In Chapter 1 we matched the core symptoms of anxiety disorders with the brain circuits that hypothetically mediate them, and illustrated how those circuits can become sensitized and increase risk for a psychiatric disorder such as PTSD. Chapter 3 reviews the major neurotransmitter systems that regulate functioning within those brain circuits, and that are therefore potential targets of pharmacologic action in the treatment of PTSD.

The clinical implications of the SERT variant/amygdala reactivity relationship are not yet known, however. A recent meta-analysis of SERT studies found no association between SERT variant and risk for depression, neither as a main effect nor as an interaction effect between genotype and stressful life events. Thus, although it has been posited that overactivation of circuits in s carriers may confer greater risk of developing a mood or anxiety disorder in the context of multiple life stressors, current evidence does not support this.

Serotonin can have its synaptic action terminated by the serotonin transporter, SERT, which transports serotonin molecules back into the presynaptic neuron for reuse (see Chapter 4 for agents acting at SERT). Serotonin can also be destroyed by monoamine oxidase (MAO) enzymes, which convert serotonin molecules into an inactive derivative (see Figure 5.7 for agents acting at MAO enzymes).

Norepinephrine can have its synaptic action terminated by the norepinephrine transporter (NET), which transports norepinephrine molecules back into the presynaptic neuron for reuse (see Chapter 4 for agents acting at NET). Norepinephrine can also be destroyed by MAO enzymes, which convert norepinephrine molecules into an inactive derivative (see Figure 5.7 for agents acting at MAO enzymes).

In addition to the GABA transporter, there are three major types of postsynaptic GABA receptors: GABA-A, GABA-B, and GABA-C. GABA-A and -C receptors are ligand-gated ion channels that form part of an inhibitory chloride channel, while GABA-B receptors are G protein-linked and can couple with calcium or potassium channels. GABA-A receptors are particularly relevant to anxiety and to the anxiolytic effects of benzodiazepines, and are discussed in more detail in Figure 5.10.

Unlike GABA, which has had a recognized role in anxiety and its treatment for some time, glutamate has only recently received focus in this area. Shown on the following pages are some of the potential targets for modulating the glutamatergic system. Investigational agents that act at these sites are discussed in Figure 5.35.