D2 Receptor Research Articles

Cocaine diminishes consolidation of cued fear memory in female rats through interactions with ventral hippocampal D2 receptors

In addition to cocaine's addictive properties, cocaine use may lead to heightened risk-taking behavior. The disruptive effects of cocaine on aversive memory formation may underlie this behavior. The present study investigated the effects of cocaine on fear memory using a cued fear conditioning paradigm in female Sprague Dawley rats, and further determined the role of D2 receptors in modulating the effect of cocaine on cued fear expression. Animals received six evenly spaced shocks preceded by a tone. The following day, rats were returned to the fear chamber where tones, but no shocks, were delivered. In Experiment 1, separate or concurrent administrations of cocaine (15 mg/kg; i.p.) and the D2 receptor antagonist eticlopride (0.1 mg/kg; i.p.) were given immediately after conditioning trials. It was determined that cocaine administration during the consolidation period diminished the expression of cued fear during the subsequent test day. Concurrent eticlopride administration attenuated this effect, indicating the involvement of D2 receptors in the deleterious effects of cocaine on fear memory consolidation. In Experiment 2, eticlopride (0.05 μg) was infused directly into the ventral hippocampus (VH) after fear conditioning and before cocaine administration. Cocaine continued to disrupt consolidation of cued and contextual fear memory, and concurrent intra-VH eticlopride blocked this effect, thereby demonstrating that VH D2 receptors mediate cocaine-induced impairment of fear memory consolidation. Overall, the present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation.

Dual 5-HT2A and 5-HT2C Receptor Inverse Agonist That Affords In Vivo Antipsychotic Efficacy with Minimal hERG Inhibition for the Treatment of Dementia-Related Psychosis.

Psychosis is a distressing symptom commonly occurring in people with dementia. To treat Parkinson's disease psychosis, pimavanserin (1), a 5-HT2A receptor inverse agonist having minimal 5-HT2C receptor affinity and no dopamine D2 receptor affinity, was approved in the United States, but not for dementia-related psychosis due to limited efficacy issues. Herein, we report on the identification of a potent and dual 5-HT2A and 5-HT2C receptor inverse agonist 8 having minimal hERG inhibition, after having demonstrated the involvement of both 5-HT2A and 5-HT2C receptors to deliver antipsychotic efficacy in an MK-801-induced locomotor model and having conducted 5-HT2A and 5-HT2C occupancy studies including a surrogate method. The introduction of a spirocyclopropyl group boosting 5-HT2C affinity in 1 followed by further optimization to control lipophilicity resulted in balanced dual potency and metabolic stability, and mitigating hERG inhibition led to 8 that showed significant antipsychotic efficacy due to the involvement of both receptors.

Structural and computational analysis of a nickel(II) complex with S-benzyldithiocarbazate Schiff base ligand: Synthesis, X-ray crystallography, MEP, HOMO-LUMO, Hirshfeld surface analysis, and molecular docking

A new compound, benzyl N-[1-(thiophen-2-yl)propylidene]hydrazinecarbodithioate (LH), and its nickel(II) complex (NiL2), were synthesized and structurally identified. Single crystal X-ray diffraction analyses determined that both the LH ligand and the NiL2 complex crystallized in the monoclinic system, with space group P21/c and Z = 4. The LH ligand exhibited lattice parameters of a = 9.661(2)Å, b = 8.995(2)Å, c = 18.939(4)Å, β = 102.677(4)°, V = 1605.7(7)Å3, whereas, NiL2 exhibited a = 17.805(7)Å, b = 10.548(4)Å, c = 18.100(7)Å, β = 108.279(6)°, V = 3228(2)Å3. The NiL2 complex was found to possess a slightly distorted square planar geometry with the LH deprotonated ligand acting as a monoanionic bidentate by coordinating through the azomethine nitrogen and thiolate sulfur atoms. It was observed that the HOMO-LUMO energy gap of the NiL2 complex (0.3654 eV) was lower than that of the LH ligand (2.4425 eV), indicating that NiL2 possesses a higher reactivity than the LH ligand. Intermolecular hydrogen bonding interactions were examined by Hirshfeld surface and 2D fingerprint analysis, which showed predominant H…H interactions for both the LH ligand and the NiL2 complex. A molecular docking simulation study with the dopamine D4 receptor (DRD4) and farnesyltransferase (FTase) revealed that NiL2 was able to interact with 13 residues in FTase, as compared to the farnesyl-Cys drug interacted with 11 residues.

