Nuklearmedizin 2014; 53(06): 227-337
DOI: 10.3413/Nukmed-0647-14-03
Original article
Schattauer GmbH

Focus on GABAA receptor function

A comparative analysis of in vivo imaging studies in neuropsychiatric disordersGABAA-Rezeptorfunktion im FokusEine vergleichende Analyse zur In-vivo-Bildgebung bei neuropsychiatrischen Störungen
S. Nikolaus
1   Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
,
H. Hautzel
1   Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
,
H.-W. Müller
1   Clinic of Nuclear Medicine, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received: 12 March 2014

accepted in revised form: 21 August 2014

Publication Date:
04 January 2018 (online)

Summary

Impairment of GABAA receptor function is increasingly recognized to play a major role in the pathophysiology of neuropsychiatric diseases including anxiety disorder (AD), major depressive disorder (MDD) and schizophrenia (SZ). Patients, method: We conducted a PUBMED search, which provided a total of 23 in vivo investigations with PET and SPECT, in which GABAA receptor binding in patients with the primary diagnosis of AD (n = 14, 160 patients, 172 controls), MDD (n = 2, 24 patients, 28 controls) or SZ (n = 6, 77 patients, 90 controls) was compared to healthy individuals. Results: A retrospective analysis revealed that AD, MDD and SZ differed as to both site(s) and extent(s) of GABAergic impairment. Additionally, it may be stated that, while the decline of GABAA receptor binding AD involved the whole mesolimbocortical system, in SZ it was confined to the frontal and temporal cortex. Conclusion: As GABA is known to inhibit dopamine and serotonin, GABAergic dysfunction may be associated with the disturbances of dopaminergic and serotonergic neurotransmission in neuropsychiatric disorders.

Zusammenfassung

In zunehmendem Maße wird erkannt, dass eine Fehlfunktion der GABAA-Rezeptoren eine Bedeutung für die Pathophysiologie von neuropsychiatrischen Erkrankungen wie Angststörung, unipolarer Depression und Schizophrenie haben könnte. Patienten, Methode: Eine PUBMED-Recherche ergab insgesamt 23 In-vivo-Untersuchungen mit PET oder SPECT, in denen die GABAA-Rezeptorbindung bei Patienten mit der primären Diagnose Angststörung (n = 14, 160 Patienten, 172 Kontrollen), unipolare Depression (n = 2, 24 Patienten, 28 Kontrollen) oder Schizophrenie (n = 6, 77 Patienten, 90 Kontrollen) mit gesunden Probanden verglichen wurde. Ergebnisse: Unsere retrospektive Analyse zeigte, dass sich Angststörung, unipolare Depression und Schizophrenie hinsichtlich des Ortes und des Ausmaßes der Beeinträchtigung unterscheiden. Außerdem betrifft die Abnahme der GABAA-Rezeptorbindung bei der Angststörung das gesamte mesolimbokortikale System, während sie sich bei der Schizophrenie auf den frontalen und temporalen Kortex beschränkt. Schlussfolgerung: Da GABA Do- pamin und Serotonin inhibiert, steht die GABAerge Fehlfunktion wahrscheinlich in Zusammenhang mit den Störungen der dopa- minergen und serotonergen Neurotransmission bei neuropsychiatrischen Erkrankungen.

