Degenerative Diseases of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Dyskinesias are abnormal involuntary movements occurring as a complication of dopaminergic therapy. The cause is unclear, but may be related to: Upregulation of dopamine receptors.Postsynaptic changes associated with both PD and exposure to levodopa.Influences of glutamatergic projections and other transmitter systems including serotonergic, alpha-2 adrenergic, histaminergic, and cannabinoid pathways.
A Genetic Framework for Addiction
Hanna Pickard, Serge H. Ahmed in The Routledge Handbook of Philosophy and Science of Addiction, 2019
Other dopamine receptor genes have been linked with drug addiction. Thus, several SNPs have been identified in the DRD1 gene, and ten association studies have been conducted to date on different substance addictions (alcohol use disorder, heavy smoking, and methamphetamine use), most of them with negative results. For the DRD3 gene, again most of the results are negative, except from an association with nicotine dependence that was detected in preliminary studies but requires further replication. The role of a variable number of tandem repeats (VNTR) polymorphism located in the third exon of the DRD4 gene is most convincing in nicotine dependence and opioid dependence, while its association with alcohol use disorder is heterogeneous (Gorwood 2012; Le Foll 2009). The DRD5 gene is an exon that encodes the receptor and only rs7655090 is associated with withdrawal severity score in alcohol dependence.
In Vitro Autoradiographic Studies of Drugs Acting at Dopamine Receptor Sites
Edythe D. London in Imaging Drug Action in the Brain, 2017
Dopamine may play a central role in the mediation of the addictive potential as well as in the toxic effects of many drugs of abuse including, but not restricted to, cocaine and the amphetamines. These agents are recognized inhibitors of dopamine uptake (Horn, 1990) and may also act to enhance dopamine release through interaction with the transmembrane dopamine transporter complex (Ritz and Kuhar, 1989; Madras et al., 1989b). In fact, there is considerable evidence that the addictive potential of these agents is directly proportional to their individual potency at dopamine uptake sites (Ritz et al., 1987). In addition, numerous studies have suggested that self-administration by animals of a variety of drugs of abuse is modulated by dopamine receptor stimulation (Galloway, 1988), particularly within me-solimbic structures such as the nucleus accumbens. Thus, autoradiographic studies of cocaine binding sites, dopamine uptake sites, and dopamine receptors may allow for better anatomical resolution of the pharmacological processes which underlie drug self-administration, abuse, and addiction.
Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs
Published in Expert Opinion on Drug Discovery, 2019
Verònica Casadó-Anguera, Antoni Cortés, Vicent Casadó, Estefanía Moreno
The bitopic ligand SB269652 (Figure 2(b)) was described as the first allosteric molecule able to distinguish between D2R and D3R monomers and homodimers. This molecule binds in a bitopic mode to one protomer of a dopamine receptor dimer. In this scenario, part of the ligand binds to the orthosteric site and another part to an allosteric site, causing a change in the ability of ligands to bind the orthosteric binding pocket of the other promoter within the homodimer. However, it acts as a competitive antagonist with receptor monomers [139,140]. Thus, when increasing the concentration of a dopamine receptor agonist, more dimers are occupied and more evident is the allosteric effect [140]. As for allosteric ligands, there are no reported bitopic ligands for D1R heteromers.
Pharmacogenetics and levodopa induced motor complications
Published in International Journal of Neuroscience, 2019
Kallirhoe Kalinderi, Vasileios Papaliagkas, Liana Fidani
Dopamine exerts its physiological actions through the activation of dopamine receptors. There are five types of dopamine receptors (DRD1–DRD5). The D1 receptors include types D1 (DRD1) and D5 (DRD5) and the D2 receptors include types D2 (DRD2), D3 (DRD3), and D4 (DRD4). Normally dopamine has an excitatory response through D1 receptors on direct pathways and an inhibitory response through D2 receptors on the indirect pathway. Motor movements are mediated by the activation of direct pathways and reduced by the activation of indirect pathways. In PD, which is characterized by the loss of dopamine, underactivity of direct pathways and overactivity of indirect pathways prevails, leading to a decrease in thalamocortical glutamatergic output and hypokinetic movements [32]. It is thought that with chronic levodopa therapy, there is overstimulation of D1 and D2 receptors, which leads to overactivity of direct pathways and inhibition of indirect pathways accompanied by increased glutamatergic thalamocortical output and LID (Table 1).
On the path toward personalized medicine: implications of pharmacogenetic studies of alcohol use disorder medications
Published in Expert Review of Precision Medicine and Drug Development, 2020
Steven J. Nieto, Erica N. Grodin, Lara A. Ray
Alcohol, like most drugs of abuse, increases dopamine release in the ventral striatum. There are five main types of dopamine receptors that are organized into two families, D1-like and D2-like, all of which are G-coupled protein receptors. The Taq1A polymorphism, located downstream of the dopamine receptor 2 (DRD2) and within the Ankyrin Repeat and Kinase Domain Containing 1 (ANKK1) gene, has been shown to moderate treatments in individuals with AUD (see Table 2). Ooteman et al. [49] found that AUD individuals who were A1 homozygotes benefited more from acamprosate versus NTX on cue-induced craving relative to A2 homozygotes, who benefited more from NTX versus acamprosate. In another study of AUD individuals, A1 carriers treated with bromocriptine, a D2 agonist, had lower craving for alcohol relative to A2 homozygotes [69]. Additionally, dopamine can be converted to the neurotransmitter norepinephrine by the enzyme dopamine beta-hydroxylase (DBH). A SNP (rs1611115) in the DBH gene has been shown to moderate NTX responses in AUD individuals. Specifically, NTX-treated T carriers had more abstinence from heavy drinking than those with the CC genotype on NTX [54]. Conversely, NTX-treated C homozygotes had lower abstinence rates compared to placebo-treated C homozygotes. Taken together, genetic variants in the catecholamine system may help identify individuals with AUD who will respond better or do worse on NTX relative to placebo.
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