Abstract
Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394:939–51.
Harvey PD, Strassnig M. Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms, and health status. World Psychiatry. 2012;11:73–9.
Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261:717–9.
Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192:481–3.
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA. 2000;97:8104–9.
Hurd YL, Suzuki M, Sedvall GC. D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J Chem Neuroanat. 2001;22:127–37.
Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–86.
Bell DS. The experimental reproduction of amphetamine psychosis. Arch Gen Psychiatry. 1973;29:35–40.
Barch DM, Carter CS. Amphetamine improves cognitive function in medicated individuals with schizophrenia and in healthy volunteers. Schizophr Res. 2005;77:43–58.
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78:189–225.
Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry. 2015;72:316–24.
McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci. 2019;42:205–20.
Akhlaghpour H, Wiskerke J, Choi JY, Taliaferro JP, Au J, Witten IB. Dissociated sequential activity and stimulus encoding in the dorsomedial striatum during spatial working memory. Elife. 2016;55:e19507.
Graybiel AM. The basal ganglia and cognitive pattern generators. Schizophr Bull. 1997;23:459–69.
Poldrack RA, Packard MG. Competition among multiple memory systems: converging evidence from animal and human brain studies. Neuropsychologia. 2003;41:245–51.
Bäckman CM, Malik N, Zhang Y, Shan L, Grinberg A, Hoffer BJ, et al. Characterization of a mouse strain expressing Cre recombinase from the 3’ untranslated region of the dopamine transporter locus. Genesis. 2006;44:383–90.
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, et al. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science. 2000;288:306–13.
Parker JG, Marshall JD, Ahanonu B, Wu YW, Kim TH, Grewe BF, et al. Diametric neural ensemble dynamics in parkinsonian and dyskinetic states. Nature. 2018;557:177–82.
Fernandez Espejo E. Prefrontocortical dopamine loss in rats delays long-term extinction of contextual conditioned fear, and reduces social interaction without affecting short-term social interaction memory. Neuropsychopharmacology. 2003;28:490–8.
Bolkan SS, Stujenske JM, Parnaudeau S, Spellman TJ, Rauffenbart C, Abbas AI, et al. Thalamic projections sustain prefrontal activity during working memory maintenance. Nat Neurosci. 2017;20:987–96.
Guler AD, Rainwater A, Parker JG, Jones GL, Argilli E, Arenkiel BR, et al. Transient activation of specific neurons in mice by selective expression of the capsaicin receptor. Nat Commun. 2012;3:746.
Dietrich MO, Zimmer MR, Bober J, Horvath TL. Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell. 2015;160:1222–32.
van den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophr Bull. 2010;36:246–70.
Moghaddam B, Bunney BS. Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine. Synapse. 1989;4:156–61.
Roth BL. DREADDs for neuroscientists. Neuron. 2016;89:683–94.
Beutler LR, Chen Y, Ahn JS, Lin YC, Essner RA, Knight ZA. Dynamics of gut-brain communication underlying hunger. Neuron. 2017;96:461–75.e5.
Poulin JF, Caronia G, Hofer C, Cui Q, Helm B, Ramakrishnan C, et al. Mapping projections of molecularly defined dopamine neuron subtypes using intersectional genetic approaches. Nat Neurosci. 2018;21:1260–71.
Poulin JF, Gaertner Z, Moreno-Ramos OA, Awatramani R. Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches. Trends Neurosci. 2020;43:155–69.
Azcorra M, Gaertner Z, Davidson C, Ramakrishnan C, Fenno L, Kim YS, et al. Dopaminergic axons track somatic signaling in behaving mice. bioRxiv. 2022:2022.06.20.496872.
Kelley AE, Gauthier AM, Lang CG. Amphetamine microinjections into distinct striatal subregions cause dissociable effects on motor and ingestive behavior. Behav Brain Res. 1989;35:27–39.
Kim Y, Venkataraju KU, Pradhan K, Mende C, Taranda J, Turaga SC, et al. Mapping social behavior-induced brain activation at cellular resolution in the mouse. Cell Rep. 2015;10:292–305.
Guo ZV, Inagaki HK, Daie K, Druckmann S, Gerfen CR, Svoboda K. Maintenance of persistent activity in a frontal thalamocortical loop. Nature. 2017;545:181–86.
McNab F, Klingberg T. Prefrontal cortex and basal ganglia control access to working memory. Nat Neurosci. 2008;11:103–7.
Yizhar O, Levy DR. The social dilemma: prefrontal control of mammalian sociability. Curr Opin Neurobiol. 2021;68:67–75.
Funahashi S, Chafee MV, Goldman-Rakic PS. Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task. Nature 1993;365:753–6.
