Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 2053 2022-10-24 15:06:57 |
2 format correct + 1 word(s) 2054 2022-10-27 04:12:19 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Zhang, X.;  Tsuboi, D.;  Funahashi, Y.;  Yamahashi, Y.;  Kaibuchi, K.;  Nagai, T. Phosphorylation Signals Downstream of Dopamine Receptors in NAc. Encyclopedia. Available online: https://encyclopedia.pub/entry/31332 (accessed on 24 April 2024).
Zhang X,  Tsuboi D,  Funahashi Y,  Yamahashi Y,  Kaibuchi K,  Nagai T. Phosphorylation Signals Downstream of Dopamine Receptors in NAc. Encyclopedia. Available at: https://encyclopedia.pub/entry/31332. Accessed April 24, 2024.
Zhang, Xinjian, Daisuke Tsuboi, Yasuhiro Funahashi, Yukie Yamahashi, Kozo Kaibuchi, Taku Nagai. "Phosphorylation Signals Downstream of Dopamine Receptors in NAc" Encyclopedia, https://encyclopedia.pub/entry/31332 (accessed April 24, 2024).
Zhang, X.,  Tsuboi, D.,  Funahashi, Y.,  Yamahashi, Y.,  Kaibuchi, K., & Nagai, T. (2022, October 26). Phosphorylation Signals Downstream of Dopamine Receptors in NAc. In Encyclopedia. https://encyclopedia.pub/entry/31332
Zhang, Xinjian, et al. "Phosphorylation Signals Downstream of Dopamine Receptors in NAc." Encyclopedia. Web. 26 October, 2022.
Phosphorylation Signals Downstream of Dopamine Receptors in NAc
Edit

Dopamine regulates emotional behaviors, including rewarding and aversive behaviors, through the mesolimbic dopaminergic pathway, which projects dopamine neurons from the ventral tegmental area to the nucleus accumbens (NAc). Protein phosphorylation is critical for intracellular signaling pathways and physiological functions, which are regulated by neurotransmitters in the brain. Previous studies have demonstrated that dopamine stimulated the phosphorylation of intracellular substrates, such as receptors, ion channels, and transcription factors, to regulate neuronal excitability and synaptic plasticity through dopamine receptors. Recent advances in proteomics techniques have clarified the mechanisms through which dopamine controls rewarding and aversive behaviors through signal pathways in the NAc.

dopamine dopamine receptors nucleus accumbens phosphorylation signals rewarding behavior aversive behavior

1. Introduction

Dopamine was discovered as a neurotransmitter in the brain by Dr. Arvid Carlsson in 1957 [1]. It plays important roles in a number of brain functions, including motor function, motivation, learning, and rewards [2][3][4][5]. Dysfunctions in the dopaminergic system underlie various neuropsychological diseases, including Parkinson’s disease, schizophrenia, drug addiction, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder, major depression, and restless legs syndrome [6][7][8][9][10][11][12][13].
There are several dopaminergic pathways in the brain. Two major pathways are the nigrostriatal pathway and mesolimbic pathway, which project dopamine neurons from the substantia nigra to the dorsal striatum, and from the ventral tegmental area (VTA) to the ventral striatum, including the nucleus accumbens (NAc). Nigrostriatal dopamine neurons play an important role in motor functions, and their dysfunction causes Parkinson’s disease [6]. Accumulated evidence has revealed that dopamine transmission from the VTA to NAc is critical for controlling emotional behaviors, including rewarding and aversive behaviors [14][15]. Emotional behaviors contribute to the better survival of organisms. For example, learning and memory related to rewards and aversion allow animals to efficiently obtain food or to escape from danger, in line with the theory of “survival of the fittest”.
Classical conditioning is a kind of simple reward-associated learning [16]. Extracellular dopamine levels increase in the NAc when a reward or reward cue is delivered [17]. Cue-evoked dopamine is essential for reward-associative learning, as demonstrated by both the pharmacological inhibition of dopamine receptors [17] and the optogenetic inhibition of VTA dopamine neurons [18]. Cue-evoked dopamine also promotes conditioned responses during learning [19].
In contrast with the phasic firing response of VTA dopamine neurons to rewarding stimuli, their reactions to aversive stimuli are not homologous. The firing of some VTA dopamine neurons is activated, whereas the others are transiently suppressed. The inactivation of VTA dopamine neurons elicited by the optogenetic inhibition of dopamine neurons [20] or the activation of VTA GABAergic interneurons [21] has previously been shown to induce aversive behavior. Aversive behavior induced by the inactivation of VTA dopamine neurons is mediated by dopamine D2 receptors in the NAc [20]. Therefore, reductions in dopaminergic activity are associated with aversive behavior.
Dopamine exerts its function through dopamine receptors, which are a class of G-protein-coupled receptors. There are five types of dopamine receptors: D1–5. D1 and D5 are coupled to Gs, the stimulation of which increases the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP) through adenylate cyclase (AC), thereby activating cAMP-dependent protein kinase (PKA). On the other hand, D2, D3, and D4 are coupled to Gi, the activation of which results in the inhibition of the cAMP/PKA signaling pathway [22]. Therefore, D1 and D5 receptors are called the D1-like receptor family. D2, D3, and D4 receptors are called the D2-like receptor family. In addition, D2 receptors are known to transduce the signal via noncanonical G protein–independent interactions with β-arrestins [23]. Arrestin recruitment to D2R has been shown to mediate an antipsychotic effect in several studies [24], and to mediate locomotion, but not incentive motivation, in another study [25]. In this entry, researchers focused on the canonical phosphorylation signaling pathway. Recent advances in proteomics techniques have enabled researchers to clarify the novel mechanisms through which dopamine controls both rewarding and aversive behaviors through protein phosphorylation in the NAc. 

