Search Results (134)

Nicotine addiction is a serious global public health problem, so there is an urgent necessity to develop novel effective smoking cessation treatments with fewer adverse effects. Spontaneous behavioral sensitization induced by repeated intermittent exposure to the addictive substance represents a classical animal model of addiction research. A significant contributor to nicotine addiction is its interaction with α6β2* nAChRs located on midbrain dopaminergic neurons, which leads to an increase in dopamine (DA) release. α-Conotoxin (α-CTx) TxIB is a novel potent antagonist of the α6/α3β2β3* nAChRs, with an IC50 value of 28.4 nM developed by our group. In this study, we aimed to investigate the effectiveness of α-CTx TxIB in countering nicotine-induced behavioral sensitization and moderating the impact of nicotine on dopamine accumulation in the midbrain. Our results demonstrated that repeated nicotine administration remarkably elevated the locomotor activity of mice, including the number of entries, average speed, and total distance traveled, which could be effectively attenuated by α-CTx TxIB intervention in a dose-dependent manner (1 nmol and 5 nmol TxIB per mouse). Furthermore, 5 nmol α-CTx TxIB significantly reduced the nicotine-elevated DA and norepinephrine (NE) levels in the ventral tegmental area (VTA) and nucleus accumbens (NAc) of mice. 5 nmol α-CTx TxIB also markedly decreased the expression of critical proteins such as the dopamine transporter (DAT), N-methyl-D-aspartic acid receptor (NMDAR), and c-Fos in the NAc and prefrontal cortex (PFC) of the nicotine-exposed mice. This research provided the first compelling evidence that α-CTx TxIB attenuated nicotine-induced locomotor sensitization and inhibited the nicotine-induced dopamine elevation in mice. These results open up new avenues for exploring the therapeutic potential of α-CTx TxIB in the treatment of nicotine addiction. Full article

Background: Pain is a complex condition influenced by peripheral, central, immune, and psychological factors. Multitarget approaches offer a more effective and safer alternative to single-target analgesics by enhancing efficacy, reducing side effects, and minimizing tolerance. This study aimed to identify a novel multitarget analgesic with improved pharmacological properties. Methods: An in vivo-guided screening approach was used to discover a new analgesic compound. Compound 29, derived from a novel scaffold inspired by opiranserin and vilazodone pharmacophores, was identified through analog screening in the formalin test. Its efficacy was further evaluated in the spinal nerve ligation (SNL) model of neuropathic pain. Mechanistic studies explored its interaction with neurotransmitter transporters and receptors, while pharmacokinetic and safety assessments were conducted to determine its stability, brain penetration, and potential toxicity. Results: Compound 29 demonstrated high potency in the formalin test, with an ED50 of 0.78 mg/kg in the second phase and a concentration-dependent effect in the first phase. In the SNL model, it produced dose-dependent analgesic effects, increasing withdrawal thresholds by 24% and 45% maximum possible effect (MPE) at 50 and 100 mg/kg, respectively. Mechanistic studies revealed strong triple uptake inhibition, particularly at dopamine (DAT) and serotonin (SERT) transporters, alongside high-affinity 5-HT2A receptor antagonism. Pharmacokinetic analysis indicated enhanced stability and blood–brain barrier permeability. In vitro studies confirmed its nontoxicity to HT-22 cells but revealed potential hERG inhibition and strong CYP3A4 inhibition. Conclusions: Compound 29 is a promising multitarget analgesic with potent efficacy and favorable pharmacokinetics. Ongoing optimization efforts aim to mitigate side effects and enhance its therapeutic profile for clinical application. Full article

