to drugs and thirst reports were performed. All reports of thirst in adults between 01/01/2000 and 31/12/2023 were included. Results are expressed as reporting odds ratio (ROR). Analysis of the 3186 reports of thirst (978 'serious') allowed, first, to confirm the association between thirst and exposure to vasopressin antagonists (tolvaptan), lithium, gliflozins (dapagliflozin, empagliflozin), pregabalin and antimuscarinic drugs (glycopyronium, oxybutynin, tiotropium). Second, new safety signals were described with monoamine reuptake inhibitors (antidepressants: duloxetine, venlafaxine; anti-obesity agent: sibutramine), antipsychotic (olanzapine), glucocorticoid (prednisolone), diuretic (furosemide) drugs as well with ribavirin or sodium oxybate. This study is the first to offer a list of drugs associated with thirst in humans.

Tetra-n-Butyl Ammonium Fluoride (TBAF) as an Efficient Catalyst

Abstract: Tetra-n-butylammonium fluoride (TBAF) is an organic compound with the formula C16H36FN. It can exist as anhydrous or hydrated (C16H42FNO3). It is soluble in water and THF and utilized as a base in the preparation of triple monoamine reuptake inhibitors, conjugated dienoic acid esters, and polyacetylenic glucosides. This review aims to summarize the chemistry of TBAF.

Methylone is a rapid-acting neuroplastogen with less off-target activity than MDMA.

Post-traumatic stress disorder (PTSD) is a highly prevalent psychiatric disorder that can become chronic and debilitating when left untreated. Available pharmacotherapies are limited, take weeks to show modest benefit and remain ineffective for up to 40% of patients. Methylone is currently in clinical development for the treatment of PTSD. Preclinical studies show rapid, robust and long-lasting antidepressant-like and anxiolytic effects. The mechanism of action underlying these effects is not yet fully understood. This study investigated the downstream gene expression changes and signaling pathways affected by methylone in key brain areas linked to PTSD and MDD. It also sought to determine whether neuroplasticity-related genes were involved. We compared effects of methylone with MDMA to explore similarities and differences in their brain effects because MDMA-assisted psychotherapy has recently shown benefit in clinical trials for PTSD and methylone is a structural analog of MDMA. Monoamine binding, uptake and release studies were performed and a high-throughput-screen evaluated agonist/antagonist activities at 168 GPCRs in vitro. We used RNA sequencing (RNA-seq) to probe drug-induced gene expression changes in the amygdala and frontal cortex, two brain areas responsible for emotional learning that are affected by PTSD and MDD. Rats were treated with methylone or MDMA (both 10 mg/kg, IP), and their responses were compared with controls. We performed functional enrichment analysis to identify which pathways were regulated by methylone and/or MDMA. We confirmed changes in gene expression using immunohistochemistry. Methylone, a monoamine uptake inhibitor and releaser, demonstrated no off-target effects at 168 GPCRs, unlike MDMA, which showed activity at 5HT2A and 5HT2C receptors. RNA-seq results revealed significant regulation of myelin-related genes in the amygdala, confirmed by immunohistochemistry. In the frontal cortex, methylone significantly upregulated genes implicated in neuroplasticity. Results suggest that (1) methylone is a rapid-acting neuroplastogen that affects key brain substrates for PTSD and MDD and that (2) methylone appears to exhibit higher specificity and fewer off-target effects than MDMA. Together, these results are consistent with the reported clinical experiences of methylone and MDMA and bolster the potential use of methylone in the treatment of PTSD and, potentially, other neuropsychiatric disorders.

Stereochemical optimization of N,2-substituted cycloalkylamines as norepinephrine reuptake inhibitors.

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the N,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the R 2 position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a trans-orientation of the N,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.

Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.

