Conceptual model.

<p>A schematic drawing of our conceptual model depicting interactions between dopamine and glutamate in the amygdala nuclei. The interactions between other brain areas studied and the amygdala conceptual model are also indicated. Dashed lines symbolize inhibition, while solid lines represent stimulation. Lines between brain areas represent functional connectivity between the regions. Fear stimuli are processed first by the basolateral amygdala (BLA), activating the glutamate system in this area, but do not affect dopamine levels in either the BLA or central amygdala (CEA). Output signals inducing freezing behavior from the CEA are therefore strong via the glutamate pathway. Ketamine decreases glutamate-related fear processing in the BLA and CEA and simultaneously elevates dopamine content (storage) in the CEA, by blocking dopamine release via the dopamine D₂ autoreceptor located on the cell body (possibly the VTA). The decreased dopamine release (together with the block of glutamate transmission from the BLA to the CEA) blocks the fear-related outputs by means of increased GABA inhibition via intercalated cells projecting onto the CEA. The net effect is weak output signals from the CEA and diminished freezing behavior. Clozapine, while blocking the effects of ketamine on glutamate-related processing in the BLA and CEA, does nothing to prevent changes in dopamine levels. GABA-ergic intercalated cells therefore continue to inhibit CEA and/or BLA and normal fear-conditioned behavior cannot be retained. Can chronic clozapine treatment renormalize dopamine levels and lead to long-term remediation of negative symptoms in the animal model? <i>ACC, anterior cingulate; DA, dopamine; LC, locus coeruleus; Nacc, nucleus accumbens; PVN, paraventricular nucleus; VTA, ventral tegmental area</i>