Ppp1r1b

Summary

Gene Symbol: Ppp1r1b
Description: protein phosphatase 1, regulatory (inhibitor) subunit 1B
Alias: Darpp-32, Darpp32, protein phosphatase 1 regulatory subunit 1B, dopamine- and cAMP-regulated neuronal phosphoprotein, dopamine- and cAMP-regulated phosphoprotein DARPP-32, neuronal phosphoprotein DARPP-32
Species: rat
Products:     Ppp1r1b

Top Publications

  1. Svenningsson P, Fienberg A, Allen P, Moine C, Lindskog M, Fisone G, et al. Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32. J Neurochem. 2000;75:248-57 pubmed
    ..These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32. ..
  2. Mani S, Fienberg A, O Callaghan J, Snyder G, Allen P, Dash P, et al. Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science. 2000;287:1053-6 pubmed
    ..P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice. DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice. ..
  3. Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn J, Maroteaux M, et al. A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature. 2008;453:879-84 pubmed publisher
    ..Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade. ..
  4. Dancheck B, Nairn A, Peti W. Detailed structural characterization of unbound protein phosphatase 1 inhibitors. Biochemistry. 2008;47:12346-56 pubmed publisher
    ..Together, these interactions enable potent and selective inhibition of PP1. ..
  5. Rajput P, Kharmate G, Somvanshi R, Kumar U. Colocalization of dopamine receptor subtypes with dopamine and cAMP-regulated phosphoprotein (DARPP-32) in rat brain. Neurosci Res. 2009;65:53-63 pubmed publisher
  6. Hotte M, Thuault S, Lachaise F, Dineley K, Hemmings H, Nairn A, et al. D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex. Behav Brain Res. 2006;171:127-33 pubmed
    ..These results provide insight into molecular mechanisms involved in D(1) receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role. ..
  7. Benderska N, Becker K, Girault J, Becker C, Andreadis A, Stamm S. DARPP-32 binds to tra2-beta1 and influences alternative splicing. Biochim Biophys Acta. 2010;1799:448-53 pubmed publisher
    ..DARPP-32 changes the usage of tra2-beta1 dependent alternative exons in a concentration-dependent manner, suggesting that the DARPP-32:tra2-beta1 interaction is a molecular link between signaling pathways and pre-mRNA processing. ..
  8. Chocarro Calvo A, Zaballos M, Santisteban P, García Jiménez C. DARPP-32 is required for MAPK/ERK signaling in thyroid cells. Mol Endocrinol. 2012;26:471-80 pubmed publisher
    ..Given the implications of MAPK signaling in thyroid cancer and the loss of DARPP-32 in tumor and transformed thyroid cells, DARPP-32 may represent a key therapeutic target. ..
  9. Gomez A, Midde N, Mactutus C, Booze R, Zhu J. Environmental enrichment alters nicotine-mediated locomotor sensitization and phosphorylation of DARPP-32 and CREB in rat prefrontal cortex. PLoS ONE. 2012;7:e44149 pubmed publisher
  10. Beaulieu J, Gainetdinov R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182-217 pubmed publisher

Detail Information

Publications54

  1. Svenningsson P, Fienberg A, Allen P, Moine C, Lindskog M, Fisone G, et al. Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32. J Neurochem. 2000;75:248-57 pubmed
    ..These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32. ..
  2. Mani S, Fienberg A, O Callaghan J, Snyder G, Allen P, Dash P, et al. Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science. 2000;287:1053-6 pubmed
    ..P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice. DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice. ..
  3. Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn J, Maroteaux M, et al. A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature. 2008;453:879-84 pubmed publisher
    ..Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade. ..
  4. Dancheck B, Nairn A, Peti W. Detailed structural characterization of unbound protein phosphatase 1 inhibitors. Biochemistry. 2008;47:12346-56 pubmed publisher
    ..Together, these interactions enable potent and selective inhibition of PP1. ..