 
  • References

  • 1 Abadie P, Boulenger JP, Benali K. et al. Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study. Eur J Neurosci 1999; 11: 1470-1478.
  • 2 Abi-Dargham A, Laruelle M, Krystal J. et al. No evidence of altered in vivo benzodiazepine receptor binding in schizophrenia. Neuropsychopharmacology 1999; 20: 650-661.
  • 3 Alex KD, Pehek EA. Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 2007; 113: 296-320.
  • 4 Andrews PW, Kornstein SG, Halberstadt LJ. et al. Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression. Front Psychol 2011; 2: 159.
  • 5 Asai Y, Takano A, Ito H. et al. GABAA/benzodiaze-pine receptor binding in patients with schizophrenia using [11C]Ro15-4513, a radioligand with relatively high affinity for alpha5 subunit. Schizophr Res 2008; 99: 333-340.
  • 6 Ball S, Busatto GF, David AS. et al. Cognitive functioning and GABAA/benzodiazepine receptor binding in schizophrenia. Biol Psychiatry. 1998; 43: 107-117.
  • 7 Barnes Jr. EM. Use-dependent regulation of GABAA receptors. Int Rev Neurobiol 1996; 39: 53-76.
  • 8 Benes FM, Vincent SL, Alsterberg G. et al. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 1992; 12: 924-929.
  • 9 Benes FM, Vincent SL, Marie A, Khan Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 1996; 75: 1021-1031.
  • 10 Benes FM, Berretta S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 2001; 25: 1-27.
  • 11 Brandt CA, Meller J, Keweloh L. et al. Increased benzodiazepine receptor density in the prefrontal cortex in patients with panic disorder. J Neural Transm 1998; 105: 1325-1333.
  • 12 Bremner JD, Innis RB, White T. et al. SPECT [123I]iomazenil measurement of the benzodiaze-pine receptor in panic disorder. Biol Psychiatry 2000; 47: 96-106.
  • 13 Bremner JD, Innis RB, Southwick SM. et al. Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 2000; 157: 1120-1126.
  • 14 Busatto GF, Pilowsky LS, Costa DC. et al. Correlation between reduced in vivo benzodiazepine receptor binding and severity of psychotic symptoms in schizophrenia. Am J Psychiatry 1997; 154: 56-63.
  • 15 Cameron OG, Huang GC, Nichols T. et al. Reduced gamma-aminobutyric acid(A)-benzodiazepine binding sites in insular cortex of individuals with panic disorder. Arch Gen Psychiatry 2007; 64: 793-800.
  • 16 Carlsson ML. On the role of prefrontal cortex glutamate for the antithetical phenomenology of obsessive compulsive disorder and attention deficit hyperactivity disorder. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25: 5-26.
  • 17 Cherlyn SY, Woon PS, Liu JJ. et al. Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder. Neurosci Biobehav Rev 2010; 34: 958-977.
  • 18 Coyle JT. The GABA-glutamate connection in schizophrenia: which is the proximate cause?. Biochem Pharmacol 2004; 68: 1507-1514.
  • 19 Cozzi NV, Nichols DE. 5-HT2A receptor antagonists inhibit potassium-stimulated gamma-aminobutyric acid release in rat frontal cortex. Eur J Pharmacol. 1996; 309: 25-31.
  • 20 Croarkin PE, Levinson AJ, Daskalakis ZJ. Evidence for GABAergic inhibitory deficits in major depressive disorder. Neurosci Biobehav Rev 2011; 35: 818-825.
  • 21 Deng C, Huang XF. Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia. Exp Brain Res 2006; 168: 587-590.
  • 22 Di Giovanni G, Di Matteo V, Pierucci M. et al. Central serotonin2C receptor: from physiology to pathology. Curr Top Med Chem 2006; 6: 1909-1925.
  • 23 Di Pietro NC, Seamans JK. Dopamine and serotonin interactions in the prefrontal cortex. Pharmacopsychiatry 2007; 40 (Suppl. 01) S27-S33.
  • 24 Fujita M, Southwick SM, Denucci CC. et al. Central type benzodiazepine receptors in Gulf War veterans with posttraumatic stress disorder. Biol Psychiatry 2004; 56: 95-100.
  • 25 Geuze E, van Berckel BN, Lammertsma A. et al. Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder. Mol Psychiatry 2008; 13: 74-83.
  • 26 Girault JA, Spampinato U, Glowinski J, Besson MJ. In vivo release of [3H]gamma-aminobutyric acid in the rat neostriatum-II. Neuroscience 1986; 19: 1109-1117.
