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Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic glutamatergic receptors in VTA after cocaine exposure

Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic... Glutamatergic AMPA and NMDA receptors in the ventral tegmental area ( VTA) are central for cocaine first exposure and posterior craving maintenance. However, the exact rules that coordinate the synaptic dynamics of these recep- tors in dopaminergic VTA neurons and behavioral outcomes are poorly understood. Additionally, synaptic homeo- static plasticity is present in response to chronic excitability changes in neuronal circuits, adjusting the strength of synapses to stabilize the firing rate. Despite having correspondent mechanisms, little is known about the relationship between continuous cocaine exposure and homeostatic synaptic changes in the VTA neurons. Here, we assess the role of homeostatic mechanisms in the neurobiology of cocaine addiction by providing a brief overview of the paral- lels between cocaine-induced synaptic potentiation and long-term synaptic adaptations, focusing on the regulation of GluA1- and GluN1- containing receptors. Keywords: Drug dependence, Withdrawal, Homeostatic plasticity, Synaptic scaling, Dopamine Introduction injections [2, 26]. Similarly, cocaine has been shown to Dopaminergic projections originated in the ventral teg- facilitate the experimental induction of long-term poten- mental area (VTA) are critical for reward learning and, tiation (LTP) and enhance the responsiveness of dopa- consequently, drug abuse behaviors [5, 19, 23]. Animal mine neurons to AMPA administration [29]. Despite the models of cocaine addiction are characterized by compul- broad knowledge on these mechanisms, the scientific sive drug-seeking and drug-taking even after prolonged literature does not provide details on how this synaptic periods of withdrawal [4, 11]. A central hypothesis is that reinforcement can lead to excitatory over-potentiation of these craving phenotypes reflect greater incentive moti - the reward circuitry, which in turn may trigger synaptic vation for the drug and associated stimuli [21] mediated homeostatic mechanisms [24]. by the potentiation of glutamatergic synapses on VTA The homeostatic regulation of synapses is a exten - dopamine neurons [13]. For example, VTA dopamine sively studied process [17], believed as necessary for the neurons exhibit transient NMDA receptor (NMDAR)- adequate development and function of neuronal net- dependent increases in AMPA receptor (AMPAR)-medi- works [25]. It is defined as a negative feedback response ated currents following either single or repeated cocaine mechanism to chronically elevated or reduced activity in a neural circuit, where individual neurons adapt to these changes by modifying their synaptic excitability thresh- *Correspondence: thiago.moulin@neuro.uu.se 1 old. It can be achieved through adjustments in ionotropic Functional Pharmacology Unit, Department of Neuroscience, Uppsala University, Uppsala, Sweden glutamatergic receptors synaptic modulation [7, 18]. Full list of author information is available at the end of the article During homeostatic regulation, AMPAR and NMDAR © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moulin and Schiöth Behav Brain Funct (2020) 16:6 Page 2 of 4 numbers at the postsynaptic surface are scaled down- or demonstrated that the absence of this NMDA unit blocks upwardly in response to activity overexcitation or inhi- the increase in GluA1-AMPARs after chronic cocaine bition, respectively, presumably via changing trafficking intake [12]. Nevertheless, the behavioral effects of inhib - processes, including insertion and internalization of the iting GluN1 expression are somewhat unexpected. receptors [27]. GluN1-negative animals have attenuated locomotor Homeostatic mechanisms have been shown to regu- sensitization after withdrawal [30] and are unable to the late many aspects of brain function by the interaction reinstatement of cocaine-conditioned place preference with other types of plasticity [1, 16], and to influence the [8]; however, transient absence of GluN1 applied to the pathophysiology of neuropsychiatric and neurologic dis- VTA during chronic cocaine self-administration para- orders [9]. However, the role of synaptic homeostasis in doxically enhances cocaine-seeking behavior [12]. After substance abuse and addiction was not yet investigated. withdrawal, these rats take longer to reach the breaking