Dopaminergic Neurotransmission Research Articles

MDPV (3,4-methylenedioxypyrovalerone) administered to mice during development of the central nervous system produces persistent learning and memory impairments

BackgroundSynthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice.MethodsAll experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11–20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot.ResultsExposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent.ConclusionsMDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.

Epigenetic Effects of Finasteride on Dopaminergic Signaling Pathways: A potential contributor to Post-Finasteride Syndrome

Dopamine, a widely-distributed neurotransmitter in the brain and elsewhere, is important for regulating reward-motivated behavior, sexual impetus, concentration, pleasure, emotions, and genital arousal. Findings have previously implicated aberrant dopaminergic neurotransmission in mental disorders, as well as sexual and erectile dysfunction. To evaluate the epigenetic effects of finasteride on dopaminergic signaling pathways, we treated human Leydig cells with finasteride and identified several dopaminergic pathways that were altered by differential methylation of component genes. These genes included those involved in the regulation of dopamine secretion and transport (OR56A4, OR13F1 and SYT4), the Phospholipase C-activating dopamine receptor signaling pathway (OR56A4 and OR13F1), the dopaminergic synapse (CALML4, COMT, GNAI2, GNAS, GNG10, GRIA1, GSK3A, GSK3B, KCNJ9, PPP2R2C, PPP2R3B, PPP2R3C, PPP2R5A, PPP2R5E) and the dopamine receptor activity and binding pathway (OR56A4, OR13F1). This alteration of gene methylation suggests a potential role of altered epigenetic regulation of dopaminergic pathways in the etiology and pathophysiology of post-finasteride syndrome (PFS), which should be further investigated. National Institutes of Health (NIH) R25 Resource Grant (1 R25 AG047843-01) to ABC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Beyond dopamine: Novel strategies for schizophrenia treatment.

Despite extensive research efforts aimed at discovering novel antipsychotic compounds, a satisfactory pharmacological strategy for schizophrenia treatment remains elusive. All the currently available drugs act by modulating dopaminergic neurotransmission, leading to insufficient management of the negative and cognitive symptoms of the disorder. Due to these challenges, several attempts have been made to design agents with innovative, non-dopaminergic mechanisms of action. Consequently, a number of promising compounds are currently progressing through phases 2 and 3 of clinical trials. This review aims to examine the rationale behind the most promising of these strategies while simultaneously providing a comprehensive survey of study results. We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT-1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5-HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates.

The trace amine-associated receptor 1 agonists - non-dopaminergic antipsychotics or covert modulators of D2 receptors?

A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression

BackgroundDepression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. MethodsSix patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. ResultsDepression and anxiety symptoms improved after 3–6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LimitationsThis study was limited to the small sample size and lack of a healthy control group. ConclusionsChronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

Transient receptor potential ankyrin 1 channel modulates the abuse-related mechanisms of methamphetamine through interaction with dopamine transporter.

Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA-approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse-related behaviours in rodents: self-administration, drug-primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH-induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild-type and TRPA1 knock-out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. TRPA1 antagonism blunted METH self-administration and drug-primed reinstatement of METH-seeking behaviour. Further, development of METH-induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock-out mice. Similarly, molecular studies revealed METH-induced increases in dopamine levels and expression of dopamine system-related proteins in wild-type, but not in TRPA1 knock-out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. This study demonstrates that TRPA1 is involved in the abuse-related behavioural effects of METH, potentially through its modulatory role in METH-induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder.

Amygdalar neurotransmission alterations in the BTBR mice model of idiopathic autism.

