|Baclofen: GABA(B) receptor supersensitivityand normalization of behavioral abnormalities by various GABA(B) agonists including baclofen in FMRP deficient mice
by Miklos Toth, 10/1/2006
The absence of FMRP in fragile X syndrome, besides cognitive abnormalities, is associated with hyperactivity and heightened sensory sensitivity. The hyperactivity is similar to the behavioral abnormality seen in attention deficit disorders. The sensory hyper-reactivity is manifested as anxiety and sensory defensiveness to visual, tactile and auditory stimuli. Abnormal auditory processing in fragile X can underlie inattention, poor listening skill and difficulty in speech-understanding.
Some of the symptoms of fragile X can be reproduced in the FMRP deficient mouse strain. Indeed, FMRP deficient mice have constitutive hyperactivity and sensory hyper-reactivity manifested as abnormal sound induced reflexes and even seizures.
The aim of our research is to identify drugs that can correct behavioral abnormalities in FMRP deficient mice. Since both the hyperactivity and the sensory hyper-reactivity could be due to increased neuronal excitability, we tested if augmenting inhibitory neurotransmission, mediated by gamma-aminobutyric acid (GABA), alleviates these behavioral abnormalities. We have found that administration of the GABA(B) receptor agonist baclofen normalizes the hyperactivity of FMRP deficient mice. Although its use in the treatment of fragile X syndrome would be a new application, baclofen (Lioresal®) has long been used in and approved for the treatment of reversible spasticity in multiple sclerosis and severe spasticity in patients with spinal cord injury. These applications demonstrated a good safety profile for baclofen.
Importantly, FMRP deficient mice are more sensitive than normal animals to baclofen, and that allows the use of an otherwise suboptimal or ineffective dose to normalize the hyperactivity. Nevertheless, tolerance develops against baclofen and therefore we are currently testing additional drugs and drug combinations that are expected to induce less or no tolerance to the drug(s). An additional benefit of these combinations is that they reduce anxiety, a frequent symptom in fragile X. Based on these data, targeting the GABA system/GABA(B) receptors could represent a novel therapeutic approach in the treatment of fragile X syndrome.