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A central goal in understanding brain function is to link specific cell populations to behavioral outputs. In recent years, the selective targeting of specific neural circuits has been made possible with the development of new experimental approaches, including chemogenetics. This technique allows for the control of molecularly defined subsets of cells through engineered G protein-coupled receptors (GPCRs), which have the ability to activate or silence neuronal firing. Through chemogenetics, neural circuits are being linked to behavioral outputs at an unprecedented rate. Further, the coupling of chemogenetics with imaging techniques to monitor neural activity in freely moving animals now makes it possible to deconstruct the complex whole-brain networks that are fundamental to behavioral states. In this review, we highlight a specific chemogenetic application known as DREADDs (designer receptors exclusively activated by designer drugs). DREADDs are used ubiquitously to modulate GPCR activity in vivo and have been widely applied in the basic sciences, particularly in the field of behavioral neuroscience. Here, we focus on the impact and utility of DREADD technology in dissecting the neural circuitry of various behaviors including memory, cognition, reward, feeding, anxiety and pain. By using DREADDs to monitor the electrophysiological, biochemical, and behavioral outputs of specific neuronal types, researchers can better understand the links between brain activity and behavi...

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Once neurons are adorned with DREADDs, or designer receptors exclusively activated by designer drugs, neural circuits can be activated or suppressed at will, potentially resolving neurological conditions.

Nature Communications - Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks....

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In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein–coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.

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DREADDs (designer receptors exclusively activated by designer drugs) are a powerful and tremendous new technique for selectively manipulating a specific neuronal (or non-neuronal) subpopulation. Recent studies indicate, however, that ligands used for DREADDs, such as clozapine- N -oxide or its parent compound clozapine, are not as selective as expected, even at reasonable concentrations. Although the new generation of ligands specifically developed for DREADDs or alternative chemogenetic receptors may present some improvements, the absence of potential off-target effects remains to be fully demonstrated. Together, indications from the recent literature on DREADDs should warn current and future users about some weaknesses of this expanding technique in the field of integrative neuroscience and encourage them to take some specific precautions to avoid important pitfalls with DREADDs, which remain a promising and complementary approach to optogenetics with the relevant controls. Over the past decade, chemogenetic and optogenetic techniques have revolutionized integrative neuroscience by providing new tools to reversibly manipulate the activity of specific populations or neurotransmitter systems with greater selectivity (Sternson and Roth, 2014; Roth, 2016; Wiegert et al., 2017). Compared with optogenetics, which allow fast and phasic neuronal modulation with high temporal resolution, chemogenetics allow more extended modulation of systems, which is particularly useful for studies focusing on tonic phenomena (e.g., investigation of the implication of dopamine in motivational processes; Whissell et al., 2016). Among chemogenetic tools, designer receptors exclusively activated by designer drugs (DREADDs) are widely used and are referred to as a biological “lock-and-key” system for selective manipulation of cell activity through G-protein signaling pathways. First developed very elegantly by the Roth’s group (Armbruster et al., 2007), this G-protein-coupled receptor (GPCR) is a muscarinic receptor: the lock, which was mutated to respond only to clozapine- N -oxide (CNO), the …

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Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern.

By LEWIS M. SIMES, Published on 01/01/27

Learn more about DREADD receptors and their ligands and actuators: CNO (clozapine n-oxide), perlapine, DREADD agonist 21 (Compound 21), J60, J52 and SalB (salvinorin B)

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Hello Bio manufacture higih quality DREADD receptor ligands Clz N Oxide (CNO), Salvinorin B (SalB), J60, J52 and perlapine which activate DREADD receptors in neuroscience research

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