This article considers recent evidence on the influence of point and earn more cocaine injections when compared synaptic potentiation and subsequent homeostatic regu- to controls. Extinction of this behavior was also impaired, lation in the VTA into behavioral outcomes of cocaine and the reinstatement of the drug-paired lever response craving after chronic drug exposure. We use the regu- was facilitated. lation of GluA1- and GluN1-containing glutamatergic These counterintuitive results could only be explained channels as a framework to examine the interactions of after studying the influence of homeostatic regula - these two types of synaptic plasticity and their influence tions due to the continuous change in neuronal excit- on craving behavior. ability induced by the transient manipulation of GluN1-NMDARs in VTA. In fact, it was demonstrated GluA1/GluN1 dynamics during cocaine exposure, that transient GluN1 inactivation for 3weeks enhanced re‑exposure, and withdrawal AMPAR-mediated locomotor activity and membrane NMDARs and AMPARs are necessary for the acute expression of glutamate receptor subunits, includ- cocaine-induced synaptic potentiation in VTA DA cells. ing GluA1. The overexpression of these AMPA chan - By preventing the synthesis of the AMPAR subunits nels, in turn, drove an increased motivation for cocaine GluA1 or GluA2 [8], or the NMDAR subunit GluN1 [30] in a progressive ratio testing and kept elevated the in cells expressing the DA transporter, cocaine-induced cocaine-seeking behavior elicited in both extinction and reinforcement can be prevented in glutamatergic syn- cocaine-primed reinstatement, even after 3–5  weeks of apses of the VTA DA cells. Interestingly, however, at the withdrawal [12]. This body of evidence suggests that the behavioral level these mutations are unable to change the homeostatic regulation of AMPAR is able to modulate locomotor sensitization following repeated cocaine expo- cocaine craving during chronic cocaine exposure and sure in mice. withdrawal. Additionally, GluA1-containing AMPARs were shown to have a singular pattern of expression after cocaine The role of homeostatic plasticity exposure: they are up-regulated after acute, but not These results were interpreted as a specific explanation chronic, cocaine self-administration; however, the with- for the observed cocaine-seeking after transient GluN1- drawal period is able to induce GluA1-AMPARs up- NMDARs inactivation. However, we believe these results regulation again [3, 14, 15]. Moreover, the expression of also indicate that cocaine-induced plasticity may induce this subunit is related to cocaine intake motivation, as synaptic scaling processes in the VTA at more general rats transiently over-expressing GluA1-AMPARs were conditions. For example, homeostatic plasticity mecha- shown to have increased craving in the progressive ratio nisms have been shown to modulate the pathophysiology habituation. In this paradigm, animals are trained to self- of some neurologic and neuropsychiatric disorders, such administer cocaine, but the number of necessary lever as intellectual disability [22], Rett syndrome [20], schizo- presses exponentially increases with each cocaine release. phrenia [6], and Alzheimer’s disease [28]. When analyzing the breaking point parameter, defined Moreover, when investigating the role of VTA in a by the highest ratio of responses per injection achieved social defeat stress model of depression, it was observed before a 1  h-period when no further injections were that VTA dopaminergic neurons of depression-resilient earned, rats overexpressing GluA1-AMPARs much took mice display enhanced inhibitory currents as a homeo- longer to reach this point when compared to controls [3]. static response to this behavioral challenge [10]. The This state-dependent expression pattern of GluA1- study also demonstrated that by artificially activat - AMPARs was shown to be regulated by GluN1-con- ing of VTA DA neurons in depression-susceptible ani- taining NMDARs. By using a viral-mediated expression mals, self-tuning homeostatic compensations could be of a dominant-negative GluN1 subunit in VTA, it was triggered, changing the behavior. Thus, by naturally or M oulin and Schiöth Behav Brain Funct (2020) 16:6 Page 3 of 4 Fig. 1 Schematics of the homeostatic-like characteristics of AMPAR-GluA1 dynamics after cocaine self-administration Acknowledgements experimentally establishing homeostatic balance in VTA Not applicable. dopaminergic neurons, they become