Neuroscience Bulletin

, Volume 34, Issue 6, pp 1029–1036 | Cite as

Histamine Excites Rat GABAergic Ventral Pallidum Neurons via Co-activation of H1 and H2 Receptors

  • Miao-Jin Ji
  • Xiao-Yang Zhang
  • Xiao-Chun Peng
  • Yang-Xun Zhang
  • Zi Chen
  • Lei YuEmail author
  • Jian-Jun Wang
  • Jing-Ning ZhuEmail author
Original Article


The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.


Ventral pallidum Histamine H1 receptor H2 receptor Motivation Emotion 



This work was supported by the National Natural Science Foundation of China (81671107, 31330033, 91332124, 31471112, 31600834, and the NSFC and the Research Grants Council Joint Research Scheme 31461163001); the Ministry of Education of China (Fundamental Research Funds for the Central Universities 020814380071, 020814380048 and 020814380091) and the China Postdoctoral Science Foundation (2017T100351).

Conflict of interest

All authors claim that there are no conflicts of interest.


  1. 1.
    Zahm DS, Zaborszky L, Alheid GF, Heimer L. The ventral striatopallidothalamic projection: II. The ventral pallidothalamic link. J Comp Neurol 1987, 255: 592–605.CrossRefGoogle Scholar
  2. 2.
    Maurice N, Deniau JM, Menetrey A, Glowinski J, Thierry AM. Position of the ventral pallidum in the rat prefrontal cortex-basal ganglia circuit. Neuroscience 1997, 80: 23–534.CrossRefGoogle Scholar
  3. 3.
    Tripathi A, Prensa L, Mengual E. Axonal branching patterns of ventral pallidal neurons in the rat. Brain Struct Funct 2013, 8: 1133–1157.CrossRefGoogle Scholar
  4. 4.
    Knowland D, Lilascharoen V, Pacia CP, Shin S, Wang EH, Lim BK. Distinct ventral pallidal neural populations mediate separate symptoms of depression. Cell 2017, 170: 284–297.CrossRefGoogle Scholar
  5. 5.
    Smith KS, Berridge KC. The ventral pallidum and hedonic reward: neurochemical maps of sucrose ‘‘liking’’ and food intake. J Neurosci 2005, 25: 8637–8649.CrossRefGoogle Scholar
  6. 6.
    Richard JM, Ambroggi F, Janak PH, Fields HL. Ventral pallidum neurons encode incentive value and promote cue-elicited instrumental actions. Neuron 2016, 90: 1165–1173.CrossRefGoogle Scholar
  7. 7.
    Miller JM. Anhedonia after a selective bilateral lesion of the globus pallidus. Am J Psychiatry 2006, 163: 786–788.CrossRefGoogle Scholar
  8. 8.
    Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J, et al. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 2014, 7: 577–585.CrossRefGoogle Scholar
  9. 9.
    Haas HL, Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system. Nat Rev Neurosci 2003, 4: 121–130.CrossRefGoogle Scholar
  10. 10.
    Zhu JN, Yung WH, Chow BKC, Chan YS, Wang JJ. The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration. Brain Res Rev 2006, 52: 93–106.CrossRefGoogle Scholar
  11. 11.
    Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev 2008, 88: 1183–1241.CrossRefGoogle Scholar
  12. 12.
    Li B, Zhu JN, Wang JJ. Histaminergic afferent system in the cerebellum: structure and function. Cerebellum Ataxias 2014, 1: 5.CrossRefGoogle Scholar
  13. 13.
    Panula P, Pirvola U, Auvinen S, Airaksinen MS. Histamine-immunoreactive nerve fibres in the rat brain. Neuroscience 1989, 28: 585–610.CrossRefGoogle Scholar
  14. 14.
    Cumming P, Damsma G, Fibiger HC, Vincent SR. Characterization of extracellular histamine in the striatum and bed nucleus of the stria terminalis of the rat: an in vivo microdialysis study. J Neurochem 1991, 56: 1797–1803.CrossRefGoogle Scholar
  15. 15.
    Cumming P, Laliberte C, Gjedde A. Distribution of histamine H3 binding in forebrain of mouse and guinea pig. Brain Res 1994, 664: 276–279.CrossRefGoogle Scholar
  16. 16.
    Vizuete ML, Traiffort E, Bouthenet ML, Ruat M, Souil E, Tardivel-Lacombe J, et al. Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain. Neuroscience 1997, 80: 321–343.CrossRefGoogle Scholar
  17. 17.
    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, seventh ed. Academic Press, San Diego, 2014.Google Scholar