Kim IH, Kim N, Kim S, Toda K, Catavero CM, Courtland JL, et al. Dysregulation of the synaptic cytoskeleton in the PFC drives neural circuit pathology, leading to social dysfunction. Cell Rep. 2020;32:107965.
Lewis DA. Cortical circuit dysfunction and cognitive deficits in schizophrenia–implications for preemptive interventions. Eur J Neurosci. 2012;35:1871–8.
Piskulic D, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, et al. Negative symptoms in individuals at clinical high risk of psychosis. Psychiatry Res. 2012;196:220–4.
Bora E, Lin A, Wood SJ, Yung AR, McGorry PD, Pantelis C. Cognitive deficits in youth with familial and clinical high risk to psychosis: a systematic review and meta-analysis. Acta Psychiatr Scand. 2014;130:1–15.
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.
Chernysheva M, Sych Y, Fomins A, Alatorre Warren JL, Lewis C, Capdevila LS, et al. Striatum-projecting prefrontal cortex neurons support working memory maintenance. bioRxiv. 2021:2021.12.03.471159.
McElvain LE, Chen Y, Moore JD, Brigidi GS, Bloodgood BL, Lim BK, et al. Specific populations of basal ganglia output neurons target distinct brain stem areas while collateralizing throughout the diencephalon. Neuron. 2021;109:1721–38.e4.
Lee Y, Kim H, Kim JE, Park JY, Choi J, Lee JE, et al. Excessive D1 dopamine receptor activation in the dorsal striatum promotes autistic-like behaviors. Mol Neurobiol. 2018;55:5658–71.
Kim H, Lee Y, Park JY, Kim JE, Kim TK, Choi J, et al. Loss of adenylyl cyclase type-5 in the dorsal striatum produces autistic-like behaviors. Mol Neurobiol. 2017;54:7994–8008.
Peça J, Feliciano C, Ting JT, Wang W, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472:437–42.
Krabbe S, Duda J, Schiemann J, Poetschke C, Schneider G, Kandel ER, et al. Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area. Proc Natl Acad Sci. 2015;112:E1498.
Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron. 2006;49:603–15.
Wilkinson LS. The nature of interactions involving prefrontal and striatal dopamine systems. J Psychopharmacol (Oxf, Engl). 1997;11:143–50.
Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature. 1980;286:74–77.
Li YC, Kellendonk C, Simpson EH, Kandel ER, Gao WJ. D2 receptor overexpression in the striatum leads to a deficit in inhibitory transmission and dopamine sensitivity in mouse prefrontal cortex. Proc Natl Acad Sci USA. 2011;108:12107–12.
Kim IH, Rossi MA, Aryal DK, Racz B, Kim N, Uezu A, et al. Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. Nat Neurosci. 2015;18:883–91.
Casado-Sainz A, Gudmundsen F, Baerentzen SL, Lange D, Ringsted A, Martinez-Tejada I, et al. Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats. Neuropsychopharmacology. 2022;47:454–64.
Berke JD. What does dopamine mean? Nat Neurosci. 2018;21:787–93.
Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci. 2016;17:524–32.
Elliott JM, Beveridge TJ. Psychostimulants and monoamine transporters: upsetting the balance. Curr Opin Pharm. 2005;5:94–100.
Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012;490:262–6.
Yun S, Yang B, Martin M, Yeh N-H, Contractor A, Parker J. Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect. bioRxiv; 2021.
Lee MA, Thompson PA, Meltzer HY. Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry. 1994;55:82–7.
Acknowledgements
We thank Dr. Ben Arenkiel for providing the cDNA plasmid for Trpv1. The authors have no financial disclosures to declare.
Funding
This work was supported by the Whitehall Foundation (JGP) and National Institutes of Mental Health: K01 MH11313201 (JGP) and 2T32 MH067564 (NAM), Neurological Disorders and Stroke R01 NS122840 (JGP), Drug Abuse P30DA048736 (LSZ) and Diabetes and Digestive and Kidney Diseases R01 DK128477 (LRB).
Author information
Authors and Affiliations
Contributions
Conceptualization and methodology: NAM, LRB, LSZ, JGP; Investigation and analysis: NAM, SY, SWF, MMM, JAN, JGP; Writing and editing: NAM and JGP; All authors edited and approved draft prior to submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Moya, N.A., Yun, S., Fleps, S.W. et al. The effect of selective nigrostriatal dopamine excess on behaviors linked to the cognitive and negative symptoms of schizophrenia. Neuropsychopharmacol. 48, 690–699 (2023). https://doi.org/10.1038/s41386-022-01492-1
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41386-022-01492-1
This article is cited by
-
Causal associations between iron levels in subcortical brain regions and psychiatric disorders: a Mendelian randomization study
Translational Psychiatry (2025)
-
Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission
Nature Communications (2024)
-
Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons
Nature Neuroscience (2023)
