Skip to main content
SpringerLink
Log in

Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Alterations in brainstem circuits have been proposed as a possible mechanism underlying the etiology of mood disorders. Projections from the median raphe nucleus (MnR) modulate dopaminergic activity in the forebrain and are also part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder.

Objective

The aim of this study is to assess the effect of chronic lithium treatment on behavioral disinhibition induced by MnR lesions.

Methods

MnR electrolytic lesions were performed in C57BL/6J mice, with sham-operated and intact animals as control groups. Following recovery, mice were chronically treated with lithium (LiCl, added in chow) followed by behavioral testing.

Results

MnR lesion induced manic-like behavioral alterations including hyperactivity in the open field (OF), stereotyped circling, anxiolytic/risk taking in the elevated plus maze (EPM) and light/dark box (LDB) tests, and increased basal body temperature. Lithium was specifically effective in reducing OF hyperactivity and stereotypy but did not reverse (EPM) or had a nonspecific effect (LDB) on anxiety/risk-taking measures. Additionally, lithium decreased saccharin preference and prevented weight loss during single housing.

Conclusions

Our data support electrolytic lesions of the MnR as an experimental model of a hyper-excitable/disinhibited phenotype consistent with some aspects of mania that are attenuated by the mood stabilizer lithium. Given lithium’s relatively specific efficacy in treating mania, these data support the hypothesis that manic symptoms derive not only from the stimulation of excitatory systems but also from inactivation or decreased activity of inhibitory mechanisms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Albinsson A, Andersson G, Andersson K, Vega-Matuszczyk J, Larsson K (1996) The effects of lesions in the mesencephalic raphe systems on male rat sexual behavior and locomotor activity. Behav Brain Res 80:57–63

    Article  CAS  PubMed  Google Scholar 

  • Andrade TG, Graeff FG (2001) Effect of electrolytic and neurotoxic lesions of the median raphe nucleus on anxiety and stress. Pharmacol Biochem Behav 70:1–14

    Article  CAS  PubMed  Google Scholar 

  • Andrade T, Silva A, Silva C, Graeff F (1998) Effect of electrolytic lesion of the median raphe nucleus on behavioral and physiological measures of stress. Acta Physiol Pharmacol Ther Latinoam 49:279–289

    Google Scholar 

  • Andrade TG, Zangrossi H Jr, Graeff FG (2013) The median raphe nucleus in anxiety revisited. J Psychopharmacol 27:1107–1115

    Article  PubMed  Google Scholar 

  • Arpa J, Padrino C, Rodriguez-Albarino A, de Andres I (1998) Centralis superior raphe, reticularis pontis nuclei, and sleep-wakefulness cycle in cats. J Sleep Res 7:263–275

    Article  CAS  PubMed  Google Scholar 

  • Asin KE, Fibiger HC (1983) An analysis of neuronal elements within the median nucleus of the raphe that mediate lesion-induced increases in locomotor activity. Brain Res 268:211–223

    Article  CAS  PubMed  Google Scholar 

  • Asin KE, Wirtshafter D, Fibiger HC (1985) Electrolytic, but not 5,7-dihydroxytryptamine, lesions of the nucleus medianus raphe impair acquisition of a radial maze task. Behav Neural Biol 44:415–424

    Article  CAS  PubMed  Google Scholar 

  • Baptista T, Hernandez L, Burguera J, Burguera M, Hoebel B (1990) Chronic lithium administration enhances serotonin release in the lateral hypothalamus but not in the hippocampus in rats. A microdialysis study. J Neural Transm 82:31–41

    Article  CAS  Google Scholar 

  • Beck SG, Pan YZ, Akanwa AC, Kirby LG (2004) Median and dorsal raphe neurons are not electrophysiologically identical. J Neurophysiol 91:994–1005

    Article  PubMed Central  PubMed  Google Scholar 

  • Bowden CL (2005) A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord 84:117–125

    Article  PubMed  Google Scholar 

  • Can A, Blackwell RA, Piantadosi SC, Dao DT, O’Donnell KC, Gould TD (2011) Antidepressant-like responses to lithium in genetically diverse mouse strains. Genes Brain Behav 10:434–443

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Can A, Piantadosi SC, Gould TD (2013) Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background. Psychopharmacology (Berlin) 228:411–418

    Article  CAS  Google Scholar 

  • Can A, Schulze TG, Gould TD (2014) Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav 123:3–16

  • Cannon DM, Ichise M, Rollis D, Klaver JM, Gandhi SK, Charney DS, Manji HK, Drevets WC (2007) Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol Psychiatry 62:870–877