more stable in response to environmental perturbations. Authors’ contributions TCM contributed with conceptualization, investigation, and writing of the When we look at cocaine-induced GluA1 plasticity in original draft. HBS contributed with conceptualization, supervision and fund- VTA neurons, after organizing by periods of drug intake ing acquisition. Both authors reviewed and approved the final version of the and withdrawal (Fig.  1), we can observe a stereotypi- manuscript. Both authors read and approved the final manuscript. cal process of AMPAR homeostatic regulation driven by Funding enhanced excitation (chronic cocaine administration), TCM is supported by the Kungl Vetenskapssamh Scholarship (Royal Society of followed by adaptation to decreased excitation (with- Arts and Scientists), provided by Uppsala University, Sweden. HBS is supported by the Swedish Research Council, the Swedish Brain Research Foundation, and drawal). The acute intake of cocaine leads to short-term by the FAT4BRAIN project funding from the European Union’s Horizon 2020 synaptic potentiation and enhanced expression of GluA1 research and innovation program [Grant No: 857394]. The funders had no role proteins. However, after chronic intake of cocaine, GluA1 in the design of the study or in the writing of the manuscript. expression is comparable to that of controls, indicating a Availability of data and materials homeostatic response to continuous self-administration Data sharing is not applicable to this article as no datasets were generated or of the drug. Furthermore, during cocaine withdrawal, analyzed during the current study. when the overall excitability is decreased, GluA1 levels Ethics approval and consent to participate rise again. These compensatory dynamics of AMPAR are Not applicable. consistent with homeostatic synaptic processes [24]. Consent for publication Not applicable. Conclusions Competing interests To the best of our knowledge, this is the first report sug - The authors declare that they have no competing interests. gesting a connection between synaptic scaling processes Author details and the physiological mechanisms of cocaine addiction Functional Pharmacology Unit, Department of Neuroscience, Uppsala Uni- in the VTA. Unquestionably, homeostatic regulations of versity, Uppsala, Sweden. Institute for Translational Medicine and Biotechnol- ogy, Sechenov First Moscow State Medical University, Moscow, Russia. VTA neurons are not the only responsible for craving behavior, as classic potentiation mechanisms and con- Received: 12 May 2020 Accepted: 6 June 2020 text reinforcement are also part of this process. In fact, most of the aforementioned cocaine-induced AMPAR/ NMDAR plasticity takes place in VTA after cocaine self-administration, but not with passive yoked infu- References sion, indicating a protagonist of learning and memory 1. Abbott LF, Nelson SB. Synaptic plasticity: taming the beast. Nat Neurosci. 2000;3:1178–83. https ://doi.org/10.1038/81453 . mechanisms. However, these recent results show that the 2. Borgland SL. Acute and chronic cocaine-induced potentiation of synaptic contributions of synaptic homeostatic scaling in cocaine strength in the ventral tegmental area: electrophysiological and behav- addiction must be further investigated. We believe such ioral correlates in individual rats. J Neurosci. 2004;24:7482–90. https ://doi. org/10.1523/JNEUR OSCI.1312-04.2004. discussion would advance the understanding of homeo- 3. Choi KH, Edwards S, Graham DL, Larson EB, Whisler KN, Simmons D, et al. static plasticity in behaviorally relevant in vivo models of Reinforcement-related regulation of AMPA glutamate receptor subunits addiction and provide further insight into the physiologi- in the ventral tegmental area enhances motivation for cocaine. J Neuro- sci. 2011;31:7927–37. https ://doi.org/10.1523/JNEUR OSCI.6014-10.2011. cal underpinnings of compulsion and craving. Moulin and Schiöth Behav Brain Funct (2020) 16:6 Page 4 of 4 4. Deroche-Gamonet V. Evidence for Addiction-like Behavior in the Rat. Sci- 18. Pérez-Otaño I, Ehlers MD. Homeostatic plasticity and NMDA receptor ence. 2004;305:1014–7. https ://doi.org/10.1126/scien ce.10990 20. trafficking. Trends Neurosci. 2005;28:229–38. https ://doi.org/10.1016/j. 5. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase tins.2005.03.004. synaptic dopamine concentrations in the mesolimbic system of freely 19. Pignatelli M, Bonci A. Role of dopamine neurons in reward and aversion: moving rats. Proc Natl Acad Sci. 1988;85:5274–8. https ://doi.org/10.1073/ a synaptic plasticity perspective. Neuron. 