Effects of GABA Modulator AZD7325 on Cortical Excitability
Status:
Completed
Trial end date:
2015-08-01
Target enrollment:
Participant gender:
Summary
GABA (gamma-aminobutyric acid) is the main inhibitory compound in the human brain. Drugs that
enhance its effects by binding on GABA receptors (e.g., benzodiazepines) are used to treat
various diseases such as epilepsy, insomnia, anxiety or movement disorders. However, the use
of these medications is often compromised due to their side effects, like sedation, cognitive
impairment, and addiction.
Many of these side effects have been linked to a particular type of GABA receptor (GABA A
alpha 1). Therefore, effort is being made to develop drugs that do not act on this receptor,
but maintain their beneficial properties by acting on other types of GABA receptors. AZD7325
is a drug that selectively acts on GABA A alpha 2 and A alpha 3 receptors, but not A alpha 1.
It has been tested in more than 700 people and so far proved to be generally well tolerated.
Positron emission tomography (PET) study in humans demonstrated that AZD7325 binds to GABA A
receptors in the brain after a single dose. Early clinical studies have shown that it has
less sedative and cognitive adverse events as compared with a benzodiazepine lorazepam.
In this study, we will investigate its effects on short interval intracortical inhibition
(SICI). SICI is neurophysiological marker of inhibitory processes in the motor cortex. It is
obtained non-invasively by using transcranial magnetic stimulation (TMS). In TMS, magnetic
impulses applied over the scalp that in turn induce a current in a small area of the brain.
If applied over the motor areas of the brain, impulses result in muscle twitch that is
recorded with surface electrodes. SICI is enhanced by certain drugs like benzodiazepines that
act on GABA A alpha 1,2,3, and 5 receptor subtypes, but not by zolpidem acting solely on
alpha 1 subtype. Because GABA A alpha 5 receptor subtype is less common in the cortex, it has
been concluded that the drug effects on SICI are related to GABA A alpha 2 and alpha 3
receptors.
If AZD7325 proves to enhance SICI in healthy volunteers, this would create the grounds for
the use of this medication to treat certain neurological disorders in which SICI has been
found to be impaired (e.g., dystonia).