2. Functional Model for Dopamine D1 Receptors Expressing Medium Spiny Neurons (D1R-MSN) and Dopamine D2 Receptors Expressing Medium Spiny Neurons (D2R-MSN) in Rewarding and Aversive Behaviors

In the NAc, approximately 95% of neurons are medium spiny neurons (MSN) receiving dopaminergic regulation from the VTA [26][27]. There are two types of MSN—dopamine D1 receptors expressing D1R-MSN and dopamine D2 receptors expressing D2R-MSN. Dr. Hikida and co-workers expressed the tetanus toxin light chain, which is a bacterial toxin that cleaves the synaptic-vesicle-associated VAMP2 protein and abolishes neurotransmitter release from synaptic vesicles, in D1R-MSN and D2R-MSN [28]. The cell-type-specific inhibition of D1R-MSN with the tetanus toxin resulted in diminished rewarding behavior, while that of D2R-MSN led to diminished aversive behavior. These findings indicate that the activation of D1R-MSN regulates rewarding behavior, while that of D2R-MSN encodes aversive behavior. Striatal tonic dopamine release sustains basal extracellular dopamine concentrations in the NAc. Rewarding stimuli may induce phasic dopamine release to increase dopamine concentrations, and aversive stimuli inhibit tonic dopamine release to decrease dopamine concentrations [15][29]. Although dopamine was previously regarded as a volume transmitter that signals slowly and inaccurately, a recent study revealed that striatal dopamine secretion was mediated by sparse active-zone-like release sites supporting the dynamic function of dopamine [30][31]. According to the nature of D1R and D2R, a model has been proposed to explain how the active state shifts between D1R-MSN and D2R-MSN, regulating rewarding and aversive behaviors, respectively (Figure 1)
Figure 1. Dopamine concentrations function as a switch in the active state shift between D1R-MSN and D2R-MSN to regulate rewarding and aversive behaviors, respectively. (a) At the concentration of dopamine under basal conditions, D1R-MSN and D2R-MSN are both inactive. (b) When the concentration of dopamine is high, D1R-MSN is activated, consequently leading to rewarding behavior. Under pathophysiological conditions, the dopamine hyperfunctional state may be associated with schizophrenia and drug addiction. (c) When the concentration of dopamine is low, D2R-MSN is activated to induce aversive behavior. Under pathophysiological conditions, the dopamine hypofunctional state may be associated with Parkinson’s disease, attention deficit hyperactivity disorder, and restless legs syndrome. D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; A1R, adenosine A1 receptor; A2AR, adenosine A2A receptor; MSN, medium spiny neuron; Gs, stimulatory G protein; Gi, inhibitory G protein; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A.
D1R is coupled to Gs, the stimulation of which activates PKA to trigger D1R-MSN. On the other hand, D2R is coupled to Gi, the activation of which results in the inhibition of the cAMP/PKA signaling pathway and, in turn, the suppression of D2R-MSN. D2R has a markedly higher affinity for dopamine than D1R [32], and the Kd values of D1R and D2R are around 200 nM and 10 nM, respectively [33]. Therefore, basal dopamine concentrations, which have been reported to be around 10 nM [34], are insufficient to activate D1R and induce the activation of D1R-MSN, but are adequate to activate D2R and suppress D2R-MSN activity (Figure 1a). Rewarding stimuli markedly increase extracellular dopamine (e.g., cocaine intake has been shown to increase dopamine levels to more than 280 nM [35]), which is followed by the activation of both D1R and D2R. The stimulation of D1R induces the activation of D1R-MSN, whereas that of D2R suppresses D2R-MSN activity (Figure 1b). Aversive stimuli reduce extracellular dopamine to levels (e.g., electric footshock has decreased dopamine levels to less than 10 nM [36]) at which neither D1R nor D2R is activated. Furthermore, D1R-MSN expresses the adenosine A1 receptor (A1R) [37], which couples to the Gi protein, and D2R-MSN expresses the adenosine A2A receptor (A2AR) [37], which couples to the Gs protein. Basal extracellular adenosine concentrations are sufficient to tonically activate A1R and A2AR [38]. Therefore, D2R-MSN is activated due to the disinhibition in the D2R signal (Figure 1c). With the cooperation of adenosine, dopamine concentrations function as a switch for controlling the active state shift between D1R-MSN and D2R-MSN, thereby regulating rewarding and aversive behaviors, respectively [39]. A recent study showed dopamine terminals in the ventral NAc medial shell are excited, but other NAc regions are inhibited by aversive stimuli [40]. Although changes in the dopaminergic activity seem to be different in the subregion of NAc after aversive stimuli, this model may be applicable for NAc regions, except for the ventral medial shell.

