The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Susan G Amara - One of the best experts on this subject based on the ideXlab platform.
-
Amphetamines signal through intracellular taar1 receptors coupled to gα13 and gαs in discrete subcellular domains
Molecular Psychiatry, 2019Co-Authors: Suzanne M Underhill, Patrick D Hullihen, Jingshan Chen, Cristina Fenollarferrer, M A Rizzo, Susan L Ingram, Susan G AmaraAbstract:The extensive use of Amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of Amphetamines and Amphetamine-related drugs. We have previously shown that acute Amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by Amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for Amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.
-
Amphetamines signal through intracellular TAAR1 receptors coupled to Gα 13 and Gα S in discrete subcellular domains
Molecular psychiatry, 2019Co-Authors: Suzanne M Underhill, Patrick D Hullihen, Jingshan Chen, M A Rizzo, Susan L Ingram, Cristina Fenollar-ferrer, Susan G AmaraAbstract:The extensive use of Amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of Amphetamines and Amphetamine-related drugs. We have previously shown that acute Amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by Amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for Amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.
-
Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter eaat3 in dopamine neurons
Neuron, 2014Co-Authors: Suzanne M Underhill, Susan L Ingram, Susan G Amara, David S Wheeler, Spencer D WattsAbstract:Summary Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of Amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when Amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, Amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of Amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by Amphetamine increases glutamatergic signaling and thus contributes to the effects of Amphetamine on neurotransmission.
Suzanne M Underhill - One of the best experts on this subject based on the ideXlab platform.
-
Amphetamines signal through intracellular taar1 receptors coupled to gα13 and gαs in discrete subcellular domains
Molecular Psychiatry, 2019Co-Authors: Suzanne M Underhill, Patrick D Hullihen, Jingshan Chen, Cristina Fenollarferrer, M A Rizzo, Susan L Ingram, Susan G AmaraAbstract:The extensive use of Amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of Amphetamines and Amphetamine-related drugs. We have previously shown that acute Amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by Amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for Amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.
-
Amphetamines signal through intracellular TAAR1 receptors coupled to Gα 13 and Gα S in discrete subcellular domains
Molecular psychiatry, 2019Co-Authors: Suzanne M Underhill, Patrick D Hullihen, Jingshan Chen, M A Rizzo, Susan L Ingram, Cristina Fenollar-ferrer, Susan G AmaraAbstract:The extensive use of Amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of Amphetamines and Amphetamine-related drugs. We have previously shown that acute Amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by Amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for Amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.
-
Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter eaat3 in dopamine neurons
Neuron, 2014Co-Authors: Suzanne M Underhill, Susan L Ingram, Susan G Amara, David S Wheeler, Spencer D WattsAbstract:Summary Amphetamines modify the brain and alter behavior through mechanisms generally attributed to their ability to regulate extracellular dopamine concentrations. However, the actions of Amphetamine are also linked to adaptations in glutamatergic signaling. We report here that when Amphetamine enters dopamine neurons through the dopamine transporter, it stimulates endocytosis of an excitatory amino acid transporter, EAAT3, in dopamine neurons. Consistent with this decrease in surface EAAT3, Amphetamine potentiates excitatory synaptic responses in dopamine neurons. We also show that the process of internalization is dynamin- and Rho-mediated and requires a unique sequence in the cytosolic C terminus of EAAT3. Introduction of a peptide based on this motif into dopamine neurons blocks the effects of Amphetamine on EAAT3 internalization and its action on excitatory responses. These data indicate that the internalization of EAAT3 triggered by Amphetamine increases glutamatergic signaling and thus contributes to the effects of Amphetamine on neurotransmission.
Miguel Casas - One of the best experts on this subject based on the ideXlab platform.