  18. 18.
    Yu L, Zhang XY, Cao SL, Peng SY, Ji DY, Zhu JN, et al. Na+ -Ca2+ exchanger, leak K+ channel and hyperpolarization-activated cyclic nucleotide-gated channel comediate the histamine-induced excitation on rat inferior vestibular nucleus neurons. CNS Neurosci Ther 2016, 22: 184–193.CrossRefGoogle Scholar
  19. 19.
    Zhang J, Zhuang QX, Li B, Wu GY, Yung WH, Zhu JN, et al. Selective modulation of histaminergic inputs on projection neurons of cerebellum rapidly promotes motor coordination via HCN channels. Mol Neurobiol 2016, 53: 1386–1401.CrossRefGoogle Scholar
  20. 20.
    Li B, Zhang XY, Yang AH, Peng XC, Chen ZP, Zhou JY, et al. Histamine increases neuronal excitability and sensitivity of the lateral vestibular nucleus and promotes motor behaviors via HCN channel coupled to h2 receptor. Front Cell Neurosci 2017, 10: 300.CrossRefGoogle Scholar
  21. 21.
    Gao HR, Zhuang QX, Zhang YX, Chen ZP, Li B, Zhang XY, et al. Orexin directly enhances the excitability of globus pallidus internus neurons in rat by co-activating OX1 and OX2 receptors. Neurosci Bull 2017, 33: 365–372.CrossRefGoogle Scholar
  22. 22.
    Wang Y, Chen ZP, Zhuang QX, Zhang XY, Li HZ, Wang JJ, et al. Role of corticotropin-releasing factor in cerebellar motor control and ataxia. Curr Biol 2017, 27: 2661–2669.CrossRefGoogle Scholar
  23. 23.
    Wang ZC, Li LH, Bian C, Yang L, Lv N, Zhang YQ. Involvement of NF-κB and the CX3CR1 signaling network in mechanical allodynia induced by tetanic sciatic stimulation. Neurosci Bull 2017, 34: 64–73.CrossRefGoogle Scholar
  24. 24.
    Bengtson CP, Osborne PB. Electrophysiological properties of anatomically identified ventral pallidal neurons in rat brain slices. Ann N Y Acad Sci 1999, 877: 691–694.CrossRefGoogle Scholar
  25. 25.
    Bongers G, de Esch I, Leurs R. Molecular pharmacology of the four histamine receptors. Adv Exp Med Biol 2010, 709: 11–19.CrossRefGoogle Scholar
  26. 26.
    Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A. Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 2013, 34: 33–58.CrossRefGoogle Scholar
  27. 27.
    Jutel M, Akdis M, Akdis CA. Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy 2009, 39: 1786–1800.CrossRefGoogle Scholar
  28. 28.
    Anichtchik OV, Rinne JO, Kalimo H, Panula P. An altered histaminergic innervation of the substantia nigra in Parkinson’s disease. Exp Neurol 2000, 163: 20–30.CrossRefGoogle Scholar
  29. 29.
    Chen K, Wang JJ, Yung WH, Chan YS, Chow BK. Excitatory effect of histamine on neuronal activity of rat globus pallidus by activation of H2 receptors in vitro. Neurosci Res 2005, 53: 288–297.CrossRefGoogle Scholar
  30. 30.
    Brabant C, Quertemont E, Anaclet C, Lin JS, Ohtsu H, Tirelli E. The psychostimulant and rewarding effects of cocaine in histidine decarboxylase knockout mice do not support the hypothesis of an inhibitory function of histamine on reward. Psychopharmacology (Berl) 2007, 190: 251–263.CrossRefGoogle Scholar
  31. 31.
    Iwabuchi K, Kubota Y, Ito C, Watanabe T, Yanai K. Methamphetamine and brain histamine: a study using histamine-related gene knockout mice. Ann N Y Acad Sci 2004, 1025: 129–134.CrossRefGoogle Scholar
  32. 32.
    Takahashi K, Suwa H, Ishikawa T, Kotani H. Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype. J Clin Invest 2002, 110: 1791–1799.CrossRefGoogle Scholar
  33. 33.
    Zlomuzica A, Viggiano D, De Souza Silva MA, Ishizuka T, Gironi Carnevale UA, Ruocco L A, et al. The histamine H1-receptor mediates the motivational effects of novelty. Eur J Neurosci 2008, 27: 1461–1474.CrossRefGoogle Scholar
  34. 34.
    Fang Q, Hu WW, Wang XF, Yang Y, Lou GD, Jin MM, et al. Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury. Neuropharmacology 2014, 77: 156 –166.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Pharmaceutical Biotechnology and Department of Physiology, School of Life SciencesNanjing UniversityNanjingChina

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