3. PKA and PKA Substrates

Rewarding and aversive behaviors in rodents are monitored by conditioned place preference (CPP) and passive avoidance tests, respectively. The inhibition of PKA in the NAc blocks amphetamine-induced place preference [41] and its activation in D1R-MSN enhances cocaine-induced place preference [42]. The inhibition of PKA in D2R-MSN blocks foot shock-produced avoidance, whereas its activation increases foot shock-produced avoidance [43]. These findings strongly demonstrate that PKA plays an important role in D1R-MSN and D2R-MSN to regulate rewarding and aversive behaviors, respectively.
The PKA-dependent phosphorylation of receptors, ion channels, transcription factors, and other proteins accounts for the structural and functional plasticity regulated by dopamine [44] (Figure 2).
Figure 2. The PKA-dependent phosphorylation of receptors, ion channels, transcription factors, and other proteins accounts for structural and functional plasticity regulated by dopamine. D1R, dopamine D1 receptor; Gs, stimulatory G protein; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; DARPP-32, dopamine- and cAMP-regulated phosphoprotein of 32 kDa; PP1, protein phosphatase-1; NMDAR, NMDA receptor; AMPAR, AMPA receptor; STEP, striatal-enriched protein tyrosine phosphatase; Brd4, bromodomain-containing protein 4; DGLα, diacylglycerol lipase-α; rpS6, ribosomal protein S6. “?” indicates unknown PKA substrates.

4. Phosphoproteomic Analyses Revealed New Phosphorylation Signals Downstream of Dopamine Receptors in Emotional Behaviors

Major efforts have been made to identify the target substrates of PKA so as to understand the modes of action of dopamine, and a few of its substrates, including DARPP-32, GluA1, and NR1, have been reported. The PKA-mediated phosphorylation of DARPP-32 indirectly accumulates phosphoproteins through the inhibition of protein phosphatase PP1. However, it remains unclear about the proteins directly phosphorylated by PKA. To identify the PKA substrates that are responsible for the function of dopamine, a Kinase-Oriented Substrate Screening (KiOSS) method, a novel comprehensive phosphoproteomic analysis, has been developed. To provide information on the phosphorylation signals identified by KiOSS methods, as well as those previously reported in the literature, researchers developed a novel online database, KANPHOS (https://kanphos.neuroinf.jp).