-
Amphetamines for attention deficit hyperactivity disorder adhd in adults
Cochrane Database of Systematic Reviews, 2011Co-Authors: Xavier Castells, Josep Antoni Ramosquiroga, Rosa Bosch, Mariana Nogueira, Miguel CasasAbstract:Attention Deficit Hyperactivity Disorder (ADHD) is a childhood onset psychiatric disorder that can persist into adulthood in up to 50% of patients. From a clinical point of view, ADHD is characterized by hyperactivity, mood instability, irritability, difficulties in maintaining attention, lack of organization and impulsive behaviours. The presence of other disorders occurring at the the same time is also common, especially mood disorders and substance abuse. It seems that Amphetamines could reverse the underlying neurological problems that feature in ADHD, and so improve ADHD symptoms. We found seven studies, which enrolled 1091 patients. These studies compared Amphetamines to placebo and three of them also compared Amphetamines with other drugs: guanfacine, modafinil and paroxetine. Three Amphetamine derivatives were investigated: dexAmphetamine, lisdexAmphetamine and mixed Amphetamine salts (MAS). Treatment length ranged from two to 20 weeks. All Amphetamines improved ADHD symptoms but overall they did not make people more likely to stay in treatment and were associated with a higher risk of treatment ending early due to adverse events. One type of Amphetamine, mixed Amphetamine salts, did, however, increase retention in treatment. We found no evidence that higher doses worked better than lower ones. We did not find any difference in effectiveness between immediate-release and sustained-release formulations. Therefore, it appears that short-term treatment with Amphetamines reduces ADHD symptoms, but studies assessing the effects of Amphetamines for longer periods of time are needed.
Michael Freissmuth - One of the best experts on this subject based on the ideXlab platform.
-
Amphetamines new psychoactive drugs and the monoamine transporter cycle
Trends in Pharmacological Sciences, 2015Co-Authors: Harald H. Sitte, Michael FreissmuthAbstract:In monoaminergic neurons, the vesicular transporters and the plasma membrane transporters operate in a relay. Amphetamine and its congeners target this relay to elicit their actions: most Amphetamines are substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some Amphetamines act as transporter inhibitors. Both compound classes elicit profound psychostimulant effects, which render them liable to recreational abuse. Currently, a surge of new psychoactive substances occurs on a global scale. Chemists bypass drug bans by ingenuous structural variations, resulting in a rich pharmacology. A credible transport model must account for their distinct mode of action and link this to subtle differences in activity and undesired, potentially deleterious effects.
-
ca2 calmodulin dependent protein kinase iiα αcamkii controls the activity of the dopamine transporter implications for angelman syndrome
Journal of Biological Chemistry, 2012Co-Authors: Thomas Steinkellner, Sonja Sucic, Jaewon Yang, Therese Montgomery, Weiqiang Chen, Marietherese Winkler, Gert Lubec, Michael Freissmuth, Ype Elgersma, Harald H. SitteAbstract:Abstract The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signalling. DAT is also the primary target of psychostimulant drugs, such as cocaine and Amphetamines. Conversely, methylphenidate and Amphetamine are both used clinically in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. The action of Amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates Amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP+) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKIIT305D) exhibit significantly reduced Amphetamine-triggered DAT-mediated MPP+ efflux. Additionally, we investigated mice which mimick the neurogenetic disease known as Angelman Syndrome. These mice possess reduced αCaMKII activity. Angelman Syndrome mice demonstrated an impaired DAT efflux function which was comparable to that of the αCaMKII mutant mice, indicating that DAT mediated dopaminergic signalling is affected in Angelman Syndrome.
-
Amphetamines take two to tango an oligomer based counter transport model of neurotransmitter transport explores the Amphetamine action
Molecular Pharmacology, 2005Co-Authors: Stefan Seidel, Marion Holy, Oliver Kudlacek, Petra Scholze, Ernst A. Singer, Herwig Just, Hesso Farhan, Karl Koppatz, Peter Krivanek, Michael FreissmuthAbstract:Amphetamine congeners [e.g., 3,4-methylenedioxymetAmphetamine (MDMA), or "ecstasy"] are substrates for monoamine transporters (i.e., the transporters for serotonin, norepinephrine, and dopamine); however, their in vivo-action relies on their ability to promote monoamine efflux. The mechanistic basis for this counter transport remains enigmatic. We tested the hypothesis that outward transport is contingent on the oligomeric nature of neurotransmitter transporters by creating a concatemer of the serotonin transporter and the Amphetamine-resistant GABA transporter. In cells expressing the concatemer, Amphetamine analogs promoted GABA efflux and blunted GABA influx. In contrast, the natural substrates serotonin and GABA only cause mutual inhibition of influx via the other transporter moiety in the concatemer. GABA efflux through the concatemer that was promoted by Amphetamine analogs was blocked by the protein kinase C inhibitors GF109203X (bisindoylmaleimide I) and Go6983 (2-[1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide). Thus, based on our observations, we propose that, in the presence of Amphetamine analogs, monoamine transporters operate as counter-transporters; influx and efflux occur through separate but coupled moieties. Influx and efflux are coupled via changes in the ionic gradients, but these do not suffice to account for the action of Amphetamines; the activity of a protein kinase C isoform provides a second stimulus that primes the inward facing conformation for outward transport.
