Single Neurotransmitter Research Articles

What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia.

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts and behaviors, cognitive dysfunction, and negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known as antipsychotic drugs, which aim to alleviate symptoms and improve functioning and the quality of life. Despite the availability of these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, treatment resistance, and medication side effects. This opinion article explores advancements in schizophrenia treatment, emphasizing molecular mechanisms, novel drug targets, and innovative delivery methods. One promising approach is novel strategies that target neural networks and circuits rather than single neurotransmitters, acknowledging the complexity of brain region interconnections involved in schizophrenia. Another promising approach is the development of biased agonists, which selectively activate specific signaling pathways downstream of receptors, offering potential for more precise pharmacological interventions with fewer side effects. The concept of molecular polypharmacy, where a single drug targets multiple molecular pathways, is exemplified by KarXT, a novel drug combining xanomeline and trospium to address both psychosis and cognitive dysfunction. This approach represents a comprehensive strategy for schizophrenia treatment, potentially improving outcomes for patients. In conclusion, advancing the molecular understanding of schizophrenia and exploring innovative therapeutic strategies hold promise for addressing the unmet needs in schizophrenia treatment, aiming for more effective and tailored interventions. Future research should focus on these novel approaches to achieve better clinical outcomes and improve the functional level and quality of life for individuals with schizophrenia.

Autonomic dysfunction and fatigue in Parkinson’s disease: a report from Kenya

Fatigue is a common non-motor symptom of Parkinson's disease (PD) that significantly impacts patient quality of life. However, the underlying mechanisms of fatigue in PD remain unclear. The present study aims to investigate the involvement of autonomic dysfunction, specifically cardiac sympathetic denervation, in the pathogenesis of fatigue in PD. Thirty-two Caucasian PD patients with a well-defined follow-up period and no depression or cognitive impairment were included in the study. Fatigue was evaluated using the Parkinson Fatigue Scale-16 (PFS-16), and autonomic function was assessed through MIBG scintigraphy and comprehensive autonomic function tests (AFTs). The results showed that fatigue is a prevalent issue in PD, with a prevalence of 48.15%, and is positively correlated with disease duration and reduced parasympathetic activity as measured by the deep breathing test. However, no significant correlations were found between fatigue and other AFT parameters related to sympathetic innervation or noradrenergic pathway dysfunction as measured by MIBG myocardial scintigraphy. The findings suggest that fatigue in PD has a multifaceted pathophysiology and cannot be solely attributed to dysfunction in a single neurotransmitter system. The study highlights the importance of recognizing fatigue as a significant aspect of PD and further investigating its underlying mechanisms to improve patient care and management.

Animal models for the evaluation of antipsychotic agents.

Schizophrenia, the most serious among psychoses, has negative symptoms such as anhedonia, avolition and apathy, and cognitive defects in addition to positive symptoms such as hallucinations and delusions characterising all psychotic disorders. Traditional antipsychotics had dopamine D2 receptor antagonism as their principal mechanism of action, with disabling extrapyramidal symptoms as corollary. Newer atypical agents with diverse receptor actions introduced to circumvent this issue, nevertheless, had varied side effects such as agranulocytosis, insulin resistance, seizures, and cardiac events. Also, symptoms in cognitive and negative domains do not respond well even to newer agents creating an unmet need. Designing a valid animal model with translational relevance for a complex disease such as schizophrenia is a tedious process. Induction or suppression of certain animal behaviours by test compounds (behavioural models) and antagonising effects induced by compounds with psychotic potential (pharmacological models) are the conventional models used. One among the major disadvantages with conventional models is that these paradigms are induced acutely and relate to aberration of a single neurotransmitter system, which is in sharp contrast to the chronic nature and interplay of multiple neurotransmitter systems in psychotic diseases. However, with progress in elucidation of disease mechanisms, novel models are generated utilising developmental, genetic, and environmental factors (neurodevelopmental models) to effectively reflect the human disease pathogenesis and clinical manifestations, but with paucity of studies assessing the impact of drugs on them. This review presents an overview of schizophrenia hypotheses, requisites of a valid animal model, available animal models with their advantages and disadvantages.