According to previous studies and researchers' KANPHOS data, the stimulation of D1R by dopamine increases intracellular cAMP concentrations through AC, and this is followed by the activation of PKA. PKA phosphorylates Rasgrp2 and Rap1gap to induce the activation of Rap1, which promotes the MAPK pathway. MAPK phosphorylates Kcnq2 to increase membrane excitability. MAPK also phosphorylates Npas4 and MKL2 to facilitate the gene expression, accounting for synaptic plasticity regulated by dopamine. The stimulation of A2AR without the inhibition of D2R also increases intracellular cAMP concentrations through AC, and this is followed by the activation of PKA. The activation of Rap1 induces the MAPK pathway to regulate synaptic plasticity. The stimulation of M1R induces the activation of PKC, and this is followed by the phosphorylation of Kcnq2, which accounts for the increased membrane excitability. Therefore, phosphorylation signals downstream of D1R are involved in D1R-MSN-mediated rewarding behavior, and phosphorylation signals downstream of A2AR and M1R without the inhibition of D2R are involved in D2R-MSN-mediated aversive behavior (Figure 3).

Figure 3. Phosphoproteomic analyses revealed new phosphorylation signals downstream of do-pamine receptors in emotional behaviors. (a) In D1R-MSN, the stimulation of D1R by dopamine increased intracellular cAMP concentrations through AC, and this was followed by the activation of PKA. PKA phosphorylates Rasgrp2 and Rap1gap to induce the activation of Rap1, which pro-motes the MAPK pathway. MAPK phosphorylates Kcnq2 to increase membrane excitability and phosphorylates Npas4 and MKL2 to facilitate the expression of the genes accounting for synaptic plasticity, consequently leading to rewarding behavior. (b) In D2R-MSN, a decreased dopamine concentration cancels the suppressive effects of D2R. The stimulation of A2AR without the inhibi-tion of D2R increases intracellular cAMP concentrations through AC, and this is followed by the activation of PKA. PKA phosphorylates Rasgrp2 and Rap1gap to induce the activation of Rap1, which promotes the MAPK pathway involved in synaptic plasticity. Acetylcholine/M1R signaling activates PKC to promote the phosphorylation of Kcnq2, which is involved in membrane excita-bility. These changes consequently lead to aversive behavior.