Sniffing can be initiated by dopamine's actions on ventral striatum neurons.

Sniffing is a motivated behavior displayed by nearly all terrestrial vertebrates. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The neuromodulatory systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in these regions drives increases in respiratory rate to initiate sniffing whereas inhibition of these terminals reduces respiratory rate. Both the firing of individual neurons and the activity of post-synaptic D1 and D2 receptor-expressing neurons in the ventral striatum are also coupled with sniffing and local antagonism of D1 and D2 receptors squelches sniffing. Together, these results support a model whereby sniffing can be initiated by dopamine's actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease.

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

The activation of D2-like dopamine receptors increases NMDA currents in the dorsal raphe serotonergic neurons

The dorsal raphe nucleus (DRN) receives dopaminergic inputs from the ventral tegmental area (VTA). Also, the DRN contains a small population of cells that express dopamine (DRNDA neurons). However, the physiological role of dopamine (DA) in the DRN and its interaction with serotonergic (5-HT) neurons is poorly understood. Several works have reported moderate levels of D1, D2, and D3 DA receptors in the DRN. Furthermore, it was found that the activation of D2 receptors increased the firing of putative 5-HT neurons. Other studies have reported that D1 and D2 dopamine receptors can interact with glutamate NMDA receptors, modulating the excitability of different cell types. In the present work, we used immunocytochemical techniques to determine the kind of DA receptors in the DRN. Additionally, we performed electrophysiological experiments in brainstem slices to study the effect of DA agonists on NMDA-elicited currents recorded from identified 5-HT DRN neurons. We found that D2 and D3 but not D1 receptors are present in this nucleus. Also, we demonstrated that the activation of D2-like receptors increases NMDA-elicited currents in 5-HT neurons through a mechanism involving phospholipase C (PLC) and protein kinase C (PKC) enzymes. Possible physiological implications related to the sleep-wake cycle are discussed.

Effects of access condition on substance use disorder-like phenotypes in male and female rats self-administering MDPV or cocaine

Substance use disorder (SUD) is a heterogeneous disorder, where severity, symptoms, and patterns of use vary across individuals. Yet, when rats self-administer cocaine under short-access conditions, their behavior tends to be well-regulated, though individual differences can emerge with long- or intermittent-access. In contrast, significant individual differences emerge when rats self-administer 3,4-methylenedioxypyrovalerone (MDPV), even under short-access conditions, wherein ~30 % of rats exhibit high levels of drug-taking. This study assessed SUD-like phenotypes of male and female rats self-administering MDPV or cocaine by comparing level of drug intake, responding during periods of signaled drug unavailability, and sensitivity to footshock punishment to determine whether: (1) under short-access conditions, rats that self-administer MDPV will exhibit a more robust SUD-like phenotype than rats that self-administer cocaine; (2) female rats will have a more severe phenotype than male rats; and (3) compared to short-access, long- and intermittent-access to MDPV or cocaine self-administration will result in a more robust SUD-like phenotype. Compared to cocaine, rats that self-administered MDPV exhibited a more severe phenotype, even under short-access conditions. Long- and intermittent-access to cocaine and MDPV temporarily altered drug-taking patterns but did not systematically change SUD-like phenotypes. Behavioral and quantitative autoradiography studies suggest phenotypic differences are not due to expression of dopamine transporter, dopamine D2 or D3 receptors, or 5-HT1B, 5-HT2A, or 5-HT2C receptors. This study suggests individuals who use synthetic cathinones may be at greater risk for developing a SUD, and short-access MDPV self-administration may provide a useful method to study the transition to disordered substance use in humans.

