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Neurobiology of Disease Aug 2023Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical... (Review)
Review
Parkinson's disease (PD) is currently the fastest growing disabling neurological disorder worldwide, with motor and non-motor symptoms being its main clinical manifestations. The primary pathological features include a reduction in the number of dopaminergic neurons in the substantia nigra and decrease in dopamine levels in the nigrostriatal pathway. Existing treatments only alleviate clinical symptoms and do not stop disease progression; slowing down the loss of dopaminergic neurons and stimulating their regeneration are emerging therapies. Preclinical studies have demonstrated that transplantation of dopamine cells generated from human embryonic or induced pluripotent stem cells can restore the loss of dopamine. However, the application of cell transplantation is limited owing to ethical controversies and the restricted source of cells. Until recently, the reprogramming of astrocytes to replenish lost dopaminergic neurons has provided a promising alternative therapy for PD. In addition, repair of mitochondrial perturbations, clearance of damaged mitochondria in astrocytes, and control of astrocyte inflammation may be extensively neuroprotective and beneficial against chronic neuroinflammation in PD. Therefore, this review primarily focuses on the progress and remaining issues in astrocyte reprogramming using transcription factors (TFs) and miRNAs, as well as exploring possible new targets for treating PD by repairing astrocytic mitochondria and reducing astrocytic inflammation.
Topics: Humans; Astrocytes; Dopamine; Parkinson Disease; Dopaminergic Neurons; Inflammation
PubMed: 37433411
DOI: 10.1016/j.nbd.2023.106224 -
Neuron Dec 2023Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate...
Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
Topics: Analgesics, Opioid; Oxymorphone; Pharmaceutical Preparations; Dopamine; Naloxone; Receptors, Opioid, mu
PubMed: 37848025
DOI: 10.1016/j.neuron.2023.09.017 -
International Journal of Molecular... Mar 2024The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation,... (Review)
Review
The midbrain dopamine system is a sophisticated hub that integrates diverse inputs to control multiple physiological functions, including locomotion, motivation, cognition, reward, as well as maternal and reproductive behaviors. Dopamine is a neurotransmitter that binds to G-protein-coupled receptors. Dopamine also works together with other neurotransmitters and various neuropeptides to maintain the balance of synaptic functions. The dysfunction of the dopamine system leads to several conditions, including Parkinson's disease, Huntington's disease, major depression, schizophrenia, and drug addiction. The ventral tegmental area (VTA) has been identified as an important relay nucleus that modulates homeostatic plasticity in the midbrain dopamine system. Due to the complexity of synaptic transmissions and input-output connections in the VTA, the structure and function of this crucial brain region are still not fully understood. In this review article, we mainly focus on the cell types, neurotransmitters, neuropeptides, ion channels, receptors, and neural circuits of the VTA dopamine system, with the hope of obtaining new insight into the formation and function of this vital brain region.
Topics: Humans; Dopamine; Ventral Tegmental Area; Depressive Disorder, Major; Neuropeptides; Neurotransmitter Agents
PubMed: 38612683
DOI: 10.3390/ijms25073875 -
The International Journal of... Sep 2023Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While...
BACKGROUND
Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront.
METHODS
We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays.
RESULTS
Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2.
CONCLUSIONS
Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.
Topics: Dopamine; Antipsychotic Agents; Receptors, G-Protein-Coupled; Pyrans
PubMed: 37549917
DOI: 10.1093/ijnp/pyad049 -
The Journal of Neuroscience : the... Nov 2023Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors...
Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors (D1Rs) involved in myopia remains unclear. Here, we determine whether retinal D1Rs exclusively mediate the effects of endogenous dopamine and systemically delivered D1R agonist or antagonist in the mouse form deprivation myopia (FDM) model. Male C57BL/6 mice subjected to unilateral FDM or unobstructed vision were divided into the following four groups: one noninjected and three groups that received intraperitoneal injections of a vehicle, D1R agonist SKF38393 (18 and 59 nmol/g), or D1R antagonist SCH39166 (0.1 and 1 nmol/g). The effects of these drugs on FDM were further assessed in -knock-out (-KO), retina-specific conditional -KO (-CKO) mice, and corresponding wild-type littermates. In the visually unobstructed group, neither SKF38393 nor SCH39166 affected normal refractive development, whereas myopia development was attenuated by SKF38393 and enhanced by SCH39166 injections. In -KO or -CKO mice, however, these drugs had no effect on FDM development, suggesting that activation of retinal D1Rs is pertinent to myopia suppression by the D1R agonist. Interestingly, the development of myopia was unchanged by either -KO or -CKO, and neither SKF38393 nor SCH39166 injections, nor -KO, affected the retinal or vitreal dopamine and the dopamine metabolite DOPAC levels. Effects on axial length were less marked than effects on refraction. Therefore, activation of D1Rs, specifically retinal D1Rs, inhibits myopia development in mice. These results also suggest that multiple dopamine D1R mechanisms play roles in emmetropization and myopia development. While dopamine is recognized as a "stop" signal that inhibits myopia development (myopization), the location of the dopamine D1 receptors (D1Rs) that mediate this action remains to be addressed. Answers to this key question are critical for understanding how dopaminergic systems regulate ocular growth and refraction. We report here the results of our study showing that D1Rs are essential for controlling ocular growth and myopia development in mice, and for identifying the retina as the site of action for dopaminergic control via D1Rs. These findings highlight the importance of intrinsic retinal dopaminergic mechanisms for the regulation of ocular growth and suggest specific avenues for exploring the retinal mechanisms involved in the dopaminergic control of emmetropization and myopization.