References

  1. Yeragani, V.K.; Tancer, M.; Chokka, P.; Baker, G.B. Arvid Carlsson, and the story of dopamine. Indian J. Psychiatry 2010, 52, 87.
  2. Perez-Fernandez, J.; Barandela, M.; Jimenez-Lopez, C. The Dopaminergic Control of Movement-Evolutionary Considerations. Int. J. Mol. Sci. 2021, 22, 11284.
  3. Castillo Diaz, F.; Caffino, L.; Fumagalli, F. Bidirectional role of dopamine in learning and memory-active forgetting. Neurosci. Biobehav. Rev. 2021, 131, 953–963.
  4. Watabe-Uchida, M.; Eshel, N.; Uchida, N. Neural Circuitry of Reward Prediction Error. Annu. Rev. Neurosci. 2017, 40, 373–394.
  5. Engelhard, B.; Finkelstein, J.; Cox, J.; Fleming, W.; Jang, H.J.; Ornelas, S.; Koay, S.A.; Thiberge, S.Y.; Daw, N.D.; Tank, D.W. Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons. Nature 2019, 570, 509–513.
  6. Latif, S.; Jahangeer, M.; Maknoon Razia, D.; Ashiq, M.; Ghaffar, A.; Akram, M.; El Allam, A.; Bouyahya, A.; Garipova, L.; Ali Shariati, M.; et al. Dopamine in Parkinson’s disease. Clin. Chim. Acta 2021, 522, 114–126.
  7. Weinstein, J.J.; Chohan, M.O.; Slifstein, M.; Kegeles, L.S.; Moore, H.; Abi-Dargham, A. Pathway-Specific Dopamine Ab-normalities in Schizophrenia. Biol. Psychiatry 2017, 81, 31–42.
  8. Wise, R.A.; Robble, M.A. Dopamine and Addiction. Annu. Rev. Psychol. 2020, 71, 79–106.
  9. Wise, R.A.; Jordan, C.J. Dopamine, behavior, and addiction. J. Biomed. Sci. 2021, 28, 83.
  10. Klein, M.O.; Battagello, D.S.; Cardoso, A.R.; Hauser, D.N.; Bittencourt, J.C.; Correa, R.G. Dopamine: Functions, Signaling, and Association with Neurological Diseases. Cell. Mol. Neurobiol. 2019, 39, 31–59.
  11. Belujon, P.; Grace, A.A. Dopamine System Dysregulation in Major Depressive Disorders. Int. J. Neuropsychopharmacol. 2017, 20, 1036–1046.
  12. Mitchell, U.H.; Obray, J.D.; Hunsaker, E.; Garcia, B.T.; Clarke, T.J.; Hope, S.; Steffensen, S.C. Peripheral dopamine in rest-less legs syndrome. Front. Neurol. 2018, 9, 155.
  13. Torrisi, S.A.; Leggio, G.M.; Drago, F.; Salomone, S. Therapeutic challenges of post-traumatic stress disorder: Focus on the dopaminergic system. Front. Pharmacol. 2019, 10, 404.
  14. Lammel, S.; Lim, B.K.; Ran, C.; Huang, K.W.; Betley, M.J.; Tye, K.M.; Deisseroth, K.; Malenka, R.C. Input-specific control of reward and aversion in the ventral tegmental area. Nature 2012, 491, 212–217.
  15. Sun, F.; Zeng, J.; Jing, M.; Zhou, J.; Feng, J.; Owen, S.F.; Luo, Y.; Li, F.; Wang, H.; Yamaguchi, T.; et al. A Genetically Encoded Fluorescent Sensor Enables Rapid and Specific Detection of Dopamine in Flies, Fish, and Mice. Cell 2018, 174, 481–496.e419.
  16. Rehman, I.; Mahabadi, N.; Sanvictores, T.; Rehman, C.I. Classical conditioning. In StatPearls ; StatPearls Publishing: Treasure Island, FL, USA, 2017.
  17. Flagel, S.B.; Clark, J.J.; Robinson, T.E.; Mayo, L.; Czuj, A.; Willuhn, I.; Akers, C.A.; Clinton, S.M.; Phillips, P.E.; Akil, H. A selective role for dopamine in stimulus-reward learning. Nature 2011, 469, 53–57.
  18. Van Zessen, R.; Flores-Dourojeanni, J.P.; Eekel, T.; van den Reijen, S.; Lodder, B.; Omrani, A.; Smidt, M.P.; Ramakers, G.M.J.; van der Plasse, G.; Stuber, G.D.; et al. Cue and Reward Evoked Dopamine Activity Is Necessary for Maintaining Learned Pavlovian Associations. J. Neurosci. 2021, 41, 5004–5014.
  19. Morrens, J.; Aydin, C.; Janse van Rensburg, A.; Esquivelzeta Rabell, J.; Haesler, S. Cue-Evoked Dopamine Promotes Con-ditioned Responding during Learning. Neuron 2020, 106, 142–153.e147.
  20. Danjo, T.; Yoshimi, K.; Funabiki, K.; Yawata, S.; Nakanishi, S. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens. Proc. Natl. Acad. Sci. USA 2014, 111, 6455–6460.
  21. Tan, K.R.; Yvon, C.; Turiault, M.; Mirzabekov, J.J.; Doehner, J.; Labouebe, G.; Deisseroth, K.; Tye, K.M.; Luscher, C. GABA neurons of the VTA drive conditioned place aversion. Neuron 2012, 73, 1173–1183.
  22. Bhatia, A.; Saadabadi, A. Biochemistry, Dopamine Receptors. In StatPearls ; StatPearls Publishing: Treasure Island, FL, USA, 2019.
  23. Lefkowitz, R.J.; Shenoy, S.K. Transduction of receptor signals by β-arrestins. Science 2005, 308, 512–517.