2015;86:1145–57. https ://doi. pnas.85.14.5274.org/10.1016/j.neuro n.2015.04.015. 6. Dickman DK, Davis GW. The schizophrenia susceptibility gene dysbindin 20. Qiu Z, Sylwestrak EL, Lieberman DN, Zhang Y, Liu X-Y, Ghosh A. The controls synaptic homeostasis. Science. 2009;326:1127–30. https ://doi. rett syndrome protein MeCP2 regulates synaptic scaling. J Neurosci. org/10.1126/scien ce.11796 85. 2012;32:989–94. https ://doi.org/10.1523/JNEUR OSCI.0175-11.2012. 7. Diering GH, Huganir RL. The AMPA receptor code of synaptic plasticity. 21. Robinson T. The neural basis of drug craving: an incentive-sensitiza- Neuron. 2018;100:314–29. https ://doi.org/10.1016/j.neuro n.2018.10.018. tion theory of addiction. Brain Res Rev. 1993;18:247–91. https ://doi. 8. Engblom D, Bilbao A, Sanchis-Segura C, Dahan L, Perreau-Lenz S, Bal-org/10.1016/0165-0173(93)90013 -P. land B, et al. Glutamate receptors on dopamine neurons control the 22. Soden ME, Chen L. Fragile X protein fmrp is required for homeostatic persistence of cocaine seeking. Neuron. 2008;59:497–508. https ://doi. plasticity and regulation of synaptic strength by retinoic acid. J Neurosci. org/10.1016/j.neuro n.2008.07.010. 2010;30:16910–21. https ://doi.org/10.1523/JNEUR OSCI.3660-10.2010. 9. Fernandes D, Carvalho AL. Mechanisms of homeostatic plasticity in 23. Stuber GD, Klanker M, de Ridder B, Bowers MS, Joosten RN, Feenstra MG, the excitatory synapse. J Neurochem. 2016;139:973–96. https ://doi. et al. Reward-predictive cues enhance excitatory synaptic strength onto org/10.1111/jnc.13687 . midbrain dopamine neurons. Science. 2008;321:1690–2. https ://doi. 10. Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. org/10.1126/scien ce.11608 73. Enhancing depression mechanisms in midbrain dopamine neurons 24. Turrigiano G. Homeostatic synaptic plasticity: local and global mecha- achieves homeostatic resilience. Science. 2014;344:313–9. https ://doi. nisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol. org/10.1126/scien ce.12492 40. 2012;4:a005736. https ://doi.org/10.1101/cshpe rspec t.a0057 36. 11. Grimm JW, Hope BT, Wise RA, Shaham Y. Incubation of cocaine craving 25. Turrigiano GG, Nelson SB. Homeostatic plasticity in the developing nerv- after withdrawal. Nature. 2001;412:141–2. https ://doi.org/10.1038/35084 ous system. Nat Rev Neurosci. 2004;5:97–107. https ://doi.org/10.1038/ 134.nrn13 27. 12. Guzman D, Carreira MB, Friedman AK, Adachi M, Neve RL, Monteggia LM, 26. Ungless MA, Whistler JL, Malenka RC, Bonci A. Single cocaine exposure et al. Inactivation of NMDA receptors in the ventral tegmental area dur- in vivo induces long-term potentiation in dopamine neurons. Nature. ing cocaine self-administration prevents GluA1 up-regulation but with 2001;411:583–7. https ://doi.org/10.1038/35079 077. paradoxical increases in cocaine-seeking behavior. J Neurosci. 2017. https 27. Wang G, Gilbert J, Man H-Y. AMPA receptor trafficking in homeostatic ://doi.org/10.1523/JNEUR OSCI.2828-16.2017. synaptic plasticity: functional molecules and signaling cascades. Neural 13. Kauer JA, Malenka RC. Synaptic plasticity and addiction. Nat Rev Neurosci. Plast. 2012;2012:1–12. https ://doi.org/10.1155/2012/82536 4. 2007;8:844–58. https ://doi.org/10.1038/nrn22 34. 28. Yamamoto K, Tanei Z-I, Hashimoto T, Wakabayashi T, Okuno H, Naka 14. Lane DA, Reed B, Kreek MJ, Pickel VM. Differential glutamate AMPA- Y, et al. Chronic optogenetic activation augments aβ pathology in a receptor plasticity in subpopulations of VTA neurons in the presence or mouse model of Alzheimer disease. Cell Rep. 2015;11:859–65. https ://doi. absence of residual cocaine: implications for the development of addic-org/10.1016/j.celre p.2015.04.017. tion. Neuropharmacology. 2011;61:1129–40. https ://doi.org/10.1016/j. 29. Zhang XF, Hu XT, White FJ, Wolf ME. Increased responsiveness of ventral neuro pharm .2010.12.031. tegmental area dopamine neurons to glutamate after repeated admin- 15. Lu W. Repeated administration of amphetamine or cocaine does not alter istration of cocaine or amphetamine is transient and selectively involves AMPA receptor subunit expression in the rat midbrain. Neuropsychophar- AMPA receptors. J Pharmacol Exp Ther. 1997;281:699–706. macology. 2002;26:1–13. https ://doi.org/10.1016/S0893 -133X(01)00272 30. Zweifel LS, Argilli E, Bonci A, Palmiter RD. Role of NMDA receptors in -X. dopamine neurons for plasticity and addictive behaviors. Neuron. 