The dopamine analogue CA140 alleviates AD pathology, neuroinflammation, and rescues synaptic/cognitive functions by modulating DRD1 signaling or directly binding to Abeta

BackgroundWe recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer’s disease (AD). However, the effects of CA140 on Aβ/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown.MethodsTo investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted.ResultsIn aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aβ/tau fibrillation, Aβ plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100β and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling.ConclusionsOur results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aβ/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.

Linkers in Bitopic Agonists Shape Bias Profile among Transducers for the Dopamine D2 and D3 Receptors.

Bitopic ligands bind both orthosteric and allosteric or secondary binding sites within the same receptor, often resulting in an improvement of receptor selectivity, potency, and efficacy. In particular, for both agonists and antagonists of the dopamine D2 and D3 receptors (D2R and D3R), the primary therapeutic targets for several neurological and neuropsychiatric disorders, bitopic ligand design has proved advantageous in achieving better pharmacological profiles in vitro. Although the two pharmacophores within a bitopic ligand are typically considered the main drivers of conformational change for a receptor, the role of the linker that connects the two has not yet been systematically studied for its relevance in receptor activity profiles. Here, we present a comprehensive analysis of sumanirole and PF592,379-based indole-containing bitopic compounds in agonist activity at D2R and D3R, with a focus on linker chemical space and stereochemistry through testing six distinct chirally resolved linkers and a simple aliphatic linker. The structure activity relationships (SARs) of these linkers are examined extensively, beyond the conventional level, by characterizing the activation of all putative transducers over a 44 min time course. Our multiparametric analysis reveals previously unappreciated specific linker-dependent effects on primary pharmacophores, receptors, transducer activation kinetics, and bias, highlighting the utility of this comprehensive approach and the significance of the linker type in shaping transducer bias profiles.

YTHDF1 mediates translational control by m6A mRNA methylation in adaptation to environmental challenges.

Animals adapt to environmental challenges with long-term changes at the behavioral, circuit, cellular, and synaptic levels which often require new protein synthesis. The discovery of reversible N6-methyladenosine (m6A) modifications of mRNA has revealed an important layer of post-transcriptional regulation which affects almost every phase of mRNA metabolism and therefore translational control. Many in vitro and in vivo studies have demonstrated the significant role of m6A in cell differentiation and survival, but its role in adult neurons is understudied. We used cell-type specific gene deletion of Mettl14, which encodes one of the subunits of the m6A methyltransferase, and Ythdf1, which encodes one of the cytoplasmic m6A reader proteins, in dopamine D1 receptor expressing or D2 receptor expressing neurons. Mettl14 or Ythdf1 deficiency blunted responses to environmental challenges at the behavioral, cellular, and molecular levels. In three different behavioral paradigms, gene deletion of either Mettl14 or Ythdf1 in D1 neurons impaired D1-dependent learning, whereas gene deletion of either Mettl14 or Ythdf1 in D2 neurons impaired D2-dependent learning. At the cellular level, modulation of D1 and D2 neuron firing in response to changes in environments was blunted in all three behavioral paradigms in mutant mice. Ythdf1 deletion resembled impairment caused by Mettl14 deletion in a cell type-specific manner, suggesting YTHDF1 is the main mediator of the functional consequences of m6A mRNA methylation in the striatum. At the molecular level, while striatal neurons in control mice responded to elevated cAMP by increasing de novo protein synthesis, striatal neurons in Ythdf1 knockout mice didn't. Finally, boosting dopamine release by cocaine drastically increased YTHDF1 binding to many mRNA targets in the striatum, especially those that encode structural proteins, suggesting the initiation of long-term neuronal and/or synaptic structural changes. While the m6A-YTHDF1 pathway has similar functional significance at cellular level, its cell type specific deficiency in D1 and D2 neurons often resulted in contrasting behavioral phenotypes, allowing us to cleanly dissociate the opposing yet cooperative roles of D1 and D2 neurons.