  5. Rajput P, Kharmate G, Somvanshi R, Kumar U. Colocalization of dopamine receptor subtypes with dopamine and cAMP-regulated phosphoprotein (DARPP-32) in rat brain. Neurosci Res. 2009;65:53-63 pubmed publisher
  6. Hotte M, Thuault S, Lachaise F, Dineley K, Hemmings H, Nairn A, et al. D1 receptor modulation of memory retrieval performance is associated with changes in pCREB and pDARPP-32 in rat prefrontal cortex. Behav Brain Res. 2006;171:127-33 pubmed
    ..These results provide insight into molecular mechanisms involved in D(1) receptor-dependent modulation of short- versus long-term memory in prefrontal cortex where DARPP-32 in synergy with CREB may represent a pivotal role. ..
  7. Benderska N, Becker K, Girault J, Becker C, Andreadis A, Stamm S. DARPP-32 binds to tra2-beta1 and influences alternative splicing. Biochim Biophys Acta. 2010;1799:448-53 pubmed publisher
    ..DARPP-32 changes the usage of tra2-beta1 dependent alternative exons in a concentration-dependent manner, suggesting that the DARPP-32:tra2-beta1 interaction is a molecular link between signaling pathways and pre-mRNA processing. ..
  8. Chocarro Calvo A, Zaballos M, Santisteban P, García Jiménez C. DARPP-32 is required for MAPK/ERK signaling in thyroid cells. Mol Endocrinol. 2012;26:471-80 pubmed publisher
    ..Given the implications of MAPK signaling in thyroid cancer and the loss of DARPP-32 in tumor and transformed thyroid cells, DARPP-32 may represent a key therapeutic target. ..
  9. Gomez A, Midde N, Mactutus C, Booze R, Zhu J. Environmental enrichment alters nicotine-mediated locomotor sensitization and phosphorylation of DARPP-32 and CREB in rat prefrontal cortex. PLoS ONE. 2012;7:e44149 pubmed publisher
  10. Beaulieu J, Gainetdinov R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182-217 pubmed publisher
  11. Rosenkranz K, May C, Meier C, Marcus K. Proteomic analysis of alterations induced by perinatal hypoxic-ischemic brain injury. J Proteome Res. 2012;11:5794-803 pubmed publisher
    ..Active forms of Calcineurin are associated with the dephosphorylation of Darpp-32, an effect that was also demonstrated in lesioned hemispheres after perinatal brain injury. ..
  12. Scheggi S, Raone A, De Montis M, Tagliamonte A, Gambarana C. Behavioral expression of cocaine sensitization in rats is accompanied by a distinct pattern of modifications in the PKA/DARPP-32 signaling pathway. J Neurochem. 2007;103:1168-83 pubmed
    ..These data suggest that a tonic increase in mGluR5 transmission in cocaine-sensitized rats sustains both the increase in phospho-Thr75 DARPP-32 levels and the expression of behavioral sensitization. ..
  13. Rosa D, Souza R, Souza B, Motta B, Caetano F, Jornada L, et al. DARPP-32 expression in rat brain after electroconvulsive stimulation. Brain Res. 2007;1179:35-41 pubmed
  14. Scheggi S, Rauggi R, Gambarana C, Tagliamonte A, De Montis M. Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats. J Neurochem. 2004;90:792-9 pubmed
    ..The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats. ..
  15. Segovia K, Correa M, Lennington J, Conover J, Salamone J. Changes in nucleus accumbens and neostriatal c-Fos and DARPP-32 immunoreactivity during different stages of food-reinforced instrumental training. Eur J Neurosci. 2012;35:1354-67 pubmed publisher
    ..Moreover, it appears that the separate subregions of the striatal complex are differentially activated at distinct phases of instrumental training. ..
  16. Rajput P, Kharmate G, Kumar U. Colocalization of somatostatin receptors with DARPP-32 in cortex and striatum of rat brain. J Mol Neurosci. 2012;48:696-705 pubmed
    ..Taken together, these results provide the first evidence that the SSTR-positive neurons lacking colocalization with DARPP-32 might be spared in excitotoxicity. ..
  17. Guan Q, Zhan Q, He Y, Tan L. Changes in the prodynorphin gene and DARPP-32 state in 6-OHDA-lesioned rats following long-term treatment with l-dopa. Neurosci Lett. 2007;426:64-8 pubmed
    ..Collectively, these findings suggested that changes of the DARPP-32 phosphorylation state may be important for over-activation of the direct pathway. ..
