Figure 2.
Serotonergic neurotransmission under stress and/or hyperglutamatergic states. Glutamatergic excitatory input activates a small population of serotonin neurons in the posterior part of the dorsal raphe, which leads to accumulation of extracellular serotonin, spreading to the anterior regions of the dorsal raphe thereby suppressing serotonin outflow through activation of somatodendritic 5-HT1A autoreceptors. Stress induces glutamatergic neurotransmission directed into the dorsal raphe and stress therefore “floods” the dorsal raphe with serotonin, thus “choking” serotonin outflow. Activation of 5-HT2A receptors in the mPFC activates Layer V cortical neurons enhancing glutamatergic input into the dorsal raphe. High peri-raphe 5-HT has been putatively demonstrated by high cisternal CSF taps in adversely reared non-human primates where elevations of CSF 5-HIA have been noted in adversely reared subjects in comparison to normally reared controls. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part, by “flooding” 5-HT1A autoreceptors by serotonin itself. Factors, which may exacerbate this scenario, such as presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder, are generally associated with SSRI-treatment resistance. An excess of midbrain peri-raphe serotonin is associated with a subsequent deficit at important fronto-limbic projection sites, with a compromise in serotonin-mediated neuroplasticity.