Imaging Dopamine Modulation in Brain Acute Slices for Cocaine Addiction Study with Near-Infrared Carbon Nanotube Sensors

Drug addiction is a pressing issue in modern American society that demands thorough research into its mechanisms. Cocaine locomotor sensitization is a well-established model for understanding the physiological effects of cocaine abuse. Previous studies have established loss of dopamine D2 autoreceptors in striatal tissue as a consequence of locomotor sensitization, yet how these differences in autoreceptor expression affect dopamine signaling remains unclear. Herein, we utilized non-genetically encoded near-infrared fluorescent nanosensors based on carbon nanotubes to image dopamine modulation in live acute coronal brain slices. By leveraging dopamine D2 receptor agonists along with the dopamine nanosensor, we developed a method to identify changes in density of functional D2 autoreceptors and dopamine signaling aberrations that accompany addiction, at the level of individual dopamine synapses. We apply the method to compare changes in D2 autoreceptor activity in the Nucleus Accumbens core in cocaine sensitized and saline (control) mice after prolonged cocaine exposure (5 days). Our preliminarily data indicates the decrease in the number of D2 autoreceptor in cocaine sensitized mice, consistent with the previous studies, and suggests that it leads to higher level of dopamine signaling. Furthermore, we confirm dopamine signaling changes by application of D2 Agonists (quinpirole) are from loss of individual dopamine release sites rather than changes in the quantity of dopamine released, or changes in dopamine reuptake kinetics. Our study provides a route to understand the changes in neuromodulation that underlie the neurobiology of addiction and other dopamine-centric neurological conditions.

Dopamine D4 receptor regulates kidney sodium transport and blood pressure.

Dopamine D4 receptor regulates kidney sodium transport and blood pressure.

DNA methylation at cannabinoid type 1 and dopamine D2 receptor genes in saliva samples of psychotic subjects: Is there an effect of Cannabis use?

Psychosis is a characterizing feature of many mental disorders that dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and what is not. Both genetic and environmental factors, such as stressful events or drug use, play a pivotal role in the development of symptomatology and therefore changes in the epigenome may be of relevance in modeling a psychotic phenotype. According to the well-documented dysregulation of endocannabinoid and dopaminergic system genes in schizophrenia, we investigated DNA methylation cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes in saliva samples from psychotic subjects using pyrosequencing. The epigenetic mark was significantly higher and directly correlated for both genes in psychotic subjects compared to healthy controls. We also showed that these DNA methylation levels were lower in psychotic subjects reporting current delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, resembling those of controls at least for the DRD2 gene. Overall, our data confirm the key role of CNR1 and DRD2 gene regulation in psychosis and suggest DNA methylation levels at specific CpG sites as potential biomarkers, but just in those psychotic subjects not consuming THC.

Control of Dopamine Signal in High-Order Receptor Complex on Striatal Astrocytes.

The receptor-receptor interaction (RRI) of G protein-coupled receptors (GPCRs) leads to new functional entities that are conceptually distinct from the simple addition of signals mediated by the activation of the receptors that form the heteromers. Focusing on astrocytes, there is evidence for the existence of inhibitory and facilitatory RRIs, including the heteromers formed by the adenosine A2A and the dopamine D2 receptors, by A2A and the oxytocin receptor (OTR), and the D2-OTR heteromers. The possible involvement of these receptors in mosaicism has never been investigated in striatal astrocytes. By biophysical and functional approaches, we focused our attention on the existence of an A2A-D2-OTR high-order receptor complex and its role in modulating cytosolic calcium levels and endogenous glutamate release, when striatal astrocyte processes were stimulated with 4-aminopyridine. Functional data indicate a permissive role of OTR on dopamine signaling in the regulation of the glutamatergic transmission, and an inhibitory control mediated by A2A on both the D2-mediated signaling and on the OTR-facilitating effect on D2. Imaging biochemical and bioinformatic evidence confirmed the existence of the A2A-D2-OTR complex and its ternary structure in the membrane. In conclusion, the D2 receptor appears to be a hotspot in the control of the glutamate release from the astrocytic processes and may contribute to the regulation and integration of different neurotransmitter-mediated signaling in the striatum by the A2A-D2-OTR heterotrimers. Considering the possible selectivity of allosteric interventions on GPCRs organized as receptor mosaics, A2A-D2-OTR heterotrimers may offer selective pharmacological targets in neuropsychiatric disorders and neurodegenerative diseases.