Autism Spectrum Disorders (ASD) are principally diagnosed by three core behavioural symptoms, such as stereotyped repertoire, communication impairments and social dysfunctions. This complex pathology has been linked to abnormalities of corticostriatal and limbic circuits. Despite experimental efforts in elucidating the molecular mechanisms behind these abnormalities, a clear etiopathogenic hypothesis is still lacking. To this aim, preclinical studies can be really helpful to longitudinally study behavioural alterations resembling human symptoms and to investigate the underlying neurobiological correlates. In this regard, the BTBR T+ Itpr3tf/J (BTBR) mice are an inbred mouse strain that exhibits a pattern of behaviours well resembling human ASD-like behavioural features. In this study, the BTBR mice model was used to investigate neurochemical and biomolecular alterations, regarding Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), together with GABAergic, glutamatergic, cholinergic, dopaminergic and noradrenergic neurotransmissions and their metabolites in four different brain areas, i.e. prefrontal cortex, hippocampus, amygdala and hypothalamus. In our results, BTBR strain reported decreased noradrenaline, acetylcholine and GABA levels in prefrontal cortex, while hippocampal measurements showed reduced NGF and BDNF expression levels, together with GABA levels. Concerning hypothalamus, no differences were retrieved. As regarding amygdala, we found reduced dopamine levels, accompanied by increased dopamine metabolites in BTBR mice, together with decreased acetylcholine, NGF and GABA levels and enhanced glutamate content. Taken together, our data showed that the BTBR ASD model, beyond its face validity, is a useful tool to untangle neurotransmission alterations that could be underpinned to the heterogeneous ASD-like behaviours, highlighting the crucial role played by amygdala.

Dopaminergic mesolimbic structural reserve is positively linked to better outcome after severe stroke.

The concept of brain reserve capacity has emerged in stroke recovery research in recent years. Imaging-based biomarkers of brain health have helped to better understand outcome variability in clinical cohorts. Still, outcome inferences are far from being satisfactory, particularly in patients with severe initial deficits. Neurorehabilitation after stroke is a complex process, comprising adaption and learning processes, which, on their part, are critically influenced by motivational and reward-related cognitive processes. Amongst others, dopaminergic neurotransmission is a key contributor to these mechanisms. The question arises, whether the amount of structural reserve capacity in the dopaminergic system might inform about outcome variability after severe stroke. For this purpose, this study analysed imaging and clinical data of 42 severely impaired acute stroke patients. Brain volumetry was performed within the first 2 weeks after the event using the Computational Anatomy Toolbox CAT12, grey matter volume estimates were collected for seven key areas of the human dopaminergic system along the mesocortical, mesolimbic and nigrostriatal pathways. Ordinal logistic regression models related regional volumes to the functional outcome, operationalized by the modified Rankin Scale, obtained 3-6 months after stroke. Models were adjusted for age, lesion volume and initial impairment. The main finding was that larger volumes of the amygdala and the nucleus accumbens at baseline were positively associated with a more favourable outcome. These data suggest a link between the structural state of mesolimbic key areas contributing to motor learning, motivational and reward-related brain networks and potentially the success of neurorehabilitation. They might also provide novel evidence to reconsider dopaminergic interventions particularly in severely impaired stroke patients to enhance recovery after stroke.

Tannic acid coated nanosuspension for oral delivery of chrysin intended for anti-schizophrenic effect in mice

Chrysin is a flavonoid drug with numerous therapeutic activities. It suffers from low intestinal absorption owing to its hydrophobicity. Therefore, the aim of this study is to exploit the efficient technique of nanosuspension (NSP) to formulate chrysin-NSP coated with tannic acid (TA) to improve the solubility and anti-schizophrenic activity of chrysin. A 23 full factorial design was constructed where the independent factors were type of polymer, surfactant concentration (0.5 or 1 %) and the aqueous phase volume (5 or 15 mL), while the dependent responses were the particle size (PS) of the obtained formulation as well as the % chrysin dissolved after 2 h (Q2h). The optimum formulation (NSP-4) composed of 1 % PEG 400 and 1 % Cremophor RH40 in 15 mL aqueous phase. It achieved a PS and Q2h values of 108.00 nm and 38.77 %, respectively. NSP-4 was then coated with TA (TA-coated NSP-4) for further enhancement of chrysin solubility. TA-coated NSP-4 revealed PS and zeta potential values of 150 ± 14 nm and –32.54 ± 2.45 mV, respectively. After 6 h, chrysin dissolved % were 53.97 and 80.22 for uncoated NSP-4 and TA-coated NSP-4, respectively, compared with only 9.47 for free chrysin. The developed formulations and free chrysin were assessed regarding their effect on schizophrenia induced in mice by cuprizone (CPZ). Treatment with the developed formulations and free chrysin ameliorated demyelination and behavioral deficit induced by CPZ via elevating MBP and PI3K/PKC activities as well as reducing GFAP expression levels. The developed formulations and free chrysin inhibited Galactin-3 and TGF-β expressions and stimulated GST antioxidant enzyme. Furthermore, they maintained the balances in glutamatergic and dopaminergic neurotransmission via modulation on neuregulin-1 and alleviated nuclear pyknosis and degeneration in the neurons. The order of activity was: TA-coated NSP-4 > NSP-4 > free chrysin.