Topics: Male; Mice; Animals; Dopamine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Mice, Inbred C57BL; Myopia; Retina; Receptors, Dopamine D1
PubMed: 37751999
DOI: 10.1523/JNEUROSCI.1196-23.2023 -
Environmental Pollution (Barking, Essex... Nov 2023Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to...
Caenorhabditis elegans is a useful model for examining metabolic processes and related mechanisms. We here examined the effect of exposure to N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) on dopamine metabolism and underling molecular basis in nematodes. The dopamine content was reduced by 6-PPDQ (1 and 10 μg/L). Meanwhile, dopamine related behaviors (basal slowing response and area restricted searching) were changed by 6-PPDQ (1 and 10 μg/L). Exposure to 6-PPDQ (1 and 10 μg/L) decreased expressions of genes (cat-2 and bas-1) encoding enzymes governing dopamine synthesis and cat-1 encoding dopamine transporter. Development of dopaminergic neurons was also affected by 10 μg/L 6-PPDQ as reflected by decrease in fluorescence intensity, neuronal loss, and defect in dendrite development. Exposure to 6-PPDQ (1 and 10 μg/L) altered expressions of ast-1 and rcat-1 encoding upregulators of cat-2 and bas-1. The dopamine content and expressions of cat-2 and bas-1 were inhibited by RNAi of ast-1 and increased by RNAi of rcat-1 in 6-PPDQ exposed nematodes. Using endpoints of locomotion behavior and brood size, in 6-PPDQ exposed nematodes, the susceptibility to toxicity was caused by RNAi of ast-1, cat-2, bas-1, and cat-1, and the resistance to toxicity was induced by RNAi of rcat-1. Therefore, 6-PPDQ exposure disrupted dopamine metabolism and the altered molecular basis for dopamine metabolism was associated with 6-PPDQ toxicity induction. Moreover, the defects in dopamine related behaviors and toxicity on locomotion and reproduction could be rescued by treatment with 0.1 mM dopamine.
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Oxidative Stress; Phenylenediamines; Benzoquinones
PubMed: 37777057
DOI: 10.1016/j.envpol.2023.122649 -
Nature Communications Oct 2023Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic...
Chronic pain is highly prevalent and is linked to a broad range of comorbidities, including sleep disorders. Epidemiological and clinical evidence suggests that chronic sleep disruption (CSD) leads to heightened pain sensitivity, referred to as CSD-induced hyperalgesia. However, the underlying mechanisms are unclear. The thalamic reticular nucleus (TRN) has unique integrative functions in sensory processing, attention/arousal and sleep spindle generation. We report that the TRN played an important role in CSD-induced hyperalgesia in mice, through its projections to the ventroposterior region of the thalamus. Metabolomics revealed that the level of N-arachidonoyl dopamine (NADA), an endocannabinoid, was decreased in the TRN after CSD. Using a recently developed CB1 receptor (cannabinoid receptor 1) activity sensor with spatiotemporal resolution, CB1 receptor activity in the TRN was found to be decreased after CSD. Moreover, CSD-induced hyperalgesia was attenuated by local NADA administration to the TRN. Taken together, these results suggest that TRN NADA signaling is critical for CSD-induced hyperalgesia.
Topics: Mice; Animals; Endocannabinoids; Dopamine; Hyperalgesia; Receptor, Cannabinoid, CB1; Thalamic Nuclei; Sleep
PubMed: 37880241
DOI: 10.1038/s41467-023-42283-6 -
Proceedings of the National Academy of... May 2024Individual survival and evolutionary selection require biological organisms to maximize reward. Economic choice theories define the necessary and sufficient conditions,...
