Genetic and pharmacological evidence of a role for GABA(B) receptors in the modulation of anxiety- and antidepressant-like behavior.
Although there is much evidence for a role of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the pathophysiology of anxiety and depression, the role of GABA(B) receptors in behavioral processes related to these disorders has not yet been fully established. GABA(B) receptors are G-protein-coupled receptors, which act as functional heterodimers made up of GABA(B(1)) and GABA(B(2)) subunits. Using recently generated GABA(B(1)) -/- mice, which lack functional GABA(B) receptors, and pharmacological tools we assessed the role of GABA(B) receptors in anxiety- and antidepressant-related behaviors. In the light-dark box, GABA(B(1)) -/- mice were more anxious than their wild-type littermates (less time spent in the light; reduced number of transitions). GABA(B(1)) -/- mice were also more anxious in the staircase test. Conversely, acute and chronic treatment with GS39783, a novel GABA(B) receptor positive modulator, decreased anxiety in the light-dark box and elevated zero maze tests for anxiety. On the other hand, GABA(B(1)) -/- mice had decreased immobility (antidepressant-like behavior) in the forced swim test (FST). These behavioral effects are unrelated to alterations in locomotor activity. In confirmation of the genetic data, acute and chronic treatment with CGP56433A, a selective GABA(B) receptor antagonist, also decreased immobility in the FST, whereas GS39783 did not alter this behavior. Taken together, these data suggest that positive modulation of the GABA(B) receptor may serve as a novel therapeutic strategy for the development of anxiolytics, whereas GABA(B) receptor antagonism may serve as a basis for the generation of novel antidepressants.
Mombereau
Cedric
C
Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
Kaupmann
Klemens
K
Froestl
Wolfgang
W
Sansig
Gilles
G
van der Putten
Herman
H
Cryan
John F
JF
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D001522:Behavior, Animal; D001565:Benzoates / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D058788:GABA-B Receptor Antagonists; D019417:Hindlimb Suspension; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010721:Phosphinic Acids / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D018080:Receptors, GABA-B / Q000235:genetics / Q000502:physiology*; D013550:Swimming
D000928:Antidepressive Agents; D001565:Benzoates; D003517:Cyclopentanes; D058788:GABA-B Receptor Antagonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D010721:Phosphinic Acids; D011743:Pyrimidines; D018080:Receptors, GABA-B; C105509:(3-(1-((3-(cyclohexylmethyl)hydroxyphosphinyl)-2-hydroxypropyl)amino)ethyl)benzoic acid