Therapeutic strategies for colorectal cancer: antitumor efficacy of dopamine D2 receptor antagonists.

Colorectal cancer (CRC) is one of the leading causes of death, accounting for more than half a million deaths annually. Even worse, an increasing number of cancer cases are diagnosed yearly, and two and a half million new cancer cases are estimated to be diagnosed in 2035. Some antipsychotic drugs, especially those targeting dopamine receptor (DR) D2, demonstrated anticancer activity. Studies have revealed the potential of DRD2 antagonists as anticancer therapeutics, whether alone or as an adjuvant, in treating breast cancer, lung cancer, and others. Emerging evidences indicate DRD2 is involved in the CRC biology, and the association between DRD2 and CRC could be utilized in treating CRC. This study selected DRD2 antagonists with anticancer activity to elucidate the possibility of DRD2 antagonists as new therapeutics for treating CRC.

Methylphenidate Reversal of Dexmedetomidine-Induced Versus Ketamine-Induced Sedation in Rats.

Dexmedetomidine and ketamine have long elimination half-lives in humans and have no clinically approved reversal agents. Methylphenidate enhances dopaminergic and noradrenergic neurotransmission by inhibiting reuptake transporters for these arousal-promoting neurotransmitters. Previous studies in rats demonstrated that intravenous methylphenidate induces emergence from isoflurane and propofol general anesthesia. These 2 anesthetics are thought to act primarily through enhancement of inhibitory Gamma-aminobutyric acid type A (GABAA) receptors. In this study, we tested the behavioral and neurophysiological effects of methylphenidate in rats after low and high doses of dexmedetomidine (an alpha-2 adrenergic receptor agonist) and ketamine (an N-methyl-D-aspartate [NMDA] receptor antagonist) that induce sedation and unconsciousness, respectively. All experiments used adult male and female Sprague-Dawley rats (n = 32 total) and all drugs were administered intravenously in a crossover, blinded experimental design. Locomotion after sedating doses of dexmedetomidine (10 µg/kg) or ketamine (10 mg/kg) with and without methylphenidate (5 mg/kg) was tested using the open field test (n = 16). Recovery of righting reflex after either high-dose dexmedetomidine (50 µg/kg) or high-dose ketamine (50 mg/kg) with and without methylphenidate (1-5 mg/kg) was assessed in a second cohort of rats (n = 8). Finally, in a third cohort of rats (n = 8), frontal electroencephalography (EEG) was recorded for spectral analysis under both low and high doses of dexmedetomidine and ketamine with and without methylphenidate. Low-dose dexmedetomidine reduced locomotion by 94% in rats. Methylphenidate restored locomotion after low-dose dexmedetomidine (rank difference = 88.5, 95% confidence interval [CI], 70.8-106) and the effect was blocked by coadministration with a dopamine D1 receptor antagonist (rank difference = 86.2, 95% CI, 68.6-104). Low-dose ketamine transiently attenuated mobility by 58% and was not improved with methylphenidate. Methylphenidate did not affect the return of righting reflex latency in rats after high-dose dexmedetomidine nor ketamine. Frontal EEG analysis revealed that methylphenidate reversed spectral changes induced by low-dose dexmedetomidine (F [8,87] = 3.27, P = .003) but produced only transient changes after high-dose dexmedetomidine. Methylphenidate did not induce spectral changes in the EEG after low- or high-dose ketamine. Methylphenidate reversed behavioral and neurophysiological correlates of sedation, but not unconsciousness, induced by dexmedetomidine. In contrast, methylphenidate did not affect sedation, unconsciousness, nor EEG signatures in rats after ketamine. These findings suggest that methylphenidate may be efficacious to reverse dexmedetomidine sedation in humans.