16. Moulin TC, Petiz LL, Rayêe D, Winne J, Maia RG, Lima da Cruz RV, et al. 2008;59:486–96. https ://doi.org/10.1016/j.neuro n.2008.05.028. Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus. Publisher’s Note Hippocampus. 2019. https ://doi.org/10.1002/hipo.23080 . Springer Nature remains neutral with regard to jurisdictional claims in pub- 17. Moulin TC, Rayêe D, Williams MJ, Schiöth HB. The synaptic scaling lished maps and institutional affiliations. literature: A systematic review of methodologies and quality of reporting. Front: Cell. Neurosci; 2020. https ://doi.org/10.3389/fncel .2020.00164 . Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Excitability, synaptic balance, and addiction: The homeostatic dynamics of ionotropic glutamatergic receptors in VTA after cocaine exposure

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Abstract

Glutamatergic AMPA and NMDA receptors in the ventral tegmental area ( VTA) are central for cocaine first exposure and posterior craving maintenance. However, the exact rules that coordinate the synaptic dynamics of these recep- tors in dopaminergic VTA neurons and behavioral outcomes are poorly understood. Additionally, synaptic homeo- static plasticity is present in response to chronic excitability changes in neuronal circuits, adjusting the strength of synapses to stabilize the firing rate. Despite having correspondent mechanisms, little is known about the relationship between continuous cocaine exposure and homeostatic synaptic changes in the VTA neurons. Here, we assess the role of homeostatic mechanisms in the neurobiology of cocaine addiction by providing a brief overview of the paral- lels between cocaine-induced synaptic potentiation and long-term synaptic adaptations, focusing on the regulation of GluA1- and GluN1- containing receptors. Keywords: Drug dependence, Withdrawal, Homeostatic plasticity, Synaptic scaling, Dopamine Introduction injections [2, 26]. Similarly, cocaine has been shown to Dopaminergic projections originated in the ventral teg- facilitate the experimental induction of long-term poten- mental area (VTA) are critical for reward learning and, tiation (LTP) and enhance the responsiveness of dopa- consequently, drug abuse behaviors [5, 19, 23]. Animal mine neurons to AMPA administration [29]. Despite the models of cocaine addiction are characterized by compul- broad knowledge on these mechanisms, the scientific sive drug-seeking and drug-taking even after prolonged literature does not provide details on how this synaptic periods of withdrawal [4, 11]. A central hypothesis is that reinforcement can lead to excitatory over-potentiation of these craving phenotypes reflect greater incentive moti - the reward circuitry, which in turn may trigger synaptic vation for the drug and associated stimuli [21] mediated homeostatic mechanisms [24]. by the potentiation of glutamatergic synapses on VTA The homeostatic regulation of synapses is a exten - dopamine neurons [13]. For example, VTA dopamine sively studied process [17], believed as necessary for the neurons exhibit transient NMDA receptor (NMDAR)- adequate development and function of neuronal net- dependent increases in AMPA receptor (AMPAR)-medi- works [25]. It is defined as a negative feedback response ated currents following either single or repeated cocaine mechanism to chronically elevated or reduced activity in a neural circuit, where individual neurons adapt to these changes by modifying their synaptic excitability thresh- *Correspondence: thiago.moulin@neuro.uu.se 1 old. It can be achieved through adjustments in ionotropic Functional Pharmacology Unit, Department of Neuroscience, Uppsala University, Uppsala, Sweden glutamatergic receptors synaptic modulation [7, 18]. Full list of author information is available at the end of the article During homeostatic regulation, AMPAR and NMDAR © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Moulin and Schiöth Behav Brain Funct (2020) 16:6 Page 2 of 4 numbers at the postsynaptic surface are scaled down- or demonstrated that the absence of this NMDA unit blocks upwardly in response to activity overexcitation or inhi- the increase in GluA1-AMPARs after chronic cocaine bition, respectively, presumably via changing trafficking intake [12]. Nevertheless, the behavioral effects of inhib - processes, including insertion and internalization of the iting GluN1 expression are somewhat unexpected. receptors [27]. GluN1-negative animals have attenuated locomotor Homeostatic