  18. Yger M, Girault J. DARPP-32, Jack of All Trades… Master of Which?. Front Behav Neurosci. 2011;5:56 pubmed publisher
    DARPP-32 (PPP1R1B) was discovered as a substrate of cAMP-dependent protein kinase (PKA) enriched in dopamine-innervated brain areas. It is one of three related, PKA-regulated inhibitors of protein phosphatase-1 (PP1)...
  19. Souza R, Soares E, Rosa D, Souza B, Gomes K, Valvassori S, et al. Cerebral DARPP-32 expression after methylphenidate administration in young and adult rats. Int J Dev Neurosci. 2009;27:1-7 pubmed publisher
  20. Blom H, Rönnlund D, Scott L, Westin L, Widengren J, Aperia A, et al. Spatial distribution of DARPP-32 in dendritic spines. PLoS ONE. 2013;8:e75155 pubmed publisher
  21. Liu L, Huang Y, Huang Q, Zhao Z, Yu J, Wang L. Muscarinic acetylcholine M4 receptors play a critical role in oxotremorine-induced DARPP-32 phosphorylation at threonine 75 in isolated medium spiny neurons. Neuropharmacology. 2017;117:376-386 pubmed publisher
  22. Ehrman L, Williams M, Schaefer T, Gudelsky G, Reed T, Fienberg A, et al. Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice. Genes Brain Behav. 2006;5:540-51 pubmed
    ..PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 ..
  23. Rosa D, Souza R, Souza B, Guimarães M, Carneiro D, Valvassori S, et al. DARPP-32 expression in rat brain after an inhibitory avoidance task. Neurochem Res. 2008;33:2257-62 pubmed publisher
    ..These changes suggest that DARPP-32 might play a central role in the IA, as previously described as an integrator of the dopaminergic signal. ..
  24. Comim C, Silva N, Mina F, Dominguini D, Scaini G, Morais M, et al. Evaluation of NCS-1, DARPP-32, and neurotrophins in hippocampus and prefrontal cortex in rats submitted to sepsis. Synapse. 2014;68:474-9 pubmed publisher
  25. Zhang H, Okubo S, Hua Y, Keep R, Xi G. Basal Ganglia Damage in Experimental Subarachnoid Hemorrhage. Acta Neurochir Suppl. 2016;121:141-4 pubmed publisher
    ..45 in rats without hydrocephalus and 1.10 ± 0.28 in sham, p < 0.05). In conclusion, SAH resulted in severe basal ganglia damage, which is associated with hydrocephalus development. ..
  26. Chen P, Chen J. Enhanced Cdk5 activity and p35 translocation in the ventral striatum of acute and chronic methamphetamine-treated rats. Neuropsychopharmacology. 2005;30:538-49 pubmed
    ..The overall results demonstrate that Cdk5/p35 and downstream signaling in the ventral striatum play a critical role in the effects of acute METH treatment as well as the development of behavioral METH sensitization. ..
  27. Delli Carri A, Onorati M, Lelos M, Castiglioni V, Faedo A, Menon R, et al. Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development. 2013;140:301-12 pubmed publisher
  28. Nishi A, Matamales M, Musante V, Valjent E, Kuroiwa M, Kitahara Y, et al. Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution. J Biol Chem. 2017;292:1462-1476 pubmed publisher
  29. Lin X, Hashimoto T, Kitamura N, Murakami N, Shirakawa O, Maeda K. Decreased calcineurin and increased phosphothreonine-DARPP-32 in the striatum of rats behaviorally sensitized to methamphetamine. Synapse. 2002;44:181-7 pubmed
    ..These results indicate that the activity of signal transduction via CaN is functionally decreased in the striatum of Meth-sensitized rats. ..
  30. Frye C, Walf A. Infusions of anti-sense oligonucleotides for DARPP-32 to the ventral tegmental area reduce effects of progesterone- and a dopamine type 1-like receptor agonist to facilitate lordosis. Behav Brain Res. 2010;206:286-92 pubmed publisher
    ..Together, these findings suggest that, in the midbrain VTA, P4's actions to facilitate sexual behavior of female rodents, involving D1 receptors, may require DARPP-32. ..
  31. Ignatowski T, Aalinkeel R, Reynolds J, Nair B, Sykes D, Gleason C, et al. Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction. J Neuroimmune Pharmacol. 2015;10:136-52 pubmed publisher
  32. Kunii Y, Hyde T, Ye T, Li C, Kolachana B, Dickinson D, et al. Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. Mol Psychiatry. 2014;19:192-9 pubmed publisher
    Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling...
