The expected compensation of autoreceptor down-modulation to enhanced peri-raphe 5-HT is overwhelmed by the magnitude of agonism during “flooding” and putatively exceeds the capacity of the autoreceptor to sufficiently “down-modulate” (Blier et al., 1998) (Figure 3), a contention supported by 5-HT1A irreversible KO rodent studies described below (see Bipolar Versus Unipolar Depression: Data from Animal Models). The gene discussed is HTR1A; the disease is major depressive disorder.