Possible prospects for the combined administration of antidepressants and antioxidants in neurological patients

Antidepressants (ADs) are a group of drugs whose action primarily consists of stimulating neurotransmitter systems (dopaminergic, serotonergic and noradrenergic systems). Neurologists prescribe them for the treatment of post-stroke and other depression, chronic pain syndromes, neuropathic pain, panic attacks, correction of post-Covid syndrome, for the prevention of migraines, Parkinson’s disease and neurodegenerative diseases, including Alzheimer’s disease. However, even with appropriate therapy, many people with depressive disorder may experience subsyndromal symptoms and complete remission is short-lived, so there is a need to use other therapeutic approaches. Combining two or more antidepressants may target different neurochemical pathways while increasing the risk of side effects and the development of resistance. Therefore, the search for alternative treatments is urgent, and oxidative stress appears to be an interesting therapeutic target. The combined use of AD and antioxidants may provide an effective and safe approach to enhancing antidepressant effects by synergistically enhancing certain antidepressant activities (eg, enhancing monoamine reuptake inhibition) or by additive pharmacological effects, such as adjusting neurotransmitters and reducing the damaging effects of active agents. forms of oxygen. There are a number of clinical studies to prove the effectiveness of the combined use of antioxidants and antioxidants. In the group of patients receiving a combination of antioxidants and antidepressants/anti-anxiety drugs, there was a better regression of symptoms and severity of depression, which probably indicates the usefulness of adjuvant antioxidant therapy with regular psychotropic treatment. The use of combination drugs in complex therapy with blood pressure seems to be a promising direction and requires further study.

Serotonin is a common thread linking different classes of antidepressants

Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of escitalopram, fluoxetine, reboxetine, and ketamine. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking, and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis, and the monoamine hypothesis).

Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters.

Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively. Potencies were determined via fluorescence-based substrate uptake assays in the absence and presence of other inhibitors to test the multi-drug effects on individual transporters, resulting in antagonistic effects on DAT. In detail, fluoxetine resulted in a 1.6-fold increased IC50 value of vanoxerine for DAT, and nisoxetine produced a more drastic increase in the IC50 value by six folds. Furthermore, the effects of different inhibitors, specifically monovalent ions, were tested on DAT inhibition by vanoxerine. Interestingly, these ions also reduced vanoxerine potency in a similar manner. The homology models of DAT suggested a potential secondary inhibitor binding site that affects inhibition in an allosteric manner. These findings imply that the use of combination therapy with monoamine reuptake inhibitors should be approached cautiously, as antagonistic effects may occur.

Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry.

The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers 7h and 8h, we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors.

Ethanol inhibits dopamine uptake via organic cation transporter 3: Implications for ethanol and cocaine co-abuse

Concurrent cocaine and alcohol use is among the most frequent drug combination, and among the most dangerous in terms of deleterious outcomes. Cocaine increases extracellular monoamines by blocking dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transporters (DAT, NET and SERT, respectively). Likewise, ethanol also increases extracellular monoamines, however evidence suggests that ethanol does so independently of DAT, NET and SERT. Organic cation transporter 3 (OCT3) is an emergent key player in the regulation of monoamine signaling. Using a battery of in vitro, in vivo electrochemical, and behavioral approaches, as well as wild-type and constitutive OCT3 knockout mice, we show that ethanol’s actions to inhibit monoamine uptake are dependent on OCT3. These findings provide a novel mechanistic basis whereby ethanol enhances the neurochemical and behavioral effects of cocaine and encourage further research into OCT3 as a target for therapeutic intervention in the treatment of ethanol and ethanol/cocaine use disorders.

