General Conclusions

  • Caio Maximino
Part of the SpringerBriefs in Neuroscience book series (BRIEFSNEUROSCI)


While the Deakin-Graeff hypothesis of serotonin function in anxiety disorders was appropriate to explain the data collected on the behavioral effects of serotonergic drugs microinjected in the amygdala or PAG, posterior analyses proved the reality to be far more nuanced than this hypothesis could cover. At the same time, while 5-HT1A agonists decrease anxiety- and fear-like behavior when microinjected in the basolateral amygdala and PAG, they increase anxiety-like behavior when microinjected in the septo-hippocampal system. Similarly, while 5-HT2 receptor agonists in the PAG reduce measures of fear and anxiety, they increase anxiety-like behavior when microinjected into the basolateral amygdala and septo-hippocampal system. Overall, these pharmacological results suggest that the regulation of anxiety-like behavior by serotonin is complex, with different receptors producing different results depending on the structure.


Anxiety Disorder Dorsal Raphe Nucleus Basolateral Amygdala Receptor Editing Serotonergic Drug 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Zangrossi H Jr, Viana MB, Graeff FG (1999) Anxiolytic effect of intra-amygdala injection of midazolam and 8-hydroxy-2-(di-n-propylamino)tetralin in the elevated T-maze. Eur J Pharmacol 369:267–270PubMedCrossRefGoogle Scholar
  2. 2.
    VdP Soares, Zangrossi H Jr (2004) Involvement of 5-HT1A and 5-HT2 receptors of the dorsal periaqueductal gray in the regulation of the defensive behaviors generated by the elevated T-maze. Brain Res Bull 64:181–188CrossRefGoogle Scholar
  3. 3.
    VdP Soares, Zangrossi H Jr (2009) Stimulation of 5-HT1A or 5-HT2A receptors in the ventrolateral periaqueductal gray causes anxiolytic-, but not panicolytic-like effect in rats. Behav Brain Res 197:178–185CrossRefGoogle Scholar
  4. 4.
    Hogg S, Andrews N, File SE (1994) Contrasting behavioural effects of 8-OHDPAT in the dorsal raphe nucleus and ventral hippocampus. Neuropharmacology 33:343–348PubMedCrossRefGoogle Scholar
  5. 5.
    Cervo L, Mocaër E, Bertaglia A, Samanin R (2000) Roles of 5-HT1A receptors in the dorsal raphe and dorsal hippocampus in anxiety assessed by the behavioral effects of 8-OH-DPAT and S 15535 in a modified Geller–Seifter conflict model. Neuropharmacology 39:1037–1043PubMedCrossRefGoogle Scholar
  6. 6.
    Viana MB, Zangrossi H Jr, Onusic GM (2008) 5-HT1A receptors of the lateral septum regulate inhibitory avoidance but not escape behavior in rats. Pharmacol Biochem Behav 89:360–366CrossRefGoogle Scholar
  7. 7.
    Cheeta S, Kenny PJ, File SE (2000) Hippocampal and septal injections of nicotine and 8-OH-DPAT distinguish among different animal tests of anxiety. Prog Neuropsychopharmacol Biol Psychiatry 24:1053–1067PubMedCrossRefGoogle Scholar
  8. 8.
    Menard J, Treit D (1998) The septum and the hippocampus differentially mediate anxiolytic effects of R(+)-8-OH-DPAT. Behav Pharmacol 9:93–101PubMedGoogle Scholar
  9. 9.
    Monassi CR, Menescal-de-Oliveira L (2004) Serotonin 5-HT2 and 5-HT1A receptors in the periaqueductal gray matter differentially modulate tonic immobility in guinea pig. Brain Res 1009:169–180PubMedCrossRefGoogle Scholar
  10. 10.
    Nunes-de-Souza V, Nunes-de-Souza RL, Rodgers RJ, Canto-de-Souza A (2008) 5-HT2 receptor activation in the midbrain periaqueductal gray (PAG) reduces anxiety-like behaviour in mice. Behav Brain Res 187:72–79PubMedCrossRefGoogle Scholar
  11. 11.
    Macedo CE, Martinez RCR, Albrechet-Souza L, Molina VA, Brandão ML (2007) 5-HT2- and D1-mechanisms of the basolateral nucleus of the amygdala enhance conditioned fear and impair unconditioned fear. Behav Brain Res 177:100–108PubMedCrossRefGoogle Scholar
  12. 12.
    Christianson JP, Ragole T, Amat J, Greenwood BN, Strong PV, Paul ED, Fleshner M, Watkins LR, Maier SF (2010) 5-hydroxytryptamine 2C receptors in the basolateral amygdala are involved in the expression of anxiety after uncontrollable traumatic stress. Biol Psychiatry 67:339–345PubMedCrossRefGoogle Scholar
  13. 13.
    Alves SH, Pinheiro G, Motta V, Landeira-Fernandez J, Cruz AP (2004) Anxiogenic effects in the rat elevated plus-maze of 5-HT(2C) agonists into ventral but not dorsal hippocampus. Behav Pharmacol 15:37–43PubMedCrossRefGoogle Scholar
  14. 14.
    Calizo LH, Ma X, Pan Y, Lemos J, Craige C, Heemstra L, Beck SG (2011) Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence. Neuropsychopharmacology (in press)Google Scholar
  15. 15.
    Crawford LK, Craige CP, Beck SG (2010) Increased intrinsic excitability of lateral wing serotonin neurons of the dorsal raphe: a mechanism for selective activation in stress circuits. J Neurophysiol 103:2652–2663PubMedCrossRefGoogle Scholar
  16. 16.
    Osterberg N, Wiehle M, Oehlke O, Heidrich S, Xu C, Fan C-M, Krieglstein K, Roussa E (2011) Sim1 is a novel regulator in the differentiation of mouse dorsal raphe serotonergic neurons. Plos One 6:e19239PubMedCrossRefGoogle Scholar
  17. 17.
    Beyer CE, Ghavami A, Lin Q, Sung A, Rhodes KJ, Dawson LA, Schechter LE, Young KH (2004) Regulators of G-protein signaling 4: Modulation of 5-HT1A-mediated neurotransmitter release in vivo. Brain Res 1022:214–220PubMedCrossRefGoogle Scholar
  18. 18.
    Liu C, Maejima T, Wyler SC, Casadesus G, Herlitze S, Deneris ES (2010) Pet-1 is required across different stages of life to regulate serotonergic function. Nat Neurosci 13:1190–1198PubMedCrossRefGoogle Scholar
  19. 19.
    Campbell BM, Merchant KM (2003) Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment. Brain Res 993:1–9PubMedCrossRefGoogle Scholar
  20. 20.
    Dracheva S, Lyddon R, Barley K, Marcus SM, Hurd YL, Byne WM (2009) Editing of serotonin 2C receptor mRNA in the prefrontal cortex characterizes high-novelty locomotor response behavioral trait. Neuropsychopharmacology 34:2237–2251PubMedCrossRefGoogle Scholar
  21. 21.
    Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (2007) Serotonin 5-HT2C receptors regulate anxiety-like behavior. Genes, Brain Behav 6:491–496CrossRefGoogle Scholar
  22. 22.
    Kimura A, Stevenson PL, Carter RN, MacColl G, French KL, Simons JP, Al-Shawi R, Kelly V, Chapman KE, Holmes MC (2009) Overexpression of 5-HT2C receptors in forebrain leads to elevated anxiety and hypoactivity. Eur J Neurosci 30:299–306PubMedCrossRefGoogle Scholar
  23. 23.
    Gross C, Zhuang X, Stark K, Ramboz S, Oosting R, Kirby L, Santarelli L, Beck S, Hen R (2002) Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416:396–400PubMedCrossRefGoogle Scholar
  24. 24.
    Gozzi A, Jain A, Giovanelli A, Bertollini C, Crestan V, Schwarz AJ, Tsetsenis T, Ragozzino D, Gross CT, Bifone A (2010) A neural switch for active and passive fear. Neuron 67:656–666PubMedCrossRefGoogle Scholar
  25. 25.
    Tsetsenis T, Ma XH, Lo Iacono L, Beck SG, Gross C (2007) Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus. Nat Neurosci 10:896–902PubMedCrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Authors and Affiliations

  • Caio Maximino
    • 1
  1. 1.Instituto de Ciencias BiologicasUniversidade Federal do ParaBelemBrazil

Personalised recommendations