Resting state changes in aging and Parkinson’s disease are shaped by underlying neurotransmission – a normative modeling study

BackgroundHuman healthy and pathological aging is linked to a steady decline in brain resting state activity and connectivity measures. The neurophysiological mechanisms underlying these changes remain poorly understood. MethodsMaking use of recent developments in normative modeling and availability of in vivo maps for various neurochemical systems, we test in the UK Biobank cohort (N=25917) if and how age- and Parkinson’s disease related resting state changes in commonly applied local and global activity and connectivity measures co-localize with underlying neurotransmitter systems. ResultsWe find the distributions of several major neurotransmitter systems including serotonergic, dopaminergic, noradrenergic, and glutamatergic neurotransmission to correlate with age-related changes as observed across functional activity and connectivity measures. Co-localization patterns in Parkinson’s disease deviate from normative aging trajectories for these, as well as for cholinergic and GABAergic, neurotransmission. The deviation from normal co-localization of brain function and GABAa correlates with disease duration. ConclusionsThese findings provide new insights into molecular mechanisms underlying age- and Parkinson’s related brain functional changes by extending the existing evidence elucidating the vulnerability of specific neurochemical attributes to normal aging and Parkinson’s disease. The results particularly indicate that alongside dopamine and serotonin, increased vulnerability of glutamatergic, cholinergic, and GABAergic systems may also contribute to Parkinson’s disease-related functional alterations. Combining normative modeling and neurotransmitter mapping may aid future research and drug development through deeper understanding of neurophysiological mechanisms underlying specific clinical conditions.

Fabrication of Amisulpride Nanosuspension for Nose to Brain Delivery in the Potential Antipsychotic Treatment

ABSTRACT: Background: This research was aimed with the development of antipsychotic drug delivery for olfactory administration which could deliver drug to the brain. Amisulpride is a psychoactive drug that belongs to the benzamide derivatives class. It enhances dopaminergic neurotransmission by inhibiting presynaptic dopamine D2/D3 auto receptors selectively at lower dosages. Method: The nanosuspension was prepared by media milling technique for nose to brain delivery. The nose to brain delivery developed an effective route to bypass the BBB and deliver the drug to the brain. Factorial design was used for the designing and optimizing formulation based on various process and formulation factors. The optimized batch further analyzed to determine particle size, PDI, zeta potential, and drug content. With appropriate selection of process parameters like speed and bead amount. The media milling method is one of the effective methodology to reduce particle size and with the help of stabilizers nanoparticles could be stabilised. Result: The average particle size range of nanosuspension batch was observed 100-150 nm with a polydispersity index of 0.0927, Zeta potential +39.14 mV and drug content 88.12 ± 2 %. Conclusion: Intranasal administration is a promising alternative for bypassing the blood-brain barrier, reducing the adverse effects, and lowering the doses.

Rare CRHR2 and GRM8 variants identified as candidate factors associated with eating disorders in Japanese patients by whole exome sequencing

Eating disorders (EDs) are a type of psychiatric disorder characterized by pathological eating and related behavior and considered to be highly heritable. The purpose of this study was to explore rare variants expected to display biological functions associated with the etiology of EDs. We performed whole exome sequencing (WES) of affected sib-pairs corresponding to disease subtype through their lifetime and their parents. From those results, rare single nucleotide variants (SNVs) concordant with sib-pairs were extracted and estimated to be most deleterious in the examined families. Two non-synonymous SNVs located on corticotropin-releasing hormone receptor 2 (CRHR2) and glutamate metabotropic receptor 8 (GRM8) were identified as candidate disease susceptibility factors. The SNV of CRHR2 was included within the cholesterol binding motif of the transmembrane helix region, while the SNV of GRM8 was found to contribute to hydrogen bonds for an α-helix structure. CRHR2 plays important roles in the serotoninergic system of dorsal raphe nuclei, which is involved with feeding and stress-coping behavior, whereas GRM8 modulates glutamatergic neurotransmission. Moreover, GRM8 modulates glutamatergic neurotransmission, and is also considered to have effects on dopaminergic and adrenergic neurotransmission. Thus, identification of rare and deleterious variants in this study is expected to increase understanding and treatment of affected individuals. Further investigation regarding the biological function of these variants may provide an opportunity to elucidate the pathogenesis of EDs.