  33. Kozicz T, Arimura A. Dopamine- and cyclic AMP-regulated phosphoprotein-immunoreactive neurons activated by acute stress are innervated by fiber terminals immunopositive for pituitary adenylate cyclase-activating polypeptide in the extended amygdala in the rat. Regul Pept. 2002;109:63-70 pubmed
    ..Furthermore, interaction between neuropeptides/neurotransmitters and phosphoproteins was also demonstrated. ..
  34. García Jiménez C, Zaballos M, Santisteban P. DARPP-32 (dopamine and 3',5'-cyclic adenosine monophosphate-regulated neuronal phosphoprotein) is essential for the maintenance of thyroid differentiation. Mol Endocrinol. 2005;19:3060-72 pubmed
    ..Our results also raise the possibility that DARPP-32 may play a similar role in the maintenance of differentiation of a range of other cell types. ..
  35. Guitart Masip M, Johansson B, Fernandez Teruel A, Cañete T, Tobena A, Terenius L, et al. Divergent anatomical pattern of D1 and D3 binding and dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa mRNA expression in the Roman rat strains: Implications for drug addiction. Neuroscience. 2006;142:1231-43 pubmed
    ..Hence, RHA-I and RLA-I rats may be a useful tool to identify dopamine-related mechanisms that predispose to drug and alcohol dependence. ..
  36. Witkovsky P, Svenningsson P, Yan L, Bateup H, Silver R. Cellular localization and function of DARPP-32 in the rodent retina. Eur J Neurosci. 2007;25:3233-42 pubmed
    ..We also tested for a possible circadian rhythm of Thr 34- and Thr 75-DARPP-32 and Ser 845-GluR1 expression. No significant circadian rhythm of either DARPP-32 or GluR1 phosphorylation was found. ..
  37. Kim J, Ryu I, Seo S, Choe E. Activation of Protein Kinases and Phosphatases Coupled to Glutamate Receptors Regulates the Phosphorylation State of DARPP32 at Threonine 75 After Repeated Exposure to Cocaine in the Rat Dorsal Striatum in a Ca2+-Dependent Manner. Int J Neuropsychopharmacol. 2015;18: pubmed publisher
    Phosphorylation state of dopamine- and cAMP-regulated phosphoprotein, molecular weight 32 kDa (DARPP32) is crucial to understand drug-mediated synaptic plasticity...
  38. Engmann O, Giralt A, Gervasi N, Marion Poll L, Gasmi L, Filhol O, et al. DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nat Commun. 2015;6:10099 pubmed publisher
    ..Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system. ..
  39. Scheggi S, Melis M, De Felice M, Aroni S, Muntoni A, Pelliccia T, et al. PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors. Neuropharmacology. 2016;110:251-259 pubmed publisher
  40. Yang J, Hurley T, DePaoli Roach A. Interaction of inhibitor-2 with the catalytic subunit of type 1 protein phosphatase. Identification of a sequence analogous to the consensus type 1 protein phosphatase-binding motif. J Biol Chem. 2000;275:22635-44 pubmed
    ..A model is presented in which multiple "anchoring interactions" serve to position a segment of I-2 such that it sterically occludes the catalytic pocket but need not make high affinity contacts itself. ..
  41. Bode F, Stephan M, Suhling H, Pabst R, Straub R, Raber K, et al. Sex differences in a transgenic rat model of Huntington's disease: decreased 17beta-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males. Hum Mol Genet. 2008;17:2595-609 pubmed publisher
    ..emotional disturbance and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP32(+) medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography) and (iii) peripheral sex hormone ..
  42. Chiang Y, Chen J. The role of the cannabinoid type 1 receptor and down-stream cAMP/DARPP-32 signal in the nucleus accumbens of methamphetamine-sensitized rats. J Neurochem. 2007;103:2505-17 pubmed
    ..Overall, we demonstrated that brain CB(1) receptor and its down-stream cAMP/DARPP-32/T34/PP-2B signaling are profoundly altered in methamphetamine-sensitized animals. ..