0585 A four-week randomized, double-blind, placebo-controlled, phase 2 study of mazindol ER in the treatment of narcolepsy

Abstract Introduction Mazindol is the first partial orexin 2 receptor agonist and triple monoamine reuptake inhibitor in development for the treatment of narcolepsy. A novel extended release (ER) formulation was developed to allow once-daily dosing and may provide a differentiated treatment option. (ClinicalTrials.gov Identifier: NCT04923594). Methods Study NLS-1021 was a Phase 2, four-week, double-blind, randomized, placebo-controlled study of mazindol ER (NLS-2) for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy type 1 (NT1) or type 2 (NT2). Efficacy, safety, tolerability, and pharmacokinetics were assessed. Adult subjects diagnosed with NT1 or NT2 and washed out of narcolepsy medications at baseline were randomized 1:1 to receive placebo or 2 mg mazindol ER once-daily for one week followed by 3 mg once-daily for three weeks. The primary efficacy endpoint was the change from baseline at Week 4 in excessive daytime sleepiness using the Epworth Sleepiness Scale (ESS). Secondary efficacy endpoints included improvement in weekly cataplexy attacks and overall disease severity as rated by the investigators (Clinician Global Impression of Severity; CGI-S) and patients (Patient Global Impression of Severity; PGI-S). Results Sixty-seven subjects were randomized (n = 33 NLS-2; 34 placebo). The baseline mean [SD] ESS score was 17.9 [2.97] in subjects receiving NLS-2 and 18.0 [3.05] in placebo. NLS-2 met the pre-specified primary endpoint, demonstrating a statistically significant improvement in EDS with a least-squares mean [SE] difference (NLS-2-placebo) of –3.6 [1.33] in the ESS total score at Week 4 (p = 0.0081). Observed mean change from baseline in ESS total score was –7.1 [5.6] for NLS-2 and –3.2 [5.3] for placebo. In NT1 subjects, baseline weekly number of cataplexy episodes was 14.1 [10.8] in subjects receiving NLS-2 (n=11) and 15.0 [10.2] in placebo (n=12). At Week 4, the weekly number of cataplexy episodes was reduced to 4.1 with NLS-2 and to 8.5 with placebo. NLS-2 was generally safe and well-tolerated with no severe or serious adverse events or discontinuations due to adverse events. Conclusion In subjects with narcolepsy, NLS-2 significantly improved EDS and the number of cataplexy attacks compared with placebo. Support (if any) NLS Pharmaceutics

0578 Clinician and Patient Global Impression in a Phase 2 Study of Mazindol (NLS-1021) in Adults with Narcolepsy Type 1 and Type 2

Abstract Introduction Mazindol is the first partial orexin 2 receptor agonist and triple monoamine reuptake inhibitor in development for the treatment of narcolepsy. Clinician and Patient Global Impression (CGI and PGI, respectively) for cataplexy and excessive daytime sleepiness were assessed as secondary endpoints in the phase 2 (POLARIS, NLS-1021) multicenter study of mazindol ER in adult participants with narcolepsy type 1 (NT1) or type 2 (NT2) (ClinicalTrials.gov Identifier: NCT04923594). Methods Adults diagnosed with NT1 or NT2 who were washed out of narcolepsy medications at baseline were included into the study. Patients were treated with mazindol ER (NLS-2) at once-daily 2 mg for one week and once-daily 3 mg thereafter or matching placebo (PBO) on a 1:1 ratio. Throughout the study, CGI Severity (CGI-S) and PGI Severity (PGI-S) for cataplexy severity and excessive daytime sleepiness, respectively, were assessed and compared with scores at baseline. Both scales have five levels of severity: “None”, “Mild”, “Moderate”, “Severe”, or “Very Severe.” Results Sixty-seven participants were randomized (NT1 33.3% in NLS-2 group; 35.3% in PBO). At baseline, the mean CGI-S – Cataplexy was approximately 3.7 and CGI-S – Sleepiness approximately 3.4. Despite the small sample size, at the end of the double-blind (DB) period, the NLS-2 group demonstrated clinically and statistically significant improvements vs. PBO in both CGI-S – Sleepiness (d = –0.7, p = 0.016) and CGI-S – Cataplexy (d = –0.8, p = 0.020). At baseline, the mean PGI-S – Cataplexy was approximately 3.2 and PGI-S – Sleepiness approximately 3.7. At the end of the DB period, the NLS-2 group demonstrated clinically and statistically significant improvements vs. PBO in both PGI-S – Sleepiness (d = –0.8, p = 0.007) and PGI-S – Cataplexy (d = –0.8, p = 0.023). Conclusion Mazindol ER resulted in significant improvements of cataplexy severity and sleepiness in both conditions as rated by both clinicians and participants. These secondary outcome results support the efficacy of mazindol ER on cataplexy attacks, in NT1 participants, and on sleepiness, in NT1 as well as in NT2 participants. Support (if any) NLS Pharmaceutics