Objectives: We aimed to examine the relationship of Dopamine transporter (DAT) and vesicular monoamine transporter (VMAT-2) gene and protein levels with psychic experiences and other clinical parameters in individuals with Methamphetamine Use Disorder (MUD). Methods: This study included 50 males diagnosed with MUD and 50 males as a smoking control (SC) and nonsmoking control (NSC). Community Assessment of Psychic Experiences (CAPE) was administered to patients and controls; Addiction Profile Index, Treatment Motivation Questionnaire, and Substance Craving Scale were administered only to the patient group. DAT and VMAT2 gene and protein levels were determined in blood obtained from the controls and patient groups. Results: CAPE positive, depressive, total, and distress scores were significantly higher in the patient group. DAT protein level and VMAT2 gene and protein levels were lower in the patient group compared to the controls. The DAT gene expression level was higher in the patient group compared to the controls. There was no correlation between any clinical variables and expression levels. A low VMAT2 gene expression level could diagnose MUD with a 5% probability when NSCs were used as a reference. A high DAT gene expression level could diagnose tobacco use disorder (TUD) with a 99.9% probability when NSCs were used as a reference. Conclusions: The patient group showed more psychic experiences than healthy people. The low expression of the VMAT2 gene was identified as a predictor of MUD, while the high expression of the DAT gene was predictive of TUD. Full article

Background/Objectives: Parkinson’s disease (PD) is a debilitating neurodegenerative disease that targets the nigrostriatal dopaminergic (DAnergic) system residing in the human midbrain and is currently incurable. The aim of this study is to investigate the neuroprotective effects of ascorbic acid, vanillic acid, and ferulic acid in a zebrafish model of PD induced by MPTP by assessing the impact of these compounds on DAnergic neurons, focusing on gene expression, mitochondrial dynamics, and cellular stress responses. Methods/Results: Following exposure and qPCR and immunohistochemical analyses, ascorbic acid enhanced DAnergic function, indicated by an upregulation of the dopamine transporter (dat) gene and increased eGFP+ DAnergic cells, suggesting improved dopamine reuptake and neuroprotection. Ascorbic acid also positively affected mitochondrial dynamics and stress response pathways, countering MPTP-induced dysregulation. Vanillic acid only had modest, if any, neuroprotective effects on DAnergic neurons following MPTP administration. Ferulic acid exhibited the largest neuroprotective effects through the modulation of gene expression related to DAnergic neurons and mitochondrial dynamics. Conclusions: These findings suggest that ascorbic acid and ferulic acid can act as potential protective interventions for DAnergic neuron health, demonstrating various beneficial effects at the molecular and cellular levels. However, further investigation is needed to translate these results into clinical applications. This study enhances the understanding of neuroprotective strategies in neurodegenerative diseases, emphasizing the importance of considering interactions between physiological systems. Full article

Background: The dopaminergic theory, the oldest and most comprehensively analyzed neurotransmitter theory of schizophrenia, remains a focal point of research. Methods: This systematic review examines the association between combinations of 14 dopaminergic genes and the risk of schizophrenia. The selected genes include dopamine receptors (DRD1–5), metabolizing enzymes (COMT, MAOA, MAOB, DBH), synthesizing enzymes (TH, DDC), and dopamine transporters (DAT, VMAT1, and VMAT2). Results: Recurring functional patterns show combinations with either hyperdopaminergic effects in limbic and striatal regions or high striatal and low prefrontal dopamine levels. The protective statuses of certain alleles or genotypes are often maintained in epistatic effects; however, exceptions exist. This complexity could explain the inconsistent results in previous genetic studies. Investigating individual alleles may be insufficient due to the heterozygous advantage observed in some studies. Conclusions: Schizophrenia may not be a monolithic disease, but rather a sum of different phenotypes which respond uniquely to different treatment and prevention approaches. Full article

We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT_1A) and dopamine (D₂) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT_1A (K_i = 128.0 nM) and D₂ (K_i = 51.0 nM) receptors, and the SERT (K_i = 9.2 nM) and DAT (K_i = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: K_i = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs. Full article

Background/Objectives: This retrospective study focused on the role of Dopamine Transporter (DAT) scans in diagnosing Parkinson’s Disease (PD) in older adults with cognitive impairment (CI). Methods: We retrospectively analyzed brain imaging of 6483 individuals aged 60 and above with CI. Among these, 297 underwent a DAT scan, with 189 testing positive and 89 starting dopamine therapy. In contrast, 173 patients exhibited PD-associated structural changes on CT or MRI without receiving DAT scans or treatment. Results: Of these patients, 50 (29%) experienced falls. This points towards a potential missed diagnosis of PD, which can respond to therapy in the early stages. Conclusions: Our results suggest that providers may overlook subtle signs of parkinsonism in patients with CI, resulting in symptoms worsening and treatment delay. Since CI is often first brought to the attention of PCPs, our findings call for an increased effort to inform PCPs of the role of DAT scans in aiding the diagnosis of dopamine deficiency states. By understanding PD-related structural changes seen on brain imaging and using a DAT scan to confirm dopamine deficiency, treatment for PD or related states might be started earlier or a timely referral made to a specialist, reducing patient disability and improving their quality of life. Full article