  43. Cantrup R, Sathanantham K, Rushlow W, Rajakumar N. Chronic hyperdopaminergic activity of schizophrenia is associated with increased ?FosB levels and cdk-5 signaling in the nucleus accumbens. Neuroscience. 2012;222:124-35 pubmed publisher
    ..kinase activity as determined by increased phosphorylation of dopamine and adenosine regulated phosphoprotein-32 (DARPP32) at Thr(75) in the NA...
  44. Lin T, Tsai P, Liu H, Chen Y, Wang L, Hsieh F, et al. Characterization of the protein phosphatase 1-binding motifs of inhibitor-2 and DARPP-32 by surface plasmon resonance. J Biochem. 2005;138:697-700 pubmed
    ..Our results suggested that, compared with the common RVXF motif, the KLHY sequence in intact inhibitor-2 binds weakly to PP1. ..
  45. Meurers B, Dziewczapolski G, Shi T, Bittner A, Kamme F, Shults C. Dopamine depletion induces distinct compensatory gene expression changes in DARPP-32 signal transduction cascades of striatonigral and striatopallidal neurons. J Neurosci. 2009;29:6828-39 pubmed publisher
    ..In addition, the data have potential implications for the symptomatic treatment of the disease...
  46. Trantham Davidson H, Kroner S, Seamans J. Dopamine modulation of prefrontal cortex interneurons occurs independently of DARPP-32. Cereb Cortex. 2008;18:951-8 pubmed
  47. Han C, Nie S, Chen G, Ma K, Xiong N, Zhang Z, et al. Intrastriatal injection of ionomycin profoundly changes motor response to l-DOPA and its underlying molecular mechanisms. Neuroscience. 2017;340:23-33 pubmed publisher
    ..Results confirmed our hypothesis that ionomycin could downregulate the phosphorylation of DARPP32 at Thr-34 and reduce LID...
  48. Jin H, Xi G, Keep R, Wu J, Hua Y. DARPP-32 to quantify intracerebral hemorrhage-induced neuronal death in basal ganglia. Transl Stroke Res. 2013;4:130-4 pubmed publisher
    ..Treatment with an iron chelator, deferoxamine, attenuated the ICH-induced reduction in DARPP-32 protein levels. These results suggest that DARPP-32 is a simple and quantifiable indicator of ICH-induced neuronal death in basal ganglia. ..
  49. Flores Hernandez J, Cepeda C, Hernández Echeagaray E, Calvert C, Jokel E, Fienberg A, et al. Dopamine enhancement of NMDA currents in dissociated medium-sized striatal neurons: role of D1 receptors and DARPP-32. J Neurophysiol. 2002;88:3010-20 pubmed
  50. Zhou L, Nazarian A, Sun W, Jenab S, Quinones Jenab V. Basal and cocaine-induced sex differences in the DARPP-32-mediated signaling pathway. Psychopharmacology (Berl). 2009;203:175-83 pubmed publisher
    ..These novel results show that basal and cocaine-induced sex differences in the DARPP-32/PP-1 cascade may be responsible for the sexual dimorphism in acute cocaine-induced behavioral responses. ..
  51. Wang W, Liao X, Yang Z, Lin H, Wang Q, Wu Y, et al. [Research on expression and function of phosphorylated DARPP-32 on pentylenetetrazol-induced epilepsy model of rat]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2014;31:637-41 pubmed
  52. Partida G, Lee S, Haft Candell L, Nichols G, Ishida A. DARPP-32-like immunoreactivity in AII amacrine cells of rat retina. J Comp Neurol. 2004;480:251-63 pubmed
    ..These results suggest that the response of AII amacrine cells to dopamine is not mediated as simply as previously supposed. ..
  53. Zhu S, Chen Z, Katsha A, Hong J, Belkhiri A, el Rifai W. Regulation of CD44E by DARPP-32-dependent activation of SRp20 splicing factor in gastric tumorigenesis. Oncogene. 2016;35:1847-56 pubmed publisher
    ..The DARPP-32-SRp20 axis has a key role in regulating the CD44E splice variant that promotes gastric tumorigenesis. ..
  54. Nishi A, Kuroiwa M, Miller D, O Callaghan J, Bateup H, Shuto T, et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci. 2008;28:10460-71 pubmed publisher
    ..These data underscore the importance of individual brain-enriched cyclic-nucleotide PDE isoforms as therapeutic targets for neuropsychiatric and neurodegenerative disorders affecting dopamine neurotransmission. ..