3,4-Methylenedioxypyrovalerone High-Responder Phenotype as a Tool to Evaluate Candidate Medications for Stimulant Use Disorder.

Despite decades of research, there are no medications approved by the United States Food and Drug Administration to treat stimulant use disorders. Self-administration procedures are widely used to screen candidate medications for stimulant use disorder, although preclinical reductions in stimulant self-administration have not translated to meaningful reductions in stimulant use in humans. One possible reason for this discordance is that most preclinical studies evaluate candidate medications under conditions that promote predictable, and well-regulated patterns of drug-taking rather than the dysregulated and/or compulsive patterns of drug-taking characteristic of a stimulant use disorder. A subset of rats ("high-responders") that self-administer 3,4-methelyendioxypyrovalerone (MDPV), a monoamine uptake inhibitor, develop high levels of dysregulated drug-taking consistent with behaviors related to stimulant use disorders. Because MDPV acts on dopamine, serotonin (5-HT), and sigma receptor systems, the current studies compared the potency and effectiveness of a dopamine D3 receptor partial agonist (VK4-40) or antagonist (VK4-116), a sigma receptor antagonist (BD1063), a dopamine D2/D3/sigma receptor antagonist (haloperidol), and a 5-HT2C receptor agonist (CP-809,101) to reduce MDPV (0.0032-0.1 mg/kg/infusion) self-administration in high- and low-responding rats as well as rats self-administering cocaine (0.032-1 mg/kg/infusion). VK4-40, VK4-116, haloperidol, and CP-809,101 were equipotent and effective at reducing drug-taking in all three groups of rats, including the high-responders; however, VK4-116 and CP-809,101 were less potent at reducing drug-taking in female compared with male rats. Together, these studies suggest that drugs targeting dopamine D3 or 5-HT2C receptors can effectively reduce dysregulated patterns of stimulant use, highlighting their potential utility for treating stimulant use disorders. SIGNIFICANCE STATEMENT: There are no United States Food and Drug Administration-approved treatments for stimulant use disorder, perhaps in part because candidate medications are most often evaluated in preclinical models using male subjects with well-regulated drug-taking. In an attempt to better model aberrant drug taking, this study found compounds acting at dopamine D3 or 5-HT2C receptors can attenuate drug-taking in male and female rats that self-administered two different stimulants and exhibited either a high or low substance use disorder-like phenotype.

Current Knowledge of the Antidepressant Activity of Chemical Compounds from Crocus sativus L.

Psychotropic effect of Crocus sativus L. (family Iridaceae) biologically active chemical compounds are quite well documented and they can therefore be used in addition to the conventional pharmacological treatment of depression. This systematic review on antidepressant compounds in saffron crocus and their mechanisms of action and side effects is based on publications released between 1995−2022 and data indexed in 15 databases under the following search terms: antidepressant effect, central nervous system, Crocus sativus, cognitive impairement, crocin, crocetin, depression, dopamine, dopaminergic and serotonergic systems, picrocrocin, phytotherapy, neurotransmitters, safranal, saffron, serotonin, and biologically active compounds. The comparative analysis of the publications was based on 414 original research papers. The investigated literature indicates the effectiveness and safety of aqueous and alcoholic extracts and biologically active chemical compounds (alkaloids, anthocyanins, carotenoids, flavonoid, phenolic, saponins, and terpenoids) isolated from various organs (corms, leaves, flower petal, and stigmas) in adjuvant treatment of depression and anxiety. Monoamine reuptake inhibition, N-methyl-d-aspartate (NMDA) receptor antagonism, and gamma-aminobutyric acid (GABA)-α agonism are the main proposed mechanism of the antidepressant action. The antidepressant and neuroprotective effect of extract components is associated with their anti-inflammatory and antioxidant activity. The mechanism of their action, interactions with conventional drugs and other herbal preparations and the safety of use are not fully understood; therefore, further detailed research in this field is necessary. The presented results regarding the application of C. sativus in phytotherapy are promising in terms of the use of herbal preparations to support the treatment of depression. This is particularly important given the steady increase in the incidence of this disease worldwide and social effects.

Statins and Antidepressants: A Comprehensive Review and Clinical Outlook of the Risks and Benefits of Co-prescription (2022).

Antidepressants are the most prescribed medications in the United States, and the most frequently prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs) followed by serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin antagonist and reuptake inhibitors (SARIs), and norepinephrine-dopamine reuptake inhibitors(NDRI). On the other hand, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are the most prescribed lipid-lowering medications, and because the majority of patients with cardiovascular disease (CVD) have depressive symptoms, it is essential to understand the possible drug-drug interactions these two classes of medications can have, their potential synergistic mechanisms, and possible risks. In our research, we tried to understand the facts and uncover any missing links regarding the potential risks and benefits of statins and antidepressant co-prescription in the current clinical scenario. We reviewed all the relevant information from inception up to October 2022 regarding the antidepressant and statin polypharmacy. The databases we used were PubMed and PubMed Central, and the 11 keywords were "statins," "SSRI," "SNRI," "selective serotonin reuptake inhibitors," "serotonin-norepinephrine reuptake inhibitors," "antidepressants,""HMG-CoA reductase inhibitors," "tricyclic antidepressants," "monoamine oxidase inhibitors," "serotonin antagonist and reuptake inhibitors," and "norepinephrine-dopamine reuptake inhibitors." We carefully screened each of the relevant articles, including animal and human studies. In our study, we concluded that co-prescription of statins and SSRIs/SNRIs was generally safe and should be encouraged due to the potential synergistic nature of their effects in patients with CVD and major depression, and caution is advised with all other classes of antidepressants. We would like to encourage the undertaking of large-scale observational studies and proactive postmarketing surveillance to improve our knowledge regarding this topic considering the immense clinical importance it holds by directly and indirectly affecting half the population worldwide.

Methylphenidate Analogues as a New Class of Potential Disease-Modifying Agents for Parkinson's Disease: Evidence from Cell Models and Alpha-Synuclein Transgenic Mice.

Parkinson’s disease (PD) is characterized by dopaminergic nigrostriatal neurons degeneration and Lewy body pathology, mainly composed of α-synuclein (αSyn) fibrillary aggregates. We recently described that the neuronal phosphoprotein Synapsin III (Syn III) participates in αSyn pathology in PD brains and is a permissive factor for αSyn aggregation. Moreover, we reported that the gene silencing of Syn III in a human αSyn transgenic (tg) mouse model of PD at a pathological stage, manifesting marked insoluble αSyn deposits and dopaminergic striatal synaptic dysfunction, could reduce αSyn aggregates, restore synaptic functions and motor activities and exert neuroprotective effects. Interestingly, we also described that the monoamine reuptake inhibitor methylphenidate (MPH) can recover the motor activity of human αSyn tg mice through a dopamine (DA) transporter-independent mechanism, which relies on the re-establishment of the functional interaction between Syn III and α-helical αSyn. These findings support that the pathological αSyn/Syn III interaction may constitute a therapeutic target for PD. Here, we studied MPH and some of its analogues as modulators of the pathological αSyn/Syn III interaction. We identified 4-methyl derivative I-threo as a lead candidate modulating αSyn/Syn III interaction and having the ability to reduce αSyn aggregation in vitro and to restore the motility of αSyn tg mice in vivo more efficiently than MPH. Our results support that MPH derivatives may represent a novel class of αSyn clearing agents for PD therapy.

Review: Combining antidepressants superior to monotherapy in acute depression

Combining antidepressants was more effective than antidepressant monotherapy in the treatment of adults with acute depression, a systematic review and meta‐analysis encompassing 39 trials has found. Combinations of a monoamine reuptake inhibitor and a presynaptic alpha‐2 adrenoreceptor antagonist showed the most promising results among the studied combination treatments. Results of the review and meta‐analysis were published online February 16, 2022, in JAMA Psychiatry.

Ethanol Inhibits Dopamine Uptake and Augments Rewarding Effects of Cocaine via Organic Cation Transporter 3

Concurrent use of cocaine and alcohol is a major cause of emergency hospitalization, underscoring a vital need to understand the mechanistic basis of this highly addictive and dangerous drug combination. Both cocaine (blocker of dopamine (DA), norepinephrine and serotonin transporters, DAT, NET and SERT, respectively) and ethanol (EtOH) increase extracellular levels of these monoamines. However, we and others find no evidence for EtOH interacting with DAT, NET, or SERT, suggesting that EtOH may be acting elsewhere to inhibit uptake of these monoamines. Organic cation transporter 3 (OCT3) is emerging as a key player in the regulation of monoamine signaling. Whether EtOH acts at OCT3 to increase extracellular levels of monoamines is unknown. To this end, we first conducted studies to determine the ability of EtOH to inhibit uptake of [3H]MPP+ into cultured HEK293 cells stably overexpressing human OCT3. We found the IC50 to be 4 mM, showing that concentrations of EtOH reaching brain following behaviorally relevant doses may be sufficient to engage OCT3. We also found that cocaine does not have activity at OCT3 (Mayer et al., 2018, PMID: 29773909), raising the possibility that EtOH may interact with OCT3 to inhibit monoamine uptake, potentially increasing the addictive properties of cocaine and propagating the concurrent use of these drugs. Next, we assessed the effect of EtOH on DAT, NET, and SERT mediated uptake in real‐time by microsuperfusing fluorescent substrate (APP+ or ASP+) onto HEK293 cells stably expressing DAT, NET, or SERT (APP+) or OCT3 (ASP+) before the addition of EtOH. We found that while EtOH did not affect APP+ uptake by DAT, NET, or SERT, it did inhibit accumulation of ASP+ via OCT3 in a concentration‐dependent manner. To further parse out the relationship between EtOH and OCT3, we used high‐speed chronoamperometry to interrogate the effects of local application of EtOH, cocaine, and their combination on clearance of exogenously applied DA from extracellular fluid in striatum of male and female OCT3+/+ and constitutive OCT3‐/‐ mice in vivo. EtOH inhibited DA clearance and enhanced the ability of cocaine to inhibit DA clearance in both male and female OCT3+/+ mice, effects that were lost in OCT3‐/‐ mice. Finally, we conducted behavioral experiments to assess conditioned place preference (CPP) in response to administration of EtOH, cocaine, or both, to determine if coadministration of EtOH and cocaine enhanced place preference compared to administration of each drug individually. The combination of EtOH (1000 mg/kg) and cocaine (3.2 mg/kg), doses which by themselves did not induce CPP, produced robust CPP. CPP studies in OCT3‐/‐ mice are ongoing (n = 7M & 7F/dose) but so far demonstrate no development of CPP, regardless of treatment. Taken together, results suggest that potentiation of the neurochemical and behavioral effects of cocaine by EtOH are OCT3 dependent. OCT3 may be a putative target for therapeutic intervention in the treatment of EtOH and cocaine co‐abuse.