A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state

Many neurotransmitter receptors activate G proteins through exchange of GDP for GTP. The intermediate nucleotide-free state has eluded characterization, due largely to its inherent instability. Here we characterize a G protein variant associated with a rare neurological disorder in humans. GαoK46E has a charge reversal that clashes with the phosphate groups of GDP and GTP. As anticipated, the purified protein binds poorly to guanine nucleotides yet retains wild-type affinity for G protein βγ subunits. In cells with physiological concentrations of nucleotide, GαoK46E forms a stable complex with receptors and Gβγ, impeding effector activation. Further, we demonstrate that the mutant can be easily purified in complex with dopamine-bound D2 receptors, and use cryo-electron microscopy to determine the structure, including both domains of Gαo, without nucleotide or stabilizing nanobodies. These findings reveal the molecular basis for the first committed step of G protein activation, establish a mechanistic basis for a neurological disorder, provide a simplified strategy to determine receptor-G protein structures, and a method to detect high affinity agonist binding in cells.

Rasd2 regulates depression-like behaviors via DRD2 neurons in the prelimbic cortex afferent to nucleus accumbens core circuit.

Depressive symptoms, such as anhedonia, decreased social interaction, and lack of motivation, implicate brain reward systems in the pathophysiology of depression. Exposure to chronic stress impairs the function of brain reward circuits and is well-known to be involved in the etiology of depression. A transcriptomic analysis found that stress alters the expression of Rasd2 in mice prefrontal cortex (PFC). Similarly, in our previous study, acute fasting decreased Rasd2 expression in mice PFC, and RASD2 modulated dopamine D2 receptor (DRD2)-mediated antidepressant-like effects in ovariectomized mice. This research suggests the role of RASD2 in stress-induced depression and its underlying neural mechanisms that require further investigation. Here, we show that 5-day unpredictable mild stress (5-d UMS) exposure reduces RASD2 expression in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of mice, while overexpression (but not knock-down) of Rasd2 in the NAc core (NAcc) alleviates 5-d UMS-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Further studies investigated neuronal projections between the mPFC (Cg1, PrL, and IL) and NAcc, labeled by the retrograde tracer Fluorogold. Depression-like behaviors induced by 5-d UMS were only related to inhibition of the PrL-NAcc circuit. DREADD (Designer receptors exclusively activated by designer drug) analysis found that the activation of PrL-NAcc glutaminergic projection alleviated depression-like behaviors and increased DRD2- and RASD2-positive neurons in the NAcc. Using Drd2-cre transgenic mice, we constructed mice with Rasd2 overexpression in DRD2PrL-NAcc neurons, finding that Rasd2 overexpression ameliorated 5-d UMS-induced depression-like behaviors. These findings demonstrate a critical role for RASD2 modulation of DRD2PrL-NAcc neurons in 5-d UMS-induced depression-like behaviors. In addition, the study identifies a new potential strategy for precision medical treatment of depression.

Influence of long-term social isolation on the behavior and dopamine system of the brain in mice

The dopamine brain system is involved in the regulation of various physiological processes and behavioral responses, including social behavior. It was shown in rodents that prolonged social isolation can lead to changes in behavioral parameters and neurochemical parameters, but these data remain unclear. In this work, we studied the effects of prolonged social isolation on the behavior and state of the brain dopamine system in male C57Bl/6 mice. Animals of the experimental group from the age of 40 - 42 days were kept individually in separate cages for six weeks, while the mice of the control group were kept in-group conditions. Isolation did not affect locomotor and exploratory activity in the “open field” test compared to the content in the group. At the same time, animals subjected to prolonged isolation demonstrated a longer duration of social contacts in the “resident-intruder” model and a weakening of stereotypical behavior in the “marbles burying” test compared to the control group. These behavioral changes were accompanied by an increase in mRNA levels of the genes encoding dopamine D1 and D2 receptors in the striatum of mice. In addition, the level of the dopamine metabolite DOPAC decreased in the hypothalamus and increased in the frontal cortex of mice due to the effect of social isolation compared with the control group. The results contribute to the understanding of the effects of prolonged social isolation on the behavior and dopamine brain system in mice.

Modulating amacrine cell-derived dopamine signaling promotes optic nerve regeneration and preserves visual function.

As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific Drd1 overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.