    Article  CAS  PubMed  Google Scholar 

  • Dao DT, Mahon PB, Cai X, Kovacsics CE, Blackwell RA, Arad M, Shi J, Zandi PP, O’Donnell P, Knowles JA, Weissman MM, Coryell W, Scheftner WA, Lawson WB, Levinson DF, Thompson SM, Potash JB, Gould TD (2010) Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biol Psychiatry 68:801–810

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Di Giovanni G, Di Matteo V, Pierucci M, Esposito E (2008) Serotonin-dopamine interaction: electrophysiological evidence. Prog Brain Res 172:45–71

    Article  PubMed  Google Scholar 

  • Einat H (2006) Modelling facets of mania—new directions related to the notion of endophenotypes. J Psychopharmacol 20:714–722

    Article  PubMed  Google Scholar 

  • File SE, Hyde JR, MacLeod NK (1979) 5,7-Dihydroxytryptamine lesions of dorsal and median raphe nuclei and performance in the social interaction test of anxiety and in a home-cage aggression test. J Affect Disord 1:115–122

    Article  CAS  PubMed  Google Scholar 

  • Flaisher-Grinberg S, Einat H (2010) Strain-specific battery of tests for domains of mania: effects of valproate, lithium and imipramine. Front Psychiatry 1:10

    PubMed Central  CAS  PubMed  Google Scholar 

  • Flaisher-Grinberg S, Overgaard S, Einat H (2009) Attenuation of high sweet solution preference by mood stabilizers: a possible mouse model for the increased reward-seeking domain of mania. J Neurosci Methods 177:44–50

    Article  CAS  PubMed  Google Scholar 

  • Franklin KBJ, Paxinos G (2007) The mouse brain in stereotaxic coordinates, 3rd edn. Academic, New York

    Google Scholar 

  • Gelenberg AJ, Kane JM, Keller MB, Lavori P, Rosenbaum JF, Cole K, Lavelle J (1989) Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 321:1489–1493

    Article  CAS  PubMed  Google Scholar 

  • Gessa GL, Pani L, Fadda P, Fratta W (1995) Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol 5(Suppl):89–93

    Article  CAS  PubMed  Google Scholar 

  • Geyer MA, Puerto A, Menkes DB, Segal DS, Mandell AJ (1976) Behavioral studies following lesions of the mesolimbic and mesostriatal serotonergic pathways. Brain Res 106:257–269

    Article  CAS  PubMed  Google Scholar 

  • Giambalvo CT, Snodgrass SR (1978) Effect of p-chloroamphetamine and 5,7-dihydroxytryptamine on rotation and dopamine turnover. Brain Res 149:453–467

    Article  CAS  PubMed  Google Scholar 

  • Gould TD, Einat H (2007) Animal models of bipolar disorder and mood stabilizer efficacy: a critical need for improvement. Neurosci Biobehav Rev 31:825–831

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gould TD, O’Donnell KC, Picchini AM, Manji HK (2007) Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium. Neuropsychopharmacology 32:1321–1333

    Article  CAS  PubMed  Google Scholar 

  • Graeff FG, Silveira Filho NG (1978) Behavioral inhibition induced by electrical stimulation of the median raphe nucleus of the rat. Physiol Behav 21:477–484

    Article  CAS  PubMed  Google Scholar 

  • Graeff FG, Guimaraes FS, De Andrade TG, Deakin JF (1996) Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav 54:129–141

    Article  CAS  PubMed  Google Scholar 

  • Gray JA (1982) The neuropsychology of anxiety. Oxford University Press, New York

    Google Scholar 

  • Gray JA (1987) The psychology of fear and stress. Cambridge University Press, Cambridge

    Google Scholar 

  • Hamburger-Bar R, Robert M, Newman M, Belmaker RH (1986) Interstrain correlation between behavioural effects of lithium and effects on cortical cyclic AMP. Pharmacol Biochem Behav 24:9–13

    Article  CAS  PubMed  Google Scholar 

  • Herman L, Hougland T, El-Mallakh RS (2007) Mimicking human bipolar ion dysregulation models mania in rats. Neurosci Biobehav Rev 31:874–881

    Article  CAS  PubMed  Google Scholar 

  • Herve D, Simon H, Blanc G, Lemoal M, Glowinski J, Tassin JP (1981) Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat. Brain Res 216:422–428

    Article  CAS  PubMed  Google Scholar 

  • Ihne JL, Fitzgerald PJ, Hefner KR, Holmes A (2012) Pharmacological modulation of stress-induced behavioral changes in the light/dark exploration test in male C57BL/6J mice. Neuropharmacology 62:464–473

