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ELife Jun 2023Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least...
Motivation to work for potential rewards is critically dependent on dopamine (DA) in the nucleus accumbens (NAc). DA release from NAc axons can be controlled by at least two distinct mechanisms: (1) action potentials propagating from DA cell bodies in the ventral tegmental area (VTA), and (2) activation of β2* nicotinic receptors by local cholinergic interneurons (CINs). How CIN activity contributes to NAc DA dynamics in behaving animals is not well understood. We monitored DA release in the NAc Core of awake, unrestrained rats using the DA sensor RdLight1, while simultaneously monitoring or manipulating CIN activity at the same location. CIN stimulation rapidly evoked DA release, and in contrast to slice preparations, this DA release showed no indication of short-term depression or receptor desensitization. The sound of unexpected food delivery evoked a brief joint increase in CIN population activity and DA release, with a second joint increase as rats approached the food. In an operant task, we observed fast ramps in CIN activity during approach behaviors, either to start the trial or to collect rewards. These CIN ramps co-occurred with DA release ramps, without corresponding changes in the firing of lateral VTA DA neurons. Finally, we examined the effects of blocking CIN influence over DA release through local NAc infusion of DHβE, a selective antagonist of β2* nicotinic receptors. DHβE dose-dependently interfered with motivated approach decisions, mimicking the effects of a DA antagonist. Our results support a key influence of CINs over motivated behavior via the local regulation of DA release.
Topics: Rats; Animals; Dopamine; Motivation; Ventral Tegmental Area; Receptors, Nicotinic; Interneurons; Cholinergic Agents
PubMed: 37272423
DOI: 10.7554/eLife.85011 -
Neurosciences (Riyadh, Saudi Arabia) Jan 2023Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the... (Review)
Review
Parkinson's disease (PD) is a progressive widespread neurodegenerative disorder affecting the brain. It is characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc). Current therapeutic options ease the symptoms of PD; however, they have multiple undesirable effects and do not slow the disease progression. Exercise by itself has many positive impacts on general health. In this review, the positive impact of different forms of exercise were found to improve motor and non-motor symptoms in PD. Exercise effects is mediate by multiple mechanisms, including the upregulation of brain-derived neurotrophic factor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and autophagy regulating proteins; and downregulates proinflammatory cytokines. In this review, the significance of exercise in PD, as well as in the prevention and maintenance of the disease was discussed. Many questions are left unanswered in this manuscript, including potential genetic factors underlying response to exercise. Therefore, further high-quality studies on humans are needed.
Topics: Humans; Animals; Parkinson Disease; Dopamine; Exercise; Dopaminergic Neurons; Disease Models, Animal
PubMed: 36617448
DOI: 10.17712/nsj.2023.1.20220105 -
Molecular Psychiatry Sep 2022Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release... (Review)
Review
Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release only DA or glutamate, neither DA nor glutamate models alone recapitulate the full spectrum of schizophrenia pathophysiology. Similarly, therapeutic strategies limited to either system cannot effectively treat all three major symptom domains of schizophrenia: positive, negative, and cognitive symptoms. Increasing evidence suggests extensive interactions between the DA and glutamate systems and more effective treatments may therefore require the targeting of both DA and glutamate signaling. This offers the possibility that disrupting DA-glutamate circuitry between these two systems, particularly in the striatum and forebrain, culminate in schizophrenia pathophysiology. Yet, the mechanisms behind these interactions and their contributions to schizophrenia remain unclear. In addition to circuit- or system-level interactions between neurons that solely release either DA or glutamate, here we posit that functional alterations involving a subpopulation of neurons that co-release both DA and glutamate provide a novel point of integration between DA and glutamate systems, offering a key missing link in our understanding of schizophrenia pathophysiology. Better understanding of mechanisms underlying DA/glutamate co-release from these neurons may therefore shed new light on schizophrenia pathophysiology and lead to more effective therapeutics.
Topics: Humans; Dopamine; Glutamic Acid; Schizophrenia; Synaptic Transmission; Corpus Striatum
PubMed: 35681081
DOI: 10.1038/s41380-022-01649-w -
The Journal of Clinical Psychiatry Aug 2023Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is...
Schizophrenia is a chronic and debilitating mental health condition that significantly impacts quality of life and can shorten patients' lifetime by decades. It is characterized by symptoms including hallucinations and delusions, apathy, and cognitive impairment, and people with schizophrenia also experience many somatic comorbidities, such as metabolic disturbances, infectious diseases, cardiovascular issues, and respiratory illnesses. For decades, treatment for schizophrenia has focused on antipsychotics (APs) that reduce excess dopamine signaling to the associative striatum, which also blocks dopamine signaling in the dorsal striatum, creating movement disorders. Second-generation APs have a lower propensity to cause drug-induced movement disorders than first-generation APs. Nonetheless, only 1 out of 3 patients respond to any of the available APs; moreover, negative and cognitive symptoms tend to persist, while side effects and long-term risks can contribute to poor outcomes. However, there are new understandings in how to reduce dopamine release both presynaptically and selectively in circuits governing psychotic symptoms. These mechanisms offer a different treatment approach for patients with schizophrenia.
Topics: Humans; Schizophrenia; Dopamine; Quality of Life; Psychotic Disorders; Movement Disorders; Antipsychotic Agents
PubMed: 37555680
DOI: 10.4088/JCP.sunscz3001sho -
Trends in Neurosciences Mar 2022Our brains have evolved the ability to configure and adapt their processing states to match the unique challenges of acting and learning in diverse environments and... (Review)
Review
Our brains have evolved the ability to configure and adapt their processing states to match the unique challenges of acting and learning in diverse environments and behavioral contexts. In biological nervous systems, such state specification and adaptation arise in part from neuromodulators, including acetylcholine, noradrenaline, serotonin, and dopamine, whose diffuse release fine-tunes neuronal and synaptic dynamics and plasticity to complement the behavioral context in real-time. Despite the demonstrated effectiveness of deep neural networks for specific tasks, they remain relatively inflexible at generalizing across tasks or adapting to ever-changing behavioral demands. In this article, we provide an overview of neuromodulatory systems and their relationship to emerging pertinent principles in deep neural networks. We further outline opportunities for the integration of neuromodulatory principles into deep neural networks, towards endowing artificial intelligence with a key ingredient underlying the flexibility and learning capability of biological systems.
Topics: Artificial Intelligence; Dopamine; Humans; Neural Networks, Computer; Neurotransmitter Agents; Serotonin
PubMed: 35074219
DOI: 10.1016/j.tins.2021.12.008 -
Biological Research May 2023Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The...
BACKGROUND
Mechanoreceptor activation modulates GABA neuron firing and dopamine (DA) release in the mesolimbic DA system, an area implicated in reward and substance abuse. The lateral habenula (LHb), the lateral hypothalamus (LH), and the mesolimbic DA system are not only reciprocally connected, but also involved in drug reward. We explored the effects of mechanical stimulation (MS) on cocaine addiction-like behaviors and the role of the LH-LHb circuit in the MS effects. MS was performed over ulnar nerve and the effects were evaluated by using drug seeking behaviors, optogenetics, chemogenetics, electrophysiology and immunohistochemistry.
RESULTS
Mechanical stimulation attenuated locomotor activity in a nerve-dependent manner and 50-kHz ultrasonic vocalizations (USVs) and DA release in nucleus accumbens (NAc) following cocaine injection. The MS effects were ablated by electrolytic lesion or optogenetic inhibition of LHb. Optogenetic activation of LHb suppressed cocaine-enhanced 50 kHz USVs and locomotion. MS reversed cocaine suppression of neuronal activity of LHb. MS also inhibited cocaine-primed reinstatement of drug-seeking behavior, which was blocked by chemogenetic inhibition of an LH-LHb circuit.
CONCLUSION
These findings suggest that peripheral mechanical stimulation activates LH-LHb pathways to attenuate cocaine-induced psychomotor responses and seeking behaviors.
Topics: Humans; Cocaine-Related Disorders; Habenula; Cocaine; Neurons; Dopamine; Hypothalamus
PubMed: 37194106
DOI: 10.1186/s40659-023-00440-7 -
Scientific Reports Dec 2022To compare the behavioral roles of biogenic amines in the males of primitive and advanced eusocial bees, we determined the levels of dopamine- and octopamine-related...
To compare the behavioral roles of biogenic amines in the males of primitive and advanced eusocial bees, we determined the levels of dopamine- and octopamine-related substances in the brain, and the behavioral effects of these monoamines by drug injection in the primitive eusocial bumble bee, Bombus ignitus. The levels of dopamine and its precursors in the brain peaked at the late pupal stage, but the dopamine peak extended to adult emergence. The tyramine and octopamine levels increased from the mid-pupal to adult stages. The locomotor and flight activities, and light preference increased with age. Injection of octopamine and its receptor antagonist had significant effects on the locomotor and flight activities, whereas dopamine injection did not, indicating that these activities can be regulated by the octopaminergic system. We also determined the dynamics of dopamine-related substances in honey bee (Apis mellifera) drones. The changes in the dopamine level in the brains of honey bee drones exhibited two peaks from the pupal to adult stages, whereas the bumble bee males had only one peak. These are consistent with the behavioral functions of dopamine in honey bee drones and ineffectiveness of dopamine injection at the adult stage in bumble bee males.
Topics: Male; Animals; Bees; Octopamine; Dopamine; Biogenic Amines; Tyramine; Brain
PubMed: 36470960
DOI: 10.1038/s41598-022-25656-7 -
Journal of the American Chemical Society Aug 2023Dopamine D2-like receptors (D2R, D3R, and D4R) control diverse physiological and behavioral functions and are important targets for the treatment of a variety of...
Dopamine D2-like receptors (D2R, D3R, and D4R) control diverse physiological and behavioral functions and are important targets for the treatment of a variety of neuropsychiatric disorders. Their complex distribution and activation kinetics in the brain make it difficult to target specific receptor populations with sufficient precision. We describe a new toolkit of light-activatable, fast-relaxing, covalently taggable chemical photoswitches that fully activate, partially activate, or block D2-like receptors. This technology combines the spatiotemporal precision of a photoswitchable ligand (P) with cell type and spatial specificity of a genetically encoded membrane anchoring protein (M) to which the P tethers. These tools set the stage for targeting endogenous D2-like receptor signaling with molecular, cellular, and spatiotemporal precision using only one wavelength of light.
Topics: Dopamine; Receptors, Dopamine D2; Brain
PubMed: 37586061
DOI: 10.1021/jacs.3c02735 -
Biotechnology Journal Jun 2022Electrical stimulation of brain or muscle activities has gained attention for studying the molecular and cellular mechanisms involved in electric-induced responses. We...
Electrical stimulation of brain or muscle activities has gained attention for studying the molecular and cellular mechanisms involved in electric-induced responses. We recently showed zebrafish's response to electricity. Here, we hypothesized that this response is affected by the dopaminergic signaling pathways. The effects of multiple dopamine agonists and antagonists on the electric response of 6 days-postfertilization zebrafish larvae were investigated using a microfluidic device with enhanced control of experimentation and throughput. All dopamine antagonists decreased locomotor activities, while dopamine agonists did not induce similar behaviors. The D2-selective dopamine agonist quinpirole enhanced the movement. Exposure to nonselective and D1-selective dopamine agonists apomorphine and SKF-81297 caused no significant change in the electric response. Exposing larvae that were pretreated with nonselective and D2-selective dopamine antagonists butaclamol and haloperidol to apomorphine and quinpirole, respectively, restored the electric locomotion. These results reveal a correlation between electric response and dopamine signaling pathway. Furthermore, they demonstrate that electric-induced zebrafish larvae locomotion can be conditioned by modulating dopamine receptor functions. Our electrofluidic assay has profound application potential for fundamental electric-induced response research and brain disorder studies especially those related to the dopamine imbalance and as a chemical screening method when investigating biological pathways and behaviors.
Topics: Animals; Apomorphine; Dopamine; Dopamine Agonists; Dopamine Antagonists; Electricity; Larva; Quinpirole; Signal Transduction; Zebrafish
PubMed: 35332995
DOI: 10.1002/biot.202100561 -
Physical Chemistry Chemical Physics :... Jul 2021Psychosis is one of the psychiatric disorders that is controlled by dopaminergic drugs such as antipsychotics that have affinity for the dopamine D2 receptor (DRD2). In...
Psychosis is one of the psychiatric disorders that is controlled by dopaminergic drugs such as antipsychotics that have affinity for the dopamine D2 receptor (DRD2). In this investigation we perform quantum chemical calculations of two molecules [dopamine and risperidone] within a large cavity of DRD2 that represents the binding site of the receptor. Dopamine is an endogenous neurotransmitter and risperidone is a second-generation antipsychotic. Non-covalent interactions of dopamine and risperidone with DRD2 are analyzed using the Quantum Theory of Atoms in Molecules (QTAIM) and the Non-Covalent Interaction index (NCI). The QTAIM results show that these molecules strongly interact with the receptor. There are 22 non-covalent interactions for dopamine and 54 for risperidone. The electron density evaluated at each critical binding point is small in both systems but it is higher for dopamine than for risperidone, indicating that the interactions of DRD2 with the first are stronger than with the second molecule. However, the binding energy is higher for risperidone (-72.6 kcal mol-1) than for dopamine (-22.8 kcal mol-1). Thus, the strength of the binding energy is due to the number of contacts rather than the strength of the interactions themselves. This could be related to the ability of risperidone to block DRD2 and may explain the efficacy of this drug for controlling the symptoms of schizophrenia, but likewise its secondary effects.
Topics: Amino Acid Sequence; Binding Sites; Dopamine; Models, Molecular; Protein Binding; Protein Conformation; Receptors, Dopamine D2; Risperidone; Thermodynamics
PubMed: 34159983
DOI: 10.1039/d1cp01637g