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Angiotensin II involvement in the development and persistence of amphetamine-induced sensitization: Striatal dopamine reuptake implications.

Amphetamine (AMPH) exposure induces behavioural and neurochemical sensitization observed in rodents as hyperlocomotion and increased dopamine release in response to a subsequent dose. Brain Angiotensin II modulates dopaminergic neurotransmission through its AT1 receptors (AT1 -R), positively regulating striatal dopamine synthesis and release. This work aims to evaluate the AT1 -R role in the development and maintenance of AMPH-induced sensitization. Also, the AT1 -R involvement in striatal dopamine reuptake was analysed. The sensitization protocol consisted of daily AMPH administration for 5days and tested 21 days after withdrawal. An AT1 -R antagonist, candesartan, was administered before or after AMPH exposure to evaluate the participation of AT1 -R in the development and maintenance of sensitization, respectively. Sensitization was evaluated by locomotor activity and c-Fos immunostaining. Changes in dopamine reuptake kinetics were evaluated 1day after AT1 -R blockade withdrawal treatment, with or without the addition of AMPH in vitro. The social interaction test was performed as another behavioural output. Repeated AMPH exposure induced behavioural and neurochemical sensitization, which was prevented and reversed by candesartan. The AT1 -R blockade increased the dopamine reuptake kinetics. Neither the AMPH administration nor the AT1 -R blockade altered the performance of social interaction. Our results highlight the AT1 -R's crucial role in AMPH sensitization. The enhancement of dopamine reuptake kinetics induced by the AT1 -R blockade might attenuate the neuroadaptive changes that lead to AMPH sensitization and its self-perpetuation. Therefore, AT1 -R is a prominent candidate as a target for pharmacological treatment of pathologies related to dopamine imbalance, including drug addiction and schizophrenia.

Dementia and depression: Biological connections with amyloid β protein.

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It is estimated that dementia affects 50 million people worldwide and that Alzheimer's disease (AD) is responsible for up to 75% of cases. Small extracellular senile plaques composed of filamentous aggregates of amyloid β (Aβ) protein tend to bind to neuronal receptors, affecting cholinergic, serotonergic, dopaminergic and noradrenergic neurotransmission, leading to neuroinflammation, among other pathophysiologic processes and subsequent neuronal death, followed by dementia. The amyloid cascade hypothesis points to a pathological process in the cleavage of the amyloid precursor protein (APP), resulting in pathological Aβ. There is a close relationship between the pathologies that lead to dementia and depression. It is estimated that depression is prevalent in up to 90% of individuals diagnosed with Parkinson's disease, with varying severity, and in 20 to 30% of cases of Alzheimer's disease. The hypothalamic pituitary adrenal (HPA) axis is the great intermediary between the pathophysiological mechanisms in neurodegenerative diseases and depression. This review discusses the role of Aβ protein in the pathophysiological mechanisms of dementia and depression, considering the HPA axis, neuroinflammation, oxidative stress, signalling pathways and neurotransmission.

Genetic loss of the dopamine transporter significantly impacts behavioral and molecular responses to sub-chronic stress in mice.

Dopaminergic neurotransmission has emerged as a critical determinant of stress susceptibility and resilience. Although the dopamine transporter (DAT) is known to play a key role in maintaining dopamine (DA) homeostasis, its importance for the regulation of stress susceptibility remains largely unknown. Indeed, while numerous studies have examined the neurochemical and behavioral consequences of genetic loss of DAT, very few have compared responses to stress in wild-type and DAT-knockout (KO) animals. The current study compared the responses of male and female WT and DAT-KO mice to a model of sub-chronic stress. Our results reveal that DAT-KO mice are resistant to stress-induced increases in the latency to enter the light chamber of the light-dark emergence test and demonstrate that DAT-KO mice exhibit baseline reductions in forced swim test immobility and grooming time in the splash test of grooming behavior. In addition to these behavioral changes, our results highlight the importance of sex and dopaminergic neurotransmission on stress-induced changes in the expression and phosphorylation of several signal transduction molecules in the nucleus accumbens that have previously been implicated in the regulation of stress susceptibility, including ERK, GSK3β, and ΔFosB. Overall, these results provide further evidence of the importance of dopaminergic neurotransmission in regulating stress susceptibility and suggest that genetic loss of DAT prevents stress-induced increases in anxiety-like behavior.

Long-term exposure to 6-PPD quinone at environmentally relevant concentrations causes neurotoxicity by affecting dopaminergic, serotonergic, glutamatergic, and GABAergic neuronal systems in Caenorhabditis elegans

6-PPD quinone (6-PPDQ), an emerging environmental pollutant, is converted based on 6-PPD via ozonation. However, a systematic evaluation on possible neurotoxicity of long-term and low-dose 6-PPDQ exposure and the underlying mechanism remain unknown. In the present work, 0.1–10 μg/L 6-PPDQ was added to treat Caenorhabditis elegans for 4.5 days, with locomotion behavior, neuronal development, sensory perception behavior, neurotransmitter content, and levels of neurotransmission-related genes being the endpoints. 6-PPDQ exposure at 0.1–10 μg/L significantly reduced locomotion behavior, and that at 1–10 μg/L decreased sensory perception behavior in nematodes. Moreover, 6-PPDQ exposure at 10 μg/L notably induced damage to the development of dopaminergic, glutamatergic, serotonergic, and GABAergic neurons. Importantly, nematodes with chronic 6-PPDQ exposure at 10 μg/L were confirmed to suffer obviously decreased dopamine, serotonin, glutamate, dopamine, and GABA contents and altered neurotransmission-related gene expression. Meanwhile, the potential binding sites of 6-PPDQ and neurotransmitter synthesis-related proteins were further shown by molecular docking method. Lastly, Pearson's correlation analysis showed that locomotion behavior and sensory perception behavior were positively correlated with the dopaminergic, serotonergic, glutamatergic, and GABAergic neurotransmission. Consequently, 6-PPDQ exposure disturbed neurotransmitter transmission, while such changed molecular foundation for neurotransmitter transmission was related to 6-PPDQ toxicity induction. The present work sheds new lights on the mechanisms of 6-PPDQ and its possible neurotoxicity to organisms at environmentally relevant concentrations.

Fractional amplitude of low-frequency fluctuations associated with μ-opioid and dopamine receptor distributions in the central nervous system after high-intensity exercise bouts.

Dopaminergic, opiod and endocannabinoid neurotransmission are thought to play an important role in the neurobiology of acute exercise and, in particular, in mediating positive affective responses and reward processes. Recent evidence indicates that changes in fractional amplitude of low-frequency fluctuations (zfALFF) in resting-state functional MRI (rs-fMRI) may reflect changes in specific neurotransmitter systems as tested by means of spatial correlation analyses. Here, we investigated this relationship at different exercise intensities in twenty young healthy trained athletes performing low-intensity (LIIE), high-intensity (HIIE) interval exercises, and a control condition on three separate days. Positive And Negative Affect Schedule (PANAS) scores and rs-fMRI were acquired before and after each of the three experimental conditions. Respective zfALFF changes were analyzed using repeated measures ANOVAs. We examined the spatial correspondence of changes in zfALFF before and after training with the available neurotransmitter maps across all voxels and additionally, hypothesis-driven, for neurotransmitter maps implicated in the neurobiology of exercise (dopaminergic, opiodic and endocannabinoid) in specific brain networks associated with "reward" and "emotion." Elevated PANAS Positive Affect was observed after LIIE and HIIE but not after the control condition. HIIE compared to the control condition resulted in differential zfALFF decreases in precuneus, temporo-occipital, midcingulate and frontal regions, thalamus, and cerebellum, whereas differential zfALFF increases were identified in hypothalamus, pituitary, and periaqueductal gray. The spatial alteration patterns in zfALFF during HIIE were positively associated with dopaminergic and μ-opioidergic receptor distributions within the 'reward' network. These findings provide new insight into the neurobiology of exercise supporting the importance of reward-related neurotransmission at least during high-intensity physical activity.

Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice.

Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requiresN-methyl-D-aspartate (NMDA) receptor activity and is independent of dopaminergic neurotransmission. Our in vivo pharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior.