d1 receptor
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2022 ◽  
Vol 194 ◽  
pp. 113015
Author(s):  
Hong-Li Wei ◽  
Yang Han ◽  
Han Zhou ◽  
Tao Hou ◽  
Yu-Min Yao ◽  
...  

2022 ◽  
Vol 15 ◽  
Author(s):  
Jace Jones-Tabah ◽  
Hanan Mohammad ◽  
Emma G. Paulus ◽  
Paul B. S. Clarke ◽  
Terence E. Hébert

The dopamine D1 receptor (D1R) is a Gαs/olf-coupled GPCR that is expressed in the midbrain and forebrain, regulating motor behavior, reward, motivational states, and cognitive processes. Although the D1R was initially identified as a promising drug target almost 40 years ago, the development of clinically useful ligands has until recently been hampered by a lack of suitable candidate molecules. The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders. To develop better therapeutics, advances in ligand chemistry must be matched by an expanded understanding of D1R signaling across cell populations in the brain, and in disease states. Depending on the brain region, the D1R couples primarily to either Gαs or Gαolf through which it activates a cAMP/PKA-dependent signaling cascade that can regulate neuronal excitability, stimulate gene expression, and facilitate synaptic plasticity. However, like many GPCRs, the D1R can signal through multiple downstream pathways, and specific signaling signatures may differ between cell types or be altered in disease. To guide development of improved D1R ligands, it is important to understand how signaling unfolds in specific target cells, and how this signaling affects circuit function and behavior. In this review, we provide a summary of D1R-directed signaling in various neuronal populations and describe how specific pathways have been linked to physiological and behavioral outcomes. In addition, we address the current state of D1R drug development, including the pharmacology of newly developed non-catecholamine ligands, and discuss the potential utility of D1R-agonists in Parkinson's Disease and cognitive impairment.


2022 ◽  
Author(s):  
Bridget A Matikainen-Ankney ◽  
Alex A Legaria ◽  
Yvan M Vachez ◽  
Caitlin A Murphy ◽  
Yiyan A Pan ◽  
...  

Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. In addition to homeostatic feeding mechanisms, there is growing recognition of the involvement of food reward and motivation in the development of obesity. However, it remains unclear how brain circuits that control food reward and motivation are altered in obese animals. Here, we tested the hypothesis that signaling through pro-motivational circuits in the core of the nucleus accumbens (NAc) is enhanced in the obese state, leading to invigoration of food seeking. Using a novel behavioral assay that quantifies physical work during food seeking, we confirmed that obese mice work harder than lean mice to obtain food, consistent with an increase in the relative reinforcing value of food in the obese state. To explain this behavioral finding, we recorded neural activity in the NAc core with both in vivo electrophysiology and cell-type specific calcium fiber photometry. Here we observed greater activation of D1-receptor expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. With ex vivo slice physiology we identified both pre- and post-synaptic mechanisms that contribute to this enhancement in NAc D1SPN activity in obese mice. Finally, blocking synaptic transmission from D1SPNs decreased physical work during food seeking and attenuated high-fat diet-induced weight gain. These experiments demonstrate that obesity is associated with a selective increase in the activity of D1SPNs during food seeking, which enhances the vigor of food seeking. This work also establishes the necessity of D1SPNs in the development of diet-induced obesity, identifying a novel potential therapeutic target.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jeffrey W. Grimm ◽  
Katherine North ◽  
Madeleine Hopkins ◽  
Kyle Jiganti ◽  
Alex McCoy ◽  
...  

Abstract Background There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using Long-Evans rats. Methods Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. Results When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. Conclusions Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data provide a pre-clinical model to further evaluate sex differences in addiction behaviors and manipulations designed to reduce them.


2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Daisuke Sato ◽  
Michiko Narita ◽  
Yusuke Hamada ◽  
Tomohisa Mori ◽  
Kenichi Tanaka ◽  
...  

AbstractEmerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.


Author(s):  
Anne S. Gibson ◽  
Peter J. West ◽  
Kristen A. Keefe

Abstract Rationale Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. Objectives Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. Methods Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. Results Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. Conclusions Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.


2022 ◽  
Author(s):  
Hui Dong ◽  
Ze-Ka Chen ◽  
Han Guo ◽  
Xiang-Shan Yuan ◽  
Cheng-Wei Liu ◽  
...  

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260577
Author(s):  
Alyssa Bernanke ◽  
Elizabeth Burnette ◽  
Justine Murphy ◽  
Nathaniel Hernandez ◽  
Sara Zimmerman ◽  
...  

Females are more affected by psychiatric illnesses including eating disorders, depression, and post-traumatic stress disorder than males. However, the neural mechanisms mediating these sex differences are poorly understood. Animal models can be useful in exploring such neural mechanisms. Conditioned taste aversion (CTA) is a behavioral task that assesses how animals process the competition between associated reinforcing and aversive stimuli in subsequent task performance, a process critical to healthy behavior in many domains. The purpose of the present study was to identify sex differences in this behavior and associated neural responses. We hypothesized that females would value the rewarding stimulus (Boost®) relative to the aversive stimulus (LiCl) more than males in performing CTA. We evaluated behavior (Boost® intake, LiCl-induced behaviors, ultrasonic vocalizations (USVs), CTA performance) and Fos activation in relevant brain regions after the acute stimuli [acute Boost® (AB), acute LiCl (AL)] and the context-only task control (COT), Boost® only task (BOT) and Boost®-LiCl task (BLT). Acutely, females drank more Boost® than males but showed similar aversive behaviors after LiCl. Females and males performed CTA similarly. Both sexes produced 55 kHz USVs anticipating BOT and inhibited these calls in the BLT. However, more females emitted both 22 kHz and 55 kHz USVs in the BLT than males: the latter correlated with less CTA. Estrous cycle stage also influenced 55 kHz USVs. Fos responses were similar in males and females after AB or AL. Females engaged the gustatory cortex and ventral tegmental area (VTA) more than males during the BOT and males engaged the amygdala more than females in both the BOT and BLT. Network analysis of correlated Fos responses across brain regions identified two unique networks characterizing the BOT and BLT, in both of which the VTA played a central role. In situ hybridization with RNAscope identified a population of D1-receptor expressing cells in the CeA that responded to Boost® and D2 receptor-expressing cells that responded to LiCl. The present study suggests that males and females differentially process the affective valence of a stimulus to produce the same goal-directed behavior.


2021 ◽  
Vol 14 ◽  
Author(s):  
Lixue Lin ◽  
Yuye Lan ◽  
He Zhu ◽  
Lingling Yu ◽  
Shuang Wu ◽  
...  

As tourette syndrome (TS) is a common neurobehavioral disorder, the primary symptoms of which include behavioral stereotypies. Dysfunction of the substantia nigra–striatum network could be the main pathogenesis of TS, which is closely associated with dopamine (DA) and its receptors. TS is often resistant to conventional treatments. Therefore, it is necessary to investigate the neurobiological mechanisms underlying its pathogenesis. In this study, we investigated whether chemogenetic activation or inhibition of dopaminergic D1 receptor (D1R)- or D2 receptor (D2R)-containing neurons in the substantia nigra pars compacta (SNpc) or dorsal striatum (dSTR) affected the stereotyped behavior and motor functions of TS mice. Intraperitoneal injection of 3,3′-iminodipropionitrile (IDPN) was used to induce TS in mice. Stereotyped behavior test and open-field, rotarod, and grip strength tests were performed to evaluate stereotyped behavior and motor functions, respectively. Immunofluorescence labeling was used to detect the co-labeling of virus fluorescence and D1R or D2R. We found that chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies and motor functions in TS mice. Chemogenetic activation of D1R-containing neurons in the dSTR aggravated behavioral stereotypies and motor functions in vehicle-treated mice, but neither was aggravated in TS mice. In conclusion, chemogenetic inhibition of D1R- or D2R-containing neurons in the SNpc and dSTR alleviated behavioral stereotypies of TS, providing a new treatment target for TS. Moreover, the activation of D1R-containing neurons in the dSTR may contribute to the pathogenesis of TS, which can be chosen as a more precise target for treatment.


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