GABAB receptor ligands do not modify conditioned fear responses in BALB/c mice

Fabian F. Sweeney, Olivia F. O’Leary, John F. Cryan

The GABA(B) receptor has been well characterised as a substrate of unconditioned anxiety behaviour. Indeed, the anxiolytic effects of positive modulators of the GABA(B) receptor have been demonstrated across a range of behavioural tests of innate anxiety, whereas GABA(B) receptor deficient mice have an elevated anxiety phenotype. However, the role of the GABA(B) receptor in regulating conditioned anxiety behaviour; an important facet of the preclinical study of anxiety disorders such as post-traumatic stress disorder is less well understood. In vitro data suggests that the GABA(B) receptor plays an important role in regulating the neural circuitry that underpins conditioned fear learning and extinction, but whether these effects translate into alterations in conditioned anxiety behaviour has not been widely investigated. This represents a crucial deficit in the preclinical characterisation of these drugs as putative anxiolytic agents. Using the highly anxious mouse strain, BALB/c, and an auditory fear conditioning protocol, we sought to characterise the GABA(B) receptor positive modulator GS39783 and GABA(B) receptor antagonist CGP52432, two compounds not previously evaluated for their effects on conditioned fear. Neither GS39783 nor CGP52432 altered freezing behaviour irrespective of whether drugs were administered before the acquisition, recall or extinction training sessions. These findings suggest limitations to the potential role of GABA(B) receptor active drugs as clinical agents in the treatment of anxiety.