The finding that Benzodiazepines bind to the GABAa receptor raises a very interesting question: Why is that our brains have a naturally-occurring recognition site for these synthetic chemicals? This question led scientists to the conclusion that there had to be an endogenous neurochemical shaped like the benzodiazepines, which could bind to the same spot on the GABAa receptor. Such a compound was subsequently identified in the brains of rats and in the cerebral spinal fluid of humans. This chemical, a peptide named Diazepam Binding Inhibitor (DBI), was indeed, found to bind to the same site as the benzodiazepines, yet caused an effect that was opposite to these tranquilizers. Upon binding, DBI changes the conformation of the GABAa receptor such that the ability of GABA to bind to its receptor site is decreased. This leads to a decrease in the influx of chloride ions into the postsynaptic cell and, as a result, fewer inhibitory post-synaptic potentials. DBI is thus a negative modulator of the GABAa receptor.

In order to determine the behavioral effect of this endogenous peptide, neuroscientists worked on developing synthetic compounds which would bind to the same recognition site as DBI and which, like DBI, would act as negative modulators of the GABAa receptor. The production of these compounds, known as Inverse Agonists, have helped to confirm the role of DBI as an endogenous anxiogenic. When injected into human volunteers, one of these synthetic inverse agonists, FG7142, caused sweating, nausea, palpitations, tightness in the chest, restlessness, tremors, and feelings of worry and impending doom- all markers of increased anxiety. Some people are naturally more anxious than others. Such behavioral variation most likely results from individual differences in the steady state production of DBI, and thus the amount of this peptide normally found in the brain. The steady state production of DBI is thought to be a result of genetic background, as well as early conditioning experiences.

It has recently been discovered that certain steroids also have a binding site on the GABAa receptor. This binding site is again distinct -- it is not the place where GABA binds, nor is it the place where DBI and the benzodiazepines bind. The steroids that bind at these sites are unique in that they are synthesized from circulating cholesterol locally in the glial cells of the brain. In times of stress, cholesterol is converted to progesterone, which is then converted to allopregnanolone. Because of its direct effect on neurotransmission, allopregnanolone is called a neuroactive steroid. Like the benzodiazepines, this hormone acts as a positive modulator of the GABAa receptor, increasing the ability of GABA to bind to the receptor, and thus increasing the influx of chloride ions at the post-synaptic membrane. A second neuroactive steroid is a progesterone precursor known as pregnenolone. This neuroactive steroid differs from allopregnanolone in that it is a negative modulator of the GABAa receptor, thus producing the same effects as DBI.  For a list of some agonists/facilitators and antagonists of GABA, go to