  • 27 Grace AA, Bunney BS. Paradoxical GABA excitation of nigral dopaminergic cells. Eur J Pharmacol 1979; 59: 211-218.
  • 28 Graef S, Schönknecht P, Sabri O, Hegerl U. Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control. Psychopharmacology (Berl) 2011; 215: 205-229.
  • 29 Hajós M, Rogers BN. Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr Pharm Des 2010; 16: 538-554.
  • 30 Hasler G, Nugent AC, Carlson PJ. et al. Altered cerebral gamma-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography. Arch Gen Psychiatry 2008; 65: 1166-1175.
  • 31 Kaschka W, Feistel H, Ebert D. Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res 1995; 29: 427-434.
  • 32 Klumpers UM, Boellaard R, Veltman DJ. et al. Parametric [nC]flumazenil images. Nucl Med Commun 2012; 33: 422-430.
  • 33 Konradi C, Heckers S. Molecular aspects of glutamate dysregulation. Pharmacol Ther 2003; 97: 153-179.
  • 34 Kugaya A, Sanacora G, Verhoeff NP. et al. Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT. Biol Psychiatry 2003; 54: 792-799.
  • 35 Kuikka JT, Pitkänen A, Lepola U. et al. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun 1995; 16: 273-280.
  • 36 Luparini MR, Garrone B, Pazzagli M. et al. A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1117-1127.
  • 37 Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry 2003; 64 (Suppl. 03) 21-27.
  • 38 Malizia AL, Cunningham VJ, Bell CJ. et al. Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder. Arch Gen Psychiatry 1998; 55: 715-720.
  • 39 Mineur YS, Picciotto MR. Nicotine receptors and depression. Trends Pharmacol Sci 2010; 31: 580-586.
  • 40 Mitchell ND, Baker GB. An update on the role of glutamate in the pathophysiology of depression. Acta Psychiatr Scand 2010; 122: 192-210.
  • 41 Newell KA, Zavitsanou K, Jew SK, Huang XF. Alterations of muscarinic and GABA receptor binding in the posterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 225-233.
  • 42 Nikolaus S, Antke C, Müller HW. In vivo imaging of synaptic function in the central nervous system. Behav Brain Res 2009; 204: 32-66.
  • 43 Nikolaus S, Beu M, Antke C, Müller HW. Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders. Rev Neurosci 2010; 21: 119-139
  • 44 Nikolaus S, Hautzel H, Heinzel A, Müller HW. Key players in major and bipolar depression. Behav Brain Res 2012; 232: 358-390.
  • 45 Nikolaus S, de Souza Silva MA, Hautzel H. et al. The neurotachykinin NK1 receptor. Curr Mol Imaging 2013; 2: 130-147.
  • 46 Nikolaus S, Hautzel H, Heinzel A, Müller HW. Neurochemical dysfunction in treated and non-treated schizophrenia. Rev Neurosci 2014; 25: 25-96.
  • 47 Northoff G, Steinke R, Czcervenka C. et al. Decreased density of GABA-A receptors in the left sensorimotor cortex in akinetic catatonia. J Neurol Neurosurg Psychiatry 1999; 67: 445-450.
  • 48 Schlegel S, Steinert H, Bockisch A. et al. Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil-SPECT. Eur Arch Psychiatry Clin Neurosci 1994; 244: 49-51.
  • 49 Seeman P, Lee T. Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 1975; 188: 1217-1219.
  • 50 Stein DJ, Westenberg HG, Liebowitz MR. Social anxiety disorder and generalized anxiety disorder: serotonergic and dopaminergic neurocircuitry. J Clin Psychiatry 2002; 63 (Suppl. 06) 12-19.
  • 51 Tiihonen J, Kuikka J, Räsänen P. et al. Cerebral benzodiazepine receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiatry 1997; 2: 463-471.
  • 52 Tokunaga M, Ida I, Higuchi T, Mikuni M. Alterations of benzodiazepine receptor binding potential in anxiety and somatoform disorders measured by 123I-iomazenil SPECT. Radiat Med 1997; 15: 163-169.
  • 53 Verdurand M, Fillman SG, Weickert CS, Zavitsanou K. Increases in [3H]muscimol and [3H]flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and y2S mRNA levels respectively. PLoS One 2013; 8: e52724.
  • 54 Willner P. Dopamine and depression: a review of recent evidence. Brain Res 1983; 287: 211-224.
  • 55 Wittchen HU, Jacobi F. Size and burden of mental disorders in Europe – a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol 2005; 15: 357-376.