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jacobs BL, Wise WD, Taylor KM (1974) Differential behavioral and neurochemical effects following lesions of the dorsal or median raphe nuclei in rats. Brain Res 79:353–361

    Article  CAS  PubMed  Google Scholar 

  • Kohler C, Steinbusch H (1982) Identification of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain. Neuroscience 7:951–975

    Article  CAS  PubMed  Google Scholar 

  • Kostowski W, Samanin R, Bareggi SR, Marc V, Garattini S, Valzelli L (1974) Biochemical aspects of the interaction between midbrain raphe and locus coeruleus in the rat. Brain Res 82:178–182

    Article  CAS  PubMed  Google Scholar 

  • Kovacsics CE, Gould TD (2010) Shock-induced aggression in mice is modified by lithium. Pharmacol Biochem Behav 94:380–386

    Article  CAS  PubMed  Google Scholar 

  • Kusljic S, Copolov DL, van den Buuse M (2003) Differential role of serotonergic projections arising from the dorsal and median raphe nuclei in locomotor hyperactivity and prepulse inhibition. Neuropsychopharmacology 28:2138–2147

    CAS  PubMed  Google Scholar 

  • Martin S, van den Buuse M (2008) Phencyclidine-induced locomotor hyperactivity is enhanced in mice after stereotaxic brain serotonin depletion. Behav Brain Res 191:289–293

    Article  CAS  PubMed  Google Scholar 

  • Matthews PR, Harrison PJ (2012) A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide. J Affect Disord 137:125–134

    Article  PubMed Central  PubMed  Google Scholar 

  • Nishikawa T, Fage D, Scatton B (1986) Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat. Brain Res 373:324–336

    Article  CAS  PubMed  Google Scholar 

  • O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, Klein PS (2004) Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 24:6791–6798

    Article  PubMed  Google Scholar 

  • O’Leary OF, O’Connor RM, Cryan JF (2012) Lithium-induced effects on adult hippocampal neurogenesis are topographically segregated along the dorso-ventral axis of stressed mice. Neuropharmacology 62:247–255

    Article  PubMed  Google Scholar 

  • Ottoni EB (2000) EthoLog 2.2: a tool for the transcription and timing of behavior observation sessions. Behav Res Meth Instr 32:446–449

    Article  CAS  Google Scholar 

  • Paul ED, Lowry CA (2013) Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J Psychopharmacol 27:1090–1106

    Article  CAS  PubMed  Google Scholar 

  • Prange AJ Jr, Wilson IC, Lynn CW, Alltop LB, Stikeleather RA (1974) L-tryptophan in mania. Contribution to a permissive hypothesis of affective disorders. Arch Gen Psychiatry 30:56–62

    Article  PubMed  Google Scholar 

  • Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, Chakravarty S, Peevey J, Oehrlein N, Birnbaum S, Vitaterna MH, Orsulak P, Takahashi JS, Nestler EJ, Carlezon WA Jr, McClung CA (2007) Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 104:6406–6411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Scheuch K, Höltje M, Budde H, Lautenschlager M, Heinz A, Ahnert-Hilger G, Priller J (2010) Lithium modulates tryptophan hydroxylase 2 gene expression and serotonin release in primary cultures of serotonergic raphe neurons. Brain Res 1307:14–21

    Article  CAS  PubMed  Google Scholar 

  • Shaltiel G, Maeng S, Malkesman O, Pearson B, Schloesser RJ, Tragon T, Rogawski M, Gasior M, Luckenbaugh D, Chen G, Manji HK (2008) Evidence for the involvement of the kainate receptor subunit GluR6 (GRIK2) in mediating behavioral displays related to behavioral symptoms of mania. Mol Psychiatry 13:858–72

  • Silva R, Mesquita AR, Bessa J, Sousa JC, Sotiropoulos I, Leao P, Almeida OF, Sousa N (2008) Lithium blocks stress-induced changes in depressive-like behavior and hippocampal cell fate: the role of glycogen-synthase-kinase-3beta. Neuroscience 152:656–669

    Article  CAS  PubMed  Google Scholar 

  • Sullivan GM, Ogden RT, Oquendo MA, Kumar JS, Simpson N, Huang YY, Mann JJ, Parsey RV (2009) Positron emission tomography quantification of serotonin-1A receptor binding in medication-free bipolar depression. Biol Psychiatry 66:223–230

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Treiser SL, Cascio CS, O’Donahue TL, Thoa NB, Jacobowitz DM, Kellar KJ (1981) Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 213:1529–1531

    Article  CAS  PubMed  Google Scholar 

  • Vasconcellos AP, Tabajara AS, Ferrari C, Rocha E, Dalmaz C (2003) Effect of chronic stress on spatial memory in rats is attenuated by lithium treatment. Physiol Behav 79:143–149

    Article  CAS  PubMed  Google Scholar 

  • Vertes RP, Kinney GG, Kocsis B, Fortin WJ (1994) Pharmacological suppression of the median raphe nucleus with serotonin1A agonists, 8-OH-DPAT and buspirone, produces hippocampal theta rhythm in the rat. Neuroscience 60:441–451

    Article  CAS  PubMed  Google Scholar 

  • Vinkers CH, Oorschot RV, Olivier B, Groenink L (2009) Stress-induced hyperthermia in the mouse. In: Gould TD (ed) Mood and anxiety related phenotypes in mice: characterization using behavioral tests. Humana Press, New York, pp 139–152

    Chapter  Google Scholar 

  • Wirtshafter D, Montana W, Asin KE (1986) Behavioral and biochemical studies of the substrates of median raphe lesion induced hyperactivity. Physiol Behav 38:751–759

    Article  CAS  PubMed  Google Scholar 

  • Wirtshafter D, Klitenick MA, Asin KE (1987) Evidence against serotonin involvement in the hyperactivity produced by injections of muscimol into the median raphe nucleus. Pharmacol Biochem Behav 27:45–52

    Article  CAS  PubMed  Google Scholar 

  • Wogar MA, Bradshaw CM, Szabadi E (1991) Evidence for an involvement of 5-hydroxytryptaminergic neurones in the maintenance of operant behaviour by positive reinforcement. Psychopharmacology (Berlin) 105:119–124

    Article  CAS  Google Scholar 

  • Wogar MA, Bradshaw CM, Szabadi E (1993) Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on choice between delayed reinforcers. Psychopharmacology (Berlin) 111:239–243

    Article  CAS  Google Scholar 

  • Yamamoto T, Ueki S (1978) Effects of drugs on hyperactivity and aggression induced by raphe lesions in rats. Pharmacol Biochem Behav 9:821–826

    Article  CAS  PubMed  Google Scholar 

  • Yen YC, Anderzhanova E, Bunck M, Schuller J, Landgraf R, Wotjak CT (2013) Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety. Front Behav Neurosci 7:103

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Funded by MH091816 to TDG. FAP received CNPq (Proc. 140649/2010-7) and CAPES (Proc. 13751/12-3) research fellowships from the Brazilian government. The experiments fully comply with the current USA laws of Care and Use of Laboratory Animals.

Author information

Authors and Affiliations

  1. Instituto de Psicologia, Universidade de São Paulo, Av. Prof. Mello Moraes 1721, Sala A-6, Cidade Universitária, 05508-900, São Paulo, SP, Brazil

    Fernanda A. Pezzato & Miriam G. Mijares

  2. Department of Psychiatry, University of Maryland School of Medicine, Rm. 934D MSTF, 685 W. Baltimore St., Baltimore, MD, 21201, USA

    Fernanda A. Pezzato, Adem Can & Todd D. Gould

  3. Instituto de Biociências, Departamento de Fisiologia, Universidade Estadual Paulista Júlio de Mesquita Filho, 18618-000, Botucatu, SP, Brazil

    Katsumasa Hoshino

  4. Instituto de Biociências, Departamento de Anatomia, Universidade Estadual Paulista Júlio de Mesquita Filho, 18618970, Botucatu, SP, Brazil

    José de Anchieta C. Horta Jr.

  5. Department of Experimental Psychology, University of São Paulo, São Paulo, SP, Brazil

    Fernanda A. Pezzato & Miriam G. Mijares

  6. Department of Physiology, São Paulo State University, Botucatu, SP, Brazil

    Katsumasa Hoshino

  7. Department of Anatomy, São Paulo State University, Botucatu, SP, Brazil

    José de Anchieta C. Horta Jr.

  8. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

  9. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA

    Todd D. Gould

Authors
  1. Fernanda A. Pezzato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adem Can
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katsumasa Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José de Anchieta C. Horta Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miriam G. Mijares
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Todd D. Gould
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Todd D. Gould.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pezzato, F.A., Can, A., Hoshino, K. et al. Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus. Psychopharmacology 232, 1441–1450 (2015). https://doi.org/10.1007/s00213-014-3775-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3775-z

Keywords

Search

Navigation