mechanisms have been shown to regu- sensitization after withdrawal [30] and are unable to the late many aspects of brain function by the interaction reinstatement of cocaine-conditioned place preference with other types of plasticity [1, 16], and to influence the [8]; however, transient absence of GluN1 applied to the pathophysiology of neuropsychiatric and neurologic dis- VTA during chronic cocaine self-administration para- orders [9]. However, the role of synaptic homeostasis in doxically enhances cocaine-seeking behavior [12]. After substance abuse and addiction was not yet investigated. withdrawal, these rats take longer to reach the breaking This article considers recent evidence on the influence of point and earn more cocaine injections when compared synaptic potentiation and subsequent homeostatic regu- to controls. Extinction of this behavior was also impaired, lation in the VTA into behavioral outcomes of cocaine and the reinstatement of the drug-paired lever response craving after chronic drug exposure. We use the regu- was facilitated. lation of GluA1- and GluN1-containing glutamatergic These counterintuitive results could only be explained channels as a framework to examine the interactions of after studying the influence of homeostatic regula - these two types of synaptic plasticity and their influence tions due to the continuous change in neuronal excit- on craving behavior. ability induced by the transient manipulation of GluN1-NMDARs in VTA. In fact, it was demonstrated GluA1/GluN1 dynamics during cocaine exposure, that transient GluN1 inactivation for 3weeks enhanced re‑exposure, and withdrawal AMPAR-mediated locomotor activity and membrane NMDARs and AMPARs are necessary for the acute expression of glutamate receptor subunits, includ- cocaine-induced synaptic potentiation in VTA DA cells. ing GluA1. The overexpression of these AMPA chan - By preventing the synthesis of the AMPAR subunits nels, in turn, drove an increased motivation for cocaine GluA1 or GluA2 [8], or the NMDAR subunit GluN1 [30] in a progressive ratio testing and kept elevated the in cells expressing the DA transporter, cocaine-induced cocaine-seeking behavior elicited in both extinction and reinforcement can be prevented in glutamatergic syn- cocaine-primed reinstatement, even after 3–5  weeks of apses of the VTA DA cells. Interestingly, however, at the withdrawal [12]. This body of evidence suggests that the behavioral level these mutations are unable to change the homeostatic regulation of AMPAR is able to modulate locomotor sensitization following repeated cocaine expo- cocaine craving during chronic cocaine exposure and sure in mice. withdrawal. Additionally, GluA1-containing AMPARs were shown to have a singular pattern of expression after cocaine The role of homeostatic plasticity exposure: they are up-regulated after acute, but not These results were interpreted as a specific explanation chronic, cocaine self-administration; however, the with- for the observed cocaine-seeking after transient GluN1- drawal period is able to induce GluA1-AMPARs up- NMDARs inactivation. However, we believe these results regulation again [3, 14, 15]. Moreover, the expression of also indicate that cocaine-induced plasticity may induce this subunit is related to cocaine intake motivation, as synaptic scaling processes in the VTA at more general rats transiently over-expressing GluA1-AMPARs were conditions. For example, homeostatic plasticity mecha- shown to have increased craving in the progressive ratio nisms have been shown to modulate the pathophysiology habituation. In this paradigm, animals are trained to self- of some neurologic and neuropsychiatric disorders, such administer cocaine, but the number of necessary lever as intellectual disability [22], Rett syndrome [20], schizo- presses exponentially increases with each cocaine release. phrenia [6], and Alzheimer’s disease [28]. When analyzing the breaking point parameter, defined Moreover, when investigating the role of VTA in a by the highest ratio of responses per injection achieved social defeat stress model of depression, it was observed before a 1  h-period when no further injections were that VTA dopaminergic neurons of depression-resilient earned, rats overexpressing GluA1-AMPARs much took mice display enhanced inhibitory currents as a homeo- longer to reach this point when compared to controls [3]. static response to this behavioral challenge [10]. The This state-dependent expression pattern of GluA1- study also demonstrated that by artificially activat - AMPARs was shown to be regulated by GluN1-con- ing of VTA DA neurons in depression-susceptible ani- taining NMDARs. By using a viral-mediated expression mals, self-tuning homeostatic compensations could be of a dominant-negative GluN1 subunit in VTA, it was triggered, changing the behavior. Thus, by naturally or M oulin and Schiöth Behav Brain Funct (2020) 16:6 Page 3 of 4 Fig. 1 Schematics of the homeostatic-like characteristics of AMPAR-GluA1 dynamics after cocaine self-administration Acknowledgements experimentally establishing homeostatic balance in VTA Not applicable. dopaminergic neurons, they become more stable in response to environmental perturbations. Authors’ contributions TCM contributed with conceptualization, investigation, and writing of the When we look at cocaine-induced GluA1 plasticity in original draft. HBS contributed with conceptualization, supervision and fund- VTA neurons, after organizing by periods of drug intake ing acquisition. Both authors reviewed and approved the final version of the and withdrawal (Fig.  1), we can observe a stereotypi- manuscript. Both authors read and approved the final manuscript. cal process of AMPAR homeostatic regulation driven by Funding enhanced excitation (chronic cocaine administration), TCM is supported by the Kungl Vetenskapssamh Scholarship (Royal Society of followed by adaptation to decreased excitation (with- Arts and Scientists), provided by Uppsala University, Sweden. HBS is supported by the Swedish Research Council, the Swedish Brain Research Foundation, and drawal). The acute intake of cocaine leads to short-term by the FAT4BRAIN project funding from the European Union’s Horizon 2020 synaptic potentiation and enhanced expression of GluA1 research and innovation program [Grant No: 857394]. The funders had no role proteins. However, after chronic intake of cocaine, GluA1 in the design of the study or in the writing of the manuscript. expression is comparable to that of controls, indicating a Availability of data and materials homeostatic response to continuous self-administration Data sharing is not applicable to this article as no datasets were generated or of the drug. Furthermore, during cocaine withdrawal, analyzed during the current study. when the overall excitability is decreased, GluA1 levels Ethics approval and consent to participate rise again. These compensatory dynamics of AMPAR are Not applicable. consistent with homeostatic synaptic processes [24]. Consent for publication Not applicable. Conclusions Competing interests To the best of our knowledge, this is the first report sug - The authors declare that they have no competing interests. gesting a connection between synaptic scaling processes Author details and the physiological mechanisms of cocaine addiction Functional Pharmacology Unit, Department of Neuroscience, Uppsala Uni- in the VTA. Unquestionably, homeostatic regulations of versity, Uppsala, Sweden. Institute for Translational Medicine and Biotechnol- ogy, Sechenov First Moscow State Medical University, Moscow, Russia. VTA neurons are not the only responsible for craving behavior, as classic potentiation mechanisms and con- Received: 12 May 2020 Accepted: 6 June 2020 text reinforcement are also part of this process. In fact, most of the aforementioned cocaine-induced AMPAR/ NMDAR plasticity takes place in VTA after cocaine self-administration, but not with passive yoked infu- References sion, indicating a protagonist of learning and memory 1. Abbott LF, Nelson SB. Synaptic plasticity: taming the beast. Nat Neurosci. 2000;3:1178–83. https ://doi.org/10.1038/81453 . mechanisms. However, these recent results show that the 2. Borgland SL. Acute and chronic cocaine-induced potentiation of synaptic contributions of synaptic homeostatic scaling in cocaine strength in the ventral tegmental area: electrophysiological and behav- addiction must be further investigated. We believe such ioral correlates in individual rats. J Neurosci. 2004;24:7482–90. https ://doi. org/10.1523/JNEUR OSCI.1312-04.2004. discussion would advance the understanding of homeo- 3. Choi KH, Edwards S, Graham DL, Larson EB, Whisler KN, Simmons D, et al. static plasticity in behaviorally relevant in vivo models of Reinforcement-related regulation of AMPA glutamate receptor subunits addiction and provide further insight into the physiologi- in the ventral tegmental area enhances motivation for cocaine. 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