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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
The D2-like receptors are composed of D2R, D3R and D4R and include two D2 receptor isoforms, different isoforms of D3R, and polymorphic forms of D4R [9,11]. The coding regions of D2, D3 and D4 contain 6, 5 and 3 introns, respectively, with D3 lacking the fourth intron of D2, and D4 lacking the third and fourth introns of D2. The D2-like receptors are involved in both pre- and postsynaptic inhibition. In general, this class of receptors is associated with the regulation of mood and emotional stability in the limbic system, the control of movement in the basal ganglia, the control of cognition and memory in the prefrontal cortex, and the regulation of hormone synthesis and release from the pituitary gland.
Pharmacological MRI as a Molecular Imaging Technique
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Y. Iris Chen, Bruce G. Jenkins
Some other neurotransmitters act as modulators and can have influence both ways. For example, depending on which receptor subtype it binds to, dopamine (DA) can be either excitatory (when acting on D1-like receptors) or inhibitory (when acting on D2-like receptors). However, the neurotransmitter-receptor-mediated modulation of the postsynaptic potential only describes a superficial part of the neuronal function. The neurotransmitter-receptor innervation often leads to a chain modulation in molecular and gene expression levels. As reviewed in Greengard,9 many neurotransmitter activities are coupled to second messengers such as cAMP, cGMP, calcium, and diacylglycerol. The second messenger thus serves as a functional converging center for multiple neurotransmitters and consequently modulates gene transcription and function of membrane-bound receptors through a series of reactions at the molecular level. In the case of drug addiction or plasticity remodeling, a modulation at the molecular genetic profile can be a major contributor to the overall alteration of the neuronal function. In order to understand brain function thoroughly, it is necessary to link functions from genomolecular to neuroreceptoral through to functional circuitry levels. Fortunately, as science and technology advance, tools have been developed to allow the investigation of brain activity at different functional levels. There are imaging methods, including fMRI and PET, for mapping the activity across the whole brain in response to a particular task. In vivo neurotransmitter activity can be assessed via invasive procedures such as microdialysis and cyclic voltametry, and noninvasively via pharmacological MRI (phMRI), as we will discuss below. Changes in the molecular expression are usually done in vitro or ex vivo via immunohistology or through gene expression techniques such as polymerase chain reaction (PCR). Furthermore, recent developments show that in vivo access of molecular expression can be done via MRI using superparamagnetic iron oxide (SPIO) nanoparticle labeled precursors.10–14 In spite of all the state-of-the-art tools, linkage of knowledge is often lost or misguided by the segmented and isolated data.
Reaching Task in Rats: Quantitative Evaluation and Effects of 6-OHDA into the Striatum
Published in Journal of Motor Behavior, 2022
Yoichi Ohno, Akinori Horikoshi, Kazuyuki Imamura
Using image analysis, we examined the effects of unilateral injection of 6-OHDA into the striatum on several elements of forearm movement and postural control during RT. It has been reported that both the dopamine transporter activity and the D2-like receptor activity decrease in the unilateral striatal lesion model used in this study (Sun et al., 2010). It has also been reported that the nigrostriatal dopaminergic (DA) system is unable to maintain extracellular dopamine levels in the normal range due to disorders of 80% or more (Castaneda et al., 1990; Robinson et al., 1990). Present study showed marked deterioration of RT. Therefore, it is possible that at least 80% or more of the nigrostriatal DA system has been compromised. Accordingly, the animals showed significant functional deterioration in movement during RT, as observed in patients with PD.
A potential paradigm shift in opioid crisis management: The role of pharmacogenomics
Published in The World Journal of Biological Psychiatry, 2022
David Eapen-John, Ayeshah G. Mohiuddin, James L. Kennedy
As mentioned before, dopamine released by VTA neurons into the NAcc reinforces behaviours deemed ‘rewarding’ and produces a feeling of euphoria. Dopamine receptors are classified as D1-like and D2-like. D1-like receptors include DRD1 and DRD5. These receptors increase cAMP and activate the intracellular signalling cascade while the D2-like receptors (DRD2, DRD3, and DRD4), inhibit this process (Jalabert et al. 2011; Zhu et al. 2013; Clarke et al. 2014; Jing Li et al. 2018; Burns et al. 2019). Dopamine levels are regulated in the brain by catechol-O-methyltransferase (COMT) through the degradation of catecholamines including dopamine and norepinephrine. Some studies suggest that DRD1 and DRD2 modulate opioid reinforcement, reward, and opioid-induced neuroadaptation (Clarke et al. 2014; Burns et al. 2019).
Dopamine D3 receptor ligands: a patent review (2014–2020)
Published in Expert Opinion on Therapeutic Patents, 2022
Rita Maria Concetta Di Martino, Andrea Cavalli, Giovanni Bottegoni
Dopamine (DA) is a key neurotransmitter in the central nervous system (CNS) related to several neurological processes by activating five different receptor subtypes. DA receptors belong to the G protein-coupled receptor (GPCR) superfamily and are further divided into two subfamilies: D1-like and D2-like DA receptors according to sequence and pharmacological similarities. The D1-like receptors (D1R and D5R) couple to stimulatory Gs proteins leading to adenylyl cyclase (AC) activity enhancement and increase of cytosolic cyclic adenosine monophosphate (cAMP) levels. On the contrary, activation of D2-like DA receptors (D2R, D3R, and D4R) promotes AC inhibition and consequent decrease of cAMP levels by coupling to inhibitory Gi/o proteins [1,2]. Within the D2-like receptor subfamily, the D2 and D3 receptors are the most homologous pair due to the high degree of sequence identity within the transmembrane helices (78%) and the near identity of the orthosteric binding site (OBS) residues.[3] D3R vs D2R selectivity can be achieved targeting an accessory binding pocket in D3R (often referred to as D3R specificity binding pocket, SBP), which sits right next to the orthosteric one [4,5].