Xavier Castells - One of the best experts on this subject based on the ideXlab platform.
-
Efficacy of Psychostimulant Drugs for Amphetamine Abuse or Dependence
Cochrane Database of Systematic Reviews, 2012Co-Authors: Clara Pérez-mañá, Xavier Castells, Marta Torrens, Dolors Capellà, Magí FarréAbstract:Amphetamine dependence constitutes a public health problem with many consequences and complications. Amphetamine abuse refers to a maladaptive and hazardous pattern of use considered to be less severe than dependence. To date, no pharmacological treatment has been approved for Amphetamine abuse or dependence, and psychotherapy remains the best treatment option.\ud \ud Long-term Amphetamine use reduces dopamine levels in the brain. Drugs increasing dopamine and mimicking the effects of Amphetamines with lower abuse liability could be used as replacement therapy in Amphetamine dependence. Several psychostimulants have been studied recently for this purpose.\ud \ud In this review, the efficacy and safety of psychostimulants for Amphetamine abuse or dependence were studied. We found eleven studies enrolling 791 Amphetamine-dependent participants and assessing the effects of four different psychostimulants: dexAmphetamine, bupropion, methylphenidate and modafinil. Psychosocial interventions were additionally provided to all participants. The studies were conducted in the USA, Australia or Northern Europe, and study length ranged from 8 to 20 weeks.\ud \ud Psychostimulants did not reduce Amphetamine use or Amphetamine craving and also did not increase sustained abstinence in comparison with placebo. Retention in treatment was similar and low with both treatments. Psychostimulants also did not increase the risk of adverse events that were intense enough to induce dropouts.\ud \ud Research with larger and longer trials is needed to determine whether psychostimulants can be a useful replacement therapy for patients with Amphetamine abuse or dependence. The design of future trials should consider the level of dependence at study entry, the potency and the dose of the psychostimulant administered, the length of the trial and the representativeness of included participants
-
Amphetamines for attention deficit hyperactivity disorder adhd in adults
Cochrane Database of Systematic Reviews, 2011Co-Authors: Xavier Castells, Josep Antoni Ramosquiroga, Rosa Bosch, Mariana Nogueira, Miguel CasasAbstract:Attention Deficit Hyperactivity Disorder (ADHD) is a childhood onset psychiatric disorder that can persist into adulthood in up to 50% of patients. From a clinical point of view, ADHD is characterized by hyperactivity, mood instability, irritability, difficulties in maintaining attention, lack of organization and impulsive behaviours. The presence of other disorders occurring at the the same time is also common, especially mood disorders and substance abuse. It seems that Amphetamines could reverse the underlying neurological problems that feature in ADHD, and so improve ADHD symptoms. We found seven studies, which enrolled 1091 patients. These studies compared Amphetamines to placebo and three of them also compared Amphetamines with other drugs: guanfacine, modafinil and paroxetine. Three Amphetamine derivatives were investigated: dexAmphetamine, lisdexAmphetamine and mixed Amphetamine salts (MAS). Treatment length ranged from two to 20 weeks. All Amphetamines improved ADHD symptoms but overall they did not make people more likely to stay in treatment and were associated with a higher risk of treatment ending early due to adverse events. One type of Amphetamine, mixed Amphetamine salts, did, however, increase retention in treatment. We found no evidence that higher doses worked better than lower ones. We did not find any difference in effectiveness between immediate-release and sustained-release formulations. Therefore, it appears that short-term treatment with Amphetamines reduces ADHD symptoms, but studies assessing the effects of Amphetamines for longer periods of time are needed.