Distinct cell populations of ventral tegmental area process motivated behavior

It is well known that dopamine transmission from the ventral tegmental area (VTA) modulates motivated behavior and reinforcement learning. Although dopaminergic neurons are the major type of VTA neurons, recent studies show that a significant proportion of the VTA contains GABAergic and type 2 vesicular glutamate transporter (VGLUT2)-positive neurons. The non-dopaminergic neurons are also critically involved in regulating motivated behaviors. Some VTA neurons appear to co-release two different types of neurotransmitters. They are VGLUT2-DA neurons, VGLUT2-GABA neurons and GABA-DA neurons. These co-releasing neurons show distinct features compared to the neurons that release a single neurotransmitter. Here, we review how VTA cell populations wire to the other brain regions and how these projections differentially contribute to motivated behavior through the distinct molecular mechanism. We summarize the activities, projections and functions of VTA neurons concerning motivated behavior. This review article discriminates VTA cell populations related to the motivated behavior based on the neurotransmitters they release and extends the classical view of the dopamine-mediated reward system.

Sleep-Wake Neurochemistry.

Behavioral states naturally alternate between wakefulness and the sleep phases rapid eye movement and nonrapid eye movement sleep. Waking and sleep states are complex processes that are elegantly orchestrated by spatially fine-tuned neurochemical changes of neurotransmitters and neuromodulators including glutamate, acetylcholine, γ-aminobutyric acid, norepinephrine, dopamine, serotonin, histamine, hypocretin, melanin concentrating hormone, adenosine, and melatonin. However, as highlighted in this brief overview, no single neurotransmitter or neuromodulator, but rather their complex interactions within organized neuronal ensembles, regulate waking and sleep states. The neurochemical pathways presented here are aimed to provide a conceptual framework for the understanding of the effects of currently used sleep medications.

Dopamine Synthesis Capacity and GABA and Glutamate Levels Separate Antipsychotic-Naïve Patients With First-Episode Psychosis From Healthy Control Subjects in a Multimodal Prediction Model

BackgroundDisturbances in presynaptic dopamine activity and levels of GABA (gamma-aminobutyric acid) and glutamate plus glutamine collectively may have a role in the pathophysiology of psychosis, although separately they are poor diagnostic markers. We tested whether these neurotransmitters in combination improve the distinction of antipsychotic-naïve patients with first-episode psychosis from healthy control subjects. MethodsWe included 23 patients (mean age 22.3 years, 9 male) and 20 control subjects (mean age 22.4 years, 8 male). We determined dopamine metabolism in the nucleus accumbens and striatum from 18F-fluorodopa (18F-FDOPA) positron emission tomography. We measured GABA levels in the anterior cingulate cortex (ACC) and glutamate plus glutamine levels in the ACC and left thalamus with 3T proton magnetic resonance spectroscopy. We used binominal logistic regression for unimodal prediction when we modeled neurotransmitters individually and for multimodal prediction when we combined the 3 neurotransmitters. We selected the best combination based on Akaike information criterion. ResultsIndividual neurotransmitters failed to predict group. Three triple neurotransmitter combinations significantly predicted group after Benjamini-Hochberg correction. The best model (Akaike information criterion 48.5) carried 93.5% of the cumulative model weight. It reached a classification accuracy of 83.7% (p = .003) and included dopamine synthesis capacity (Ki4p) in the nucleus accumbens (p = .664), GABA levels in the ACC (p = .019), glutamate plus glutamine levels in the thalamus (p = .678), and the interaction term Ki4p × GABA (p = .016). ConclusionsOur multimodal approach proved superior classification accuracy, implying that the pathophysiology of patients represents a combination of neurotransmitter disturbances rather than aberrations in a single neurotransmitter. Particularly aberrant interrelations between Ki4p in the nucleus accumbens and GABA values in the ACC appeared to contribute diagnostic information.

Colocalization of different neurotransmitter transporters on synaptic vesicles is sparse except for VGLUT1 and ZnT3

Vesicular transporters (VTs) define the type of neurotransmitter that synaptic vesicles (SVs) store and release. While certain mammalian neurons release multiple transmitters, it is not clear whether the release occurs from the same or distinct vesicle pools at the synapse. Using quantitative single-vesicle imaging, we show that a vast majority of SVs in the rodent brain contain only one type of VT, indicating specificity for a single neurotransmitter. Interestingly, SVs containing dual transporters are highly diverse (27 types) but small in proportion (2% of all SVs), excluding the largest pool that carries VGLUT1 and ZnT3 (34%). Using VGLUT1-ZnT3 SVs, we demonstrate that the transporter colocalization influences the SV content and synaptic quantal size. Thus, the presence of diverse transporters on the same vesicle is bona fide, and depending on the VT types, this may act to regulate neurotransmitter type, content, and release in space and time.

Functional Constructivism Approach to Multilevel Nature of Bio-Behavioral Diversity.

Attempts to revise the existing classifications of psychiatric disorders (DSM and ICD) continue and highlight a crucial need for the identification of biomarkers underlying symptoms of psychopathology. The present review highlights the benefits of using a Functional Constructivism approach in the analysis of the functionality of the main neurotransmitters. This approach explores the idea that behavior is neither reactive nor pro-active, but constructive and generative, being a transient selection of multiple degrees of freedom in perception and actions. This review briefly describes main consensus points in neuroscience related to the functionality of eight neurochemical ensembles, summarized as a part of the neurochemical model Functional Ensemble of Temperament (FET). None of the FET components is represented by a single neurotransmitter; all neurochemical teams have specific functionality in selection of behavioral degrees of freedom and stages of action construction. The review demonstrates the possibility of unifying taxonomies of temperament and classifications of psychiatric disorders and presenting these taxonomies formally and systematically. The paper also highlights the multi-level nature of regulation of consistent bio-behavioral individual differences, in line with the concepts of diagonal evolution (proposed earlier) and Specialized Extended Phenotype.

Bridging the gap between single receptor type activity and whole-brain dynamics.

What is the effect of activating a single modulatory neuronal receptor type on entire brain network dynamics? Can such effect be isolated at all? These are important questions because characterizing elementary neuronal processes that influence network activity across the given anatomical backbone is fundamental to guide theories of brain function. Here, we introduce the concept of the cortical 'receptome' taking into account the distribution and densities of expression of different modulatory receptor types across the brain's anatomical connectivity matrix. By modelling whole-brain dynamics in silico, we suggest a bidirectional coupling between modulatory neurotransmission and neuronal connectivity hardware exemplified by the impact of single serotonergic (5-HT) receptor types on cortical dynamics. As experimental support of this concept, we show how optogenetic tools enable specific activation of a single 5-HT receptor type across the cortex as well as in vivo measurement of its distinct effects on cortical processing. Altogether, we demonstrate how the structural neuronal connectivity backbone and its modulation by a single neurotransmitter system allow access to a rich repertoire of different brain states that are fundamental for flexible behaviour. We further propose that irregular receptor expression patterns-genetically predisposed or acquired during a lifetime-may predispose for neuropsychiatric disorders like addiction, depression and anxiety along with distinct changes in brain state. Our long-term vision is that such diseases could be treated through rationally targeted therapeutic interventions of high specificity to eventually recover natural transitions of brain states.

Selective Release of Different Neurotransmitters Emulated by a p-i-n Junction Synaptic Transistor for Environment-Responsive Action Control.

The design of the first p-i-n junction synaptic transistor (JST) based on n-type TiO2 film covered with poly(methyl methacrylate) (PMMA) and with a p-type P3HT/PEO nanowire (NW) on top. Except for basic synaptic functions that can be realized by a single neurotransmitter, the electronic device emulates the multiplexed neurotransmission of different neurotransmissions, i.e., glutamate and acetylcholine, for fast switching between short- and long-term plasticity (STP and LTP). This is realized by the special p-i-n junction with hole transport in the p-type P3HT NW to form STP, and electron transport in the n-type TiO2 layer and trapped under the PMMA inversion layer to form LTP. Altering the external input induces changes of the polarity of the charge carriers in the conductive channel, promoting fast switching between STP and LTP modes. When stimulated using two parallel inputs, the response of PMMA/TiO2 emulates the synergistic effect of taste and aroma on the control of food-intake in the brain. Because of the bipolarity, the p-i-n JST has excellent reconfigurability, which importantly is attributed to simulate the plasticity of synapses and to mimic how distinct types of gustatory receptor neurons respond to different concentrations of salt. The electronic device lays the technical foundation for the realization of the future complex artificial neural networks.

Single-Cell Transcriptomic Reveals Dual and Multi-Transmitter Use in Neurons Across Metazoans

Neurotransmitter expression is widely used as a criterion for classifying neurons. It was initially thought that neurons express a single type of neurotransmitter, a phenomenon commonly recognized as Dale's principle: “one neuron, one transmitter.” Consequently, the expression of a single neurotransmitter should determine stable and distinguishable neuronal characteristics. However, this notion has been largely challenged and increasing evidence accumulates supporting a different scenario: “one neuron, multiple neurotransmitters.” Single-cell transcriptomics provides an additional path to address coexpression of neurotransmitters, by investigating the expression of genes involved in the biosynthesis and transmission of fast-acting neuromodulators. Here, we study neuronal phenotypes based on the expression of neurotransmitters, at single-cell resolution, across different animal species representing distinct clades of the tree of life. We take advantage of several existing scRNAseq datasets and analyze them in light of neurotransmitter plasticity. Our results show that while most neurons appear to predominantly express a single type of neurotransmitter, a substantial number of neurons simultaneously expresses a combination of them, across all animal species analyzed.

Memantine Derivatives as Multitarget Agents in Alzheimer's Disease.

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.

Tics induced by antiepileptic drugs: a pragmatic review

The clinical spectrum of tics induced by antiepileptic drugs (AED), a form of 'secondary Tourettism', is largely unknown. Examining the literature aimed to help clinicians identify, understand and manage these cases. Understanding the mechanism of AED-induced tics could provide valuable insights into why certain patients may be vulnerable to this adverse event. A pragmatic systematic review, adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed. Data sources included: PubMed, Medline and Cochrane Library. No lower date restrictions were employed, with December 2019 being the end date. Any tics reported in the presence of an AED were included in the review. Case reports were not excluded due to the scant evidence. Individual patient-level data was extracted from published material and the Naranjo Scale was applied to each case to assess the likelihood of causality. 181 unique papers were identified from the search. 24 manuscripts with a total of 43 subjects met eligibility for analysis. AED with different modes of action: carbamazepine, clonazepam, lacosamide, lamotrigine, levetiracetam, phenytoin and phenobarbital; were identified as causative AEDs. The clinical phenotype was broad, although a neuropsychiatric history characterised by reduced impulse control was more predictive than a previous tic in the adult population, phenomenology had a facial/truncal predominance and most tics resolved or improve with either AED withdrawal or dose reduction. Multiple AEDs with different modes of action can induce tic disorders, including newer AEDs. The cause is therefore unlikely to be an alteration to a single neurotransmitter, but rather an imbalance of networks, influenced further by individual factors.

Time-resolved neurotransmitter detection in mouse brain tissue using an artificial intelligence-nanogap

The analysis of neurotransmitters in the brain helps to understand brain functions and diagnose Parkinson’s disease. Pharmacological inhibition experiments, electrophysiological measurement of action potentials, and mass analysers have been applied for this purpose; however, these techniques do not allow direct neurotransmitter detection with good temporal resolution by using nanometre-sized electrodes. Hence, we developed a method for direct observation of a single neurotransmitter molecule with a gap width of ≤ 1 nm and on the millisecond time scale. It consists of measuring the tunnelling current that flows through a single-molecule by using nanogap electrodes and machine learning analysis. Using this method, we identified dopamine, serotonin, and norepinephrine neurotransmitters with high accuracy at the single-molecule level. The analysis of the mouse striatum and cerebral cortex revealed the order of concentration of the three neurotransmitters. Our method will be developed to investigate the neurotransmitter distribution in the brain with good temporal resolution.

M149. THE TOPOGRAPHY OF STRIATAL DOPAMINE AND SYMPTOMS IN PSYCHOSIS: AN INTEGRATIVE PET AND MRI STUDY

BackgroundStriatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfunction occurs. Positron emission tomography (PET) allows for the measurement of dopamine function across the striatum. However, when using typical atlas-based parcellation methods, the collinearity between measures of dopamine function within each striatal subdivision precludes investigation of this hypothesis.MethodsWe use a novel and data-driven parcellation method to address the above, and investigate relationships between spatial variability in dopamine synthesis capacity and psychotic symptoms. We employ a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 unmedicated and minimally-treated patients with first episode psychosis and 21 healthy controls. In each participant, we use resting state functional connectivity maps to quantify the functional connectivity of each striatal voxel to cortical networks. Network-specific striatal dopamine synthesis capacity (Kicer) was calculated for the resulting connectivity defined parcellations.ResultsConnectivity defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality to standard anatomical parcellation methods. Dopamine function within striatal areas connected to the default mode network is strongly associated with negative symptoms (p<0.001).DiscussionThese findings suggest that individual differences in the topography of striatal dopamine dysfunction contribute to shaping psychotic symptomatology.

The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study

BackgroundStriatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signaling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography allows for the quantification of dopamine function across the striatum. In the current study, we used a novel method to investigate the relationship between spatial variability in dopamine synthesis capacity and psychotic symptoms. MethodsWe used a multimodal imaging approach combining 18F-DOPA positron emission tomography and resting-state magnetic resonance imaging in 29 patients with first-episode psychosis and 21 healthy control subjects. In each participant, resting-state functional connectivity maps were used to quantify the functional connectivity of each striatal voxel to well-established cortical networks. Network-specific striatal dopamine synthesis capacity (Kicer) was then calculated for the resulting connectivity-defined parcellations. ResultsThe connectivity-defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality compared with standard anatomical parcellation methods. As a result, dopamine-symptom associations were significantly different from one another for different subdivisions, whereas no unique subdivision relationships were found when using an anatomical parcellation. In particular, dopamine function within striatal areas connected to the default mode network was strongly associated with negative symptoms (p < .001). ConclusionsThese findings suggest that individual differences in the topography of dopamine dysfunction within the striatum contribute to shaping psychotic symptomatology. Further validation of the novel approach in future studies is necessary.

Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions.

Our understanding of depression and its treatment has advanced with the advent of ketamine as a rapid acting antidepressant and the development and refinement of tools capable of selectively altering the activity of populations of neuronal subtypes. This work has resulted in a paradigm shift away from dysregulation of single neurotransmitter systems in depression towards circuit level abnormalities impacting function across multiple brain regions and neurotransmitter systems. Studies on the features of circuit level abnormalities demonstrate structural changes within the prefrontal cortex (PFC) and functional changes in its communication with distal brain structures. Treatments that impact the activity of brain regions, such as transcranial magnetic stimulation or rapid acting antidepressants like ketamine, appear to reverse depression associated circuit abnormalities though the mechanisms underlying the reversal, as well as development of these abnormalities remains unclear. Recently developed optogenetic and chemogenetic tools that allow high fidelity control of neuronal activity in pre-clinical models have begun to elucidate the contributions of the PFC and its circuitry to depression- and anxiety-like behavior. These tools offer unprecedented access to specific circuits and neuronal subpopulations that promise to offer a refined view of the circuit mechanisms surrounding depression and potential mechanistic targets for development and reversal of depression associated circuit abnormalities.

Clinical characteristics of adults with neurodevelopmental disorder: A medical records survey

Repetitive behaviors (RBs) are a core feature of autism spectrum disorders (ASD). They constitute a major barrier to learning and social adaptation. Research on potential causes of RBs is still at an early stage. However, promising new ideas and evidence are emerging from neurobiology. Instead of testing single neurotransmitter or hormone, the present study examined the associations of cortisol, serotonin, and oxytocin on subscales of repetitive behavior scales-revised (RBS-R). The results demonstrated that the individuals with ASD showed higher levels of cortisol areas under curve (cortisol AUC), higher levels of serotonin, and lower level of oxytocin compared with the typically developing (TD) individuals. For individuals with ASD, the levels of cortisol AUC, serotonin and oxytocin were all significantly associated with total scores measured by RBS-R. In addition, the cortisol AUC was positively associated with the stereotyped and restricted behavior subscales scores. The level of serotonin was positively associated with the stereotyped and self-injurious behavior subscales scores. The level of oxytocin was negatively associated with compulsive, sameness and restricted behavior subscales scores. Therefore, cortisol, serotonin and oxytocin may all be involved in the occurrence of RBs in ASD. The occurrence of RBs in ASD may due to a variety of pathological factors, not just one factor.

Co-transmission of acetylcholine and GABA regulates hippocampal states

The basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter. Yet, we find that mouse hippocampal cholinergic terminals invariably establish GABAergic synapses, and their cholinergic vesicles dock at those synapses only. We demonstrate that these synapses do not co-release but co-transmit GABA and acetylcholine via different vesicles, whose release is triggered by distinct calcium channels. This co-transmission evokes composite postsynaptic potentials, which are mutually cross-regulated by presynaptic autoreceptors. Although postsynaptic cholinergic receptor distribution cannot be investigated, their response latencies suggest a focal, intra- and/or peri-synaptic localisation, while GABAA receptors are detected intra-synaptically. The GABAergic component alone effectively suppresses hippocampal sharp wave-ripples and epileptiform activity. Therefore, the differentially regulated GABAergic and cholinergic co-transmission suggests a hitherto unrecognised level of control over cortical states. This novel model of hippocampal cholinergic neurotransmission may lead to alternative pharmacotherapies after cholinergic deinnervation seen in neurodegenerative disorders.

Sleep-Wake Neurochemistry.

The regulated alternations between wakefulness and sleep states reflect complex behavioral processes, orchestrated by distinct neurochemical changes in brain parenchyma. No single neurotransmitter or neuromodulator controls the sleep-wake states in isolation. Rather, fine-tuned interactions within organized neuronal circuits regulate waking and sleep states and drive their transitions. Structural or functional dysregulation and medications interfering with these ensembles can lead to sleep-wake disorders and exert wanted or unwanted pharmacological actions on sleep-wake states. Knowledge of the neurochemical bases of sleep-wake states, which will be discussed in this article, provides the conceptual framework for understanding pharmacological effects on sleep and wake.