Background: Coping with stress is essential for mental well-being and can be critical for highly sensitive individuals, characterized by a deeper perception and processing of stimuli. So far, the molecular bases characterizing high-sensitivity traits have not been completely investigated and gene × environment interactions might play a key role in making some people more susceptible than others. Methods: In this study, 104 young adult university students, subjects that might face overwhelming experiences more than others, were evaluated for the genetics and epigenetics of dopamine (DAT1) and serotonin (SERT) transporter genes, in addition to the expression of miR-132, miR-491, miR-16, and miR-135. Results: We found an increase in DNA methylation at one specific CpG site at DAT1 5’UTR in highly sensitive students reporting high levels of perceived stress when compared to those less sensitive and/or less stressed. Moreover, considering DAT1 VNTR at 3’UTR, we observed that this effect was even more pronounced in university students having the 9/9 genotype when compared to those with the 9/10 genotype. These data are corroborated by the higher levels of miR-491, targeting DAT1, in highly sensitive subjects with high levels of perceived stress. SERT gene DNA methylation at one specific CpG site was reported to instead be higher in subjects reporting lower perceived stress when compared to more stressed subjects. Consistently, miR-135 expression, regulating SERT, was lower in subjects with higher perceived stress. Conclusions: We here suggest that the correlation of DAT1 and SERT genetic and epigenetic data with the analysis of stress and sensitivity might be useful to suggest possible biomarkers to monitor mental health wellness in vulnerable subjects. Full article

Background/Objectives: Dopamine dysfunction (DA) is a hallmark of many neurological disorders. In this case, the mechanism of changes in dopamine transmission on behavior remains unclear. This study is a look into the intricate link between disrupted DA signaling, neuronal activity patterns, and behavioral abnormalities in a hyperdopaminergic animal model. Methods: To study the relationship between altered DA levels, neuronal activity, and behavioral deficits, local field potentials (LFPs) were recorded during four different behaviors in dopamine transporter knockout rats (DAT-KO). At the same time, local field potentials were recorded in the striatum and prefrontal cortex. Correlates of LFP and accompanying behavioral patterns in genetically modified (DAT-KO) and control animals were studied. Results: DAT-KO rats exhibited desynchronization between LFPs of the striatum and prefrontal cortex, particularly during exploratory behavior. A suppressive effect of high dopamine levels on the striatum was also observed. Wild-type rats showed greater variability in LFP patterns across certain behaviors, while DAT-KO rats showed more uniform patterns. Conclusions: The decisive role of the synchrony of STR and PFC neurons in the organization of motor acts has been revealed. The greater variability of control animals in certain forms of behavior probably suggests greater adaptability. More uniform patterns in DAT-KO rats, indicating a loss of striatal flexibility when adapting to specific motor tasks. It is likely that hyperdopaminergy in the DAT-KO rat reduces the efficiency of information processing due to less synchronized activity during active behavior. Full article

Prolonged exposure to HIV-1 transactivator of transcription (Tat) protein dysregulates monoamine transmission, a physiological change implicated as a key factor in promoting neurocognitive disorders among people living with HIV. We have demonstrated that in vivo expression of Tat in Tat transgenic mice decreases dopamine uptake through both dopamine transporter (DAT) and norepinephrine transporter (NET) in the prefrontal cortex. Further, our novel allosteric inhibitor of monoamine transporters, SRI-32743, has been shown to attenuate Tat-inhibited dopamine transport through DAT and alleviates Tat-potentiated cognitive impairments. The current study reports the pharmacological profiles of SRI-32743 in basal and Tat-induced inhibition of human NET (hNET) function. SRI-32743 exhibited less affinity for hNET binding than desipramine, a classical NET inhibitor, but displayed similar potency for inhibiting hDAT and hNET activity. SRI-32743 concentration-dependently increased hNET affinity for [³H]DA uptake but preserved the V_max of dopamine transport. SRI-32743 slowed the cocaine-mediated dissociation of [³H]Nisoxetine binding and reduced both [³H]DA and [³H]MPP+ efflux but did not affect d-amphetamine-mediated [³H]DA release through hNET. Finally, we determined that SRI-32743 attenuated a recombinant Tat_1–86-induced decrease in [³H]DA uptake via hNET. Our findings demonstrated that SRI-32743 allosterically disrupts the recombinant Tat_1–86–hNET interaction, suggesting a potential treatment for HIV-infected individuals with concurrent cocaine abuse. Full article

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT. Full article

Playing a key role in the organization of striatal motor output, the dopamine (DA)-ergic system regulates both innate and complex learned behaviors. Growing evidence clearly indicates the involvement of the DA-ergic system in different forms of repetitive (perseverative) behavior. Some of these behaviors accompany such disorders as obsessive–compulsive disorder (OCD), Tourette’s syndrome, schizophrenia, and addiction. In this study, we have traced how the inflexibility of repetitive reactions in the recently developed animal model of hyper-DA-ergia, dopamine transporter knockout rats (DAT-KO rats), affects the realization of innate behavior (grooming) and the learning of spatial (learning and reversal learning in T-maze) and non-spatial (extinction of operant reaction) tasks. We found that the microstructure of grooming in DAT-KO rats significantly differed in comparison to control rats. DAT-KO rats more often demonstrated a fixed syntactic chain, making fewer errors and very rarely missing the chain steps in comparison to control rats. DAT-KO rats’ behavior during inter-grooming intervals was completely different to the control animals. During learning and reversal learning in the T-maze, DAT-KO rats displayed pronounced patterns of hyperactivity and perseverative (stereotypical) activity, which led to worse learning and a worse performance of the task. Most of the DAT-KO rats could not properly learn the behavioral task in question. During re-learning, DAT-KO rats demonstrated rigid perseverative activity even in the absence of any reinforcement. In operant tasks, the mutant rats demonstrated poor extinction of operant lever pressing: they continued to perform lever presses despite no there being reinforcement. Our results suggest that abnormally elevated DA levels may be responsible for behavioral rigidity. It is conceivable that this phenomenon in DAT-KO rats reflects some of the behavioral traits observed in clinical conditions associated with endogenous or exogenous hyper-DA-ergia, such as schizophrenia, substance abuse, OCD, patients with Parkinson disease treated with DA mimetics, etc. Thus, DAT-KO rats may be a valuable behavioral model in the search for new pharmacological approaches to treat such illnesses. Full article

The utility of transcranial sonography (TCS) remains unclarified for the auxiliary diagnosis of Parkinson’s disease (PD). We investigated iodine-123 metaiodobenzylguanidine (MIBG) and TCS during the examination and diagnosis of high-signal-intensity substantia nigra lesion (HSI-SNL) incidence in PD patients previously diagnosed with dopamine transporter scintigraphy (DAT). The subjects were 67 patients with definitively diagnosed PD after DAT evaluation. Patients with midbrain substantia nigra visible during TCS who previously underwent MIBG were analyzed. The SN+ group comprised patients with extensive pathological HSI-SNL of Okawa class III/IV observed during TCS. The MIBG+ group comprised patients with a heart-to-mediastinum ratio of ≤2.2 during MIBG. TCS was performed to divide patients into the SN+ and SN− groups, and patient characteristics and MIBG findings were compared between the groups. PD was definitively diagnosed in 67 patients, among whom midbrain was visualized during TCS in 43 (64.1%) patients and pathological HSI-SNL was observed in 24 (35.8%). The MIBG findings were normal in six patients (27.3%) with HSI-SNL, and abnormal in seven (63.6%) without HSI-SNL. No significant differences were noted by Okawa classification in clinical characteristics based on the presence or absence of HSI-SNL. Multiple patients with normal findings during MIBG may have HSI-SNL. Thus, confirmatory imaging of HSI-SNL with TCS may be useful for diagnosis. Full article

The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron’s sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed. Full article

Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [³H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [³H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders. Full article