  24. Allen, J.A.; Yost, J.M.; Setola, V.; Chen, X.; Sassano, M.F.; Chen, M.; Peterson, S.; Yadav, P.N.; Huang, X.P.; Feng, B.; et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc. Natl. Acad. Sci. USA 2011, 108, 18488–18493.
  25. Donthamsetti, P.; Gallo, E.F.; Buck, D.C.; Stahl, E.L.; Zhu, Y.; Lane, J.R.; Bohn, L.M.; Neve, K.A.; Kellendonk, C.; Javitch, J.A. Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Mol. Psychiatry 2020, 25, 2086–2100.
  26. Xu, L.; Nan, J.; Lan, Y. The nucleus accumbens: A common target in the comorbidity of depression and addiction. Front. Neural Circuits 2020, 14, 37.
  27. Castro, D.C.; Bruchas, M.R. A motivational and neuropeptidergic hub: Anatomical and functional diversity within the nucleus accumbens shell. Neuron 2019, 102, 529–552.
  28. Hikida, T.; Kimura, K.; Wada, N.; Funabiki, K.; Nakanishi, S. Distinct roles of synaptic transmission in direct and indi-rect striatal pathways to reward and aversive behavior. Neuron 2010, 66, 896–907.
  29. Hart, A.S.; Rutledge, R.B.; Glimcher, P.W.; Phillips, P.E. Phasic dopamine release in the rat nucleus accumbens symmetri-cally encodes a reward prediction error term. J. Neurosci. 2014, 34, 698–704.
  30. Liu, C.; Kershberg, L.; Wang, J.; Schneeberger, S.; Kaeser, P.S. Dopamine Secretion Is Mediated by Sparse Active Zone-like Release Sites. Cell 2018, 172, 706–718.e715.
  31. Liu, C.; Kaeser, P.S. Mechanisms and regulation of dopamine release. Curr. Opin. Neurobiol. 2019, 57, 46–53.
  32. Martel, J.C.; Gatti McArthur, S. Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Con-cepts in Schizophrenia. Front. Pharmacol. 2020, 11, 1003.
  33. Marcellino, D.; Kehr, J.; Agnati, L.F.; Fuxe, K. Increased affinity of dopamine for D(2) -like versus D(1) -like receptors. Relevance for volume transmission in interpreting PET findings. Synapse 2012, 66, 196–203.
  34. Cadoni, C.; Solinas, M.; Di Chiara, G. Psychostimulant sensitization: Differential changes in accumbal shell and core dopamine. Eur. J. Pharmacol. 2000, 388, 69–76.
  35. Yuen, J.; Goyal, A.; Rusheen, A.E.; Kouzani, A.Z.; Berk, M.; Kim, J.H.; Tye, S.J.; Blaha, C.D.; Bennet, K.E.; Jang, D.P.; et al. Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo. Front. Pharmacol. 2021, 12, 705254.
  36. Oleson, E.B.; Gentry, R.N.; Chioma, V.C.; Cheer, J.F. Subsecond dopamine release in the nucleus accumbens predicts con-ditioned punishment and its successful avoidance. J. Neurosci. 2012, 32, 14804–14808.
  37. Borea, P.A.; Gessi, S.; Merighi, S.; Vincenzi, F.; Varani, K. Pharmacology of adenosine receptors: The state of the art. Physiol. Rev. 2018, 98, 1591–1625.
  38. Dunwiddie, T.V.; Masino, S.A. The role and regulation of adenosine in the central nervous system. Annu. Rev. Neurosci. 2001, 24, 31–55.
  39. Zhang, X.; Nagai, T.; Ahammad, R.U.; Kuroda, K.; Nakamuta, S.; Nakano, T.; Yukinawa, N.; Funahashi, Y.; Yamahashi, Y.; Amano, M.; et al. Balance between dopamine and adenosine signals regulates the PKA/Rap1 pathway in striatal me-dium spiny neurons. Neurochem. Int. 2019, 122, 8–18.
  40. De Jong, J.W.; Afjei, S.A.; Pollak Dorocic, I.; Peck, J.R.; Liu, C.; Kim, C.K.; Tian, L.; Deisseroth, K.; Lammel, S. A Neural Cir-cuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System. Neuron 2019, 101, 133–151.e137.
  41. Beninger, R.J.; Nakonechny, P.L.; Savina, I. cAMP-dependent protein kinase and reward-related learning: In-tra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats. Psychopharmacology 2003, 170, 23–32.
  42. Nagai, T.; Nakamuta, S.; Kuroda, K.; Nakauchi, S.; Nishioka, T.; Takano, T.; Zhang, X.; Tsuboi, D.; Funahashi, Y.; Nakano, T.; et al. Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo. Neuron 2016, 89, 550–565.
  43. Lin, Y.H.; Yamahashi, Y.; Kuroda, K.; Faruk, M.O.; Zhang, X.; Yamada, K.; Yamanaka, A.; Nagai, T.; Kaibuchi, K. Ac-cumbal D2R-medium spiny neurons regulate aversive behaviors through PKA-Rap1 pathway. Neurochem. Int. 2021, 143, 104935.
  44. Greengard, P. The neurobiology of slow synaptic transmission. Science 2001, 294, 1024–1030.
More
Information
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , ,
View Times: 434
Revisions: 2 times (View History)
Update Date: 27 Oct 2022
1000/1000