Toward the Rapid Treatment of Depression by Selective Inhibition of Central Stress Circuits

Abstract

Abstract:A long standing problem with antidepressant drugs is their delayed onsets of action which has made them unsatisfactory in the rapid treatment of serious depressions involving agitated and suicidal behavior. Two new approaches to this problem involve the glutamatergic antagonist, ketamine, recently reviewed, and the acute inhibition of central stress circuits, which is the subject of the present review. The rationale behind stress-circuit inhibition comes from the findings that both clinical and experimental depressions are accompanied by increased neural activity in the stress network together with inhibited activity in regions underlying active motivated behaviors, and that both changes are reversed by effective antidepressant treatment. It has been shown further that direct pharmacological inhibition of central noradrenergic stress nuclei produces immediate reversal of depressive-like passive as well as sickness behaviors. Dipivalyl-6-fluoronorepinephrine (dp6FNE), a brain-permeable pro-drug of 6FNE, a full agonist at inhibitory brainadrenoceptors in brainstem noradrenergic stress nuclei, has been developed and found in preliminary studies to cause rapid reversal of both passivity and anhedonia as well as anxiolysis without significant hypoactivity in the open field. Low doses of agonists of glucocorticoid and 5HT1A autoreceptors, which respectively inhibit the hypothalamic-pituitaryadrenal axis and serotonergic stress systems, may also share these effects as well as potentiate the actions of dp6FNE. Anti-stress effects may also be involved in the rapid therapeutic effects found with intracerebral administration of first generation antidepressants and may prove helpful in potentiating the therapeutic actions of stimulants.

PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress

“…Psychogenic stressors such as social defeat result in adrenocortical and adrenomedullary hormone secretion that are controlled by complex central circuitry in stress-sensitive regions of the limbic forebrain, hypothalamus, and brainstem, and the responses are transmitted through limbic stress pathways (Herman et al, 2003; Stone et al, 2006a,b, 2008a,b, 2012). The mPFC connects with other limbic cortical and brainstem areas associated with stress neuro-circuitry and plays a major role in the inhibition of HPA responses following emotional stressors.…”