Individual survival and evolutionary selection require biological organisms to maximize reward. Economic choice theories define the necessary and sufficient conditions, and neuronal signals of decision variables provide mechanistic explanations. Reinforcement learning (RL) formalisms use predictions, actions, and policies to maximize reward. Midbrain dopamine neurons code reward prediction errors (RPE) of subjective reward value suitable for RL. Electrical and optogenetic self-stimulation experiments demonstrate that monkeys and rodents repeat behaviors that result in dopamine excitation. Dopamine excitations reflect positive RPEs that increase reward predictions via RL; against increasing predictions, obtaining similar dopamine RPE signals again requires better rewards than before. The positive RPEs drive predictions higher again and thus advance a recursive reward-RPE-prediction iteration toward better and better rewards. Agents also avoid dopamine inhibitions that lower reward prediction via RL, which allows smaller rewards than before to elicit positive dopamine RPE signals and resume the iteration toward better rewards. In this way, dopamine RPE signals serve a causal mechanism that attracts agents via RL to the best rewards. The mechanism improves daily life and benefits evolutionary selection but may also induce restlessness and greed.
Topics: Reward; Animals; Dopamine; Dopaminergic Neurons; Humans; Reinforcement, Psychology
PubMed: 38717856
DOI: 10.1073/pnas.2316658121 -
Current Opinion in Anaesthesiology Oct 2023To summarize the recent preclinical findings investigating dopaminergic circuits for their involvement in reversing anesthetic-induced unconsciousness. (Review)
Review
PURPOSE OF REVIEW
To summarize the recent preclinical findings investigating dopaminergic circuits for their involvement in reversing anesthetic-induced unconsciousness.
RECENT FINDINGS
The release of dopamine from the ventral tegmental area onto dopamine D1 receptor-expressing neurons in the nucleus accumbens promotes emergence following general anesthesia. Two relevant targets of dopamine D1 receptor-expressing neurons in the nucleus accumbens include the lateral hypothalamus and ventral pallidum. Activating mesocortical dopaminergic projections from the ventral tegmental area to the prelimbic cortex has also been shown to hasten emergence from general anesthesia. In contrast, the nigrostriatal dopamine pathway is not involved in regulating anesthetic emergence. The role of the tuberoinfundibular endocrine dopamine pathway remains to be tested; however, recent studies have identified an important function of neuroendocrine signaling on modulating general anesthesia.
SUMMARY
Potential avenues for accelerating anesthetic emergence may be found through targeting specific arousal-promoting pathways in the brain. Accumulating evidence from rodent studies manipulating cell type- and circuit-specific signaling pathways have identified dopamine as a potent modulator of general anesthesia. Specifically, dopamine signaling along the mesolimbic and mesocortical pathways plays a fundamental role in regulating consciousness.
Topics: Humans; Dopamine; Nucleus Accumbens; Ventral Tegmental Area; Anesthetics; Receptors, Dopamine D1
PubMed: 37552017
DOI: 10.1097/ACO.0000000000001293 -
Frontiers in Public Health 2023Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been...
BACKGROUND
Previous research has outlined the health benefits of exercise including its therapeutic potential for substance use disorders (SUD). These data have already been utilized and it is now common to find exercise as part of SUD treatment and relapse prevention programs. However, we need to better understand different exercise regimens and determine which would be the most beneficial for SUDs. Recently, high intensity interval training (HIIT) has gained attention in comparison with aerobic and resistance exercise. Little is known regarding the neurobiological mechanisms of HIIT, including its effects on dopamine signaling and receptor levels in the brain. The present study examined the effects of chronic HIIT exercise on dopamine signaling as measured by dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and tyrosine hydroxylase (TH) quantification in the brains of male and female rats as measured by [H] SCH 23390 and [H] spiperone autoradiography, and TH-immunoreactive optical density values.
METHODS
Rats were separated in two groups: sedentary and HIIT exercise. Exercise was on a treadmill for 30 min daily (10 3 min cycles) for six weeks with progressive speed increased up to 0.8 mph (21.5 m/min).
RESULTS
Results showed for D2R-like binding, a significant effect across the ventral caudate putamen (V CPU) between sexes, such that mean D2R-like binding was 14% greater for males than females. In the nucleus accumbens shell (Nac Shell), the HIIT Exercise rats showed 16% greater D2R-like binding as compared to the sedentary rats. No significant effects of HIIT exercise were found across groups for brain D1R-like binding levels or TH expression.
CONCLUSION
These results suggest that HIIT exercise can modulate dopamine signaling by way of increased D2R. These findings support the premise that HIIT exercise plays an important role in dopamine signaling and, may provide a potential mechanism for how HIIT exercise can impact the brain and behavior.
Topics: Female; Male; Animals; Rats; Dopamine; High-Intensity Interval Training; Brain; Signal Transduction; Spiperone
PubMed: 38192549
DOI: 10.3389/fpubh.2023.1257629