The Deakin/Graeff hypothesis: Focus on serotonergic inhibition of panic

• DRVL/VLPAG serotoninergic neurons are part of a panic inhibition system.
• Chronic SSRIs potentiate 5-HT inhibition of DPAG-evoked panic (e.g., escape).
• These 5HT neurons are chemosensitive and respond to panicogenic agents (e.g., CO2).
• DRN serotonergic neurons express pH-sensitive ion channels (e.g., ASIC1a, TASK).
• Amygdalar CRH activates DRVL/VLPAG 5-HT neurons to promote freezing/inhibit escape.

The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including panic disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: (1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus’ (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; (2) chronic, but not acute, antidepressant treatment potentiates serotonin's panicolytic effect; (3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; (4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed.