Depression and the Glutamate/GABA-Glutamine Cycle.

Summary

Rodent models of psychological stress mirror many features of major depressive disorder, linking activation of the hypothalamic-pituitary axis to oxidative stress, neuroinflammation, dominance of cholinergic neurotransmission, increased REM sleep pressure, impaired glycolysis and brain glucose utilization, reduced energy production, and decreased glutamate/GABA-glutamine cycling. Rapidly acting antidepressants like scopolamine, ketamine, and ECT raise extracellular glutamate; scopolamine and ketamine increase glutamate/GABA-glutamine cycling in both men and rodents, providing short-term relief. Nightly use of gammahydroxybutyrate (GHB), a GABAB agonist, may achieve more permanent results and possibly prevent depression by inhibiting cholinergic neurotransmission, relieving REM sleep pressure, and generating NADPH and succinate to boost energy and glutamate synthesis.

Study at a glance

Abstract

Many features of major depressive disorder are mirrored in rodent models of psychological stress. These models have been used to examine the relationship between the activation of the hypothalamic- pituitary axis in response to stress, the development of oxidative stress and neuroinflammation, the dominance of cholinergic neurotransmission and the associated increase in REM sleep pressure. Rodent models have also provided valuable insights into the impairment of glycolysis and brain glucose utilization by the brain under stress, the resulting decrease in brain energy production and the reduction in glutamate/GABA-glutamine cycling. The rapidly acting antidepressants, scopolamine, ketamine and ECT, all raise extracellular glutamate and scopolamine and ketamine have specifically been shown to increase glutamate/GABA-glutamine cycling in men and rodents with corresponding short-term relief of depression. The nightly use of gammahydroxybutyrate (GHB) may achieve more permanent results and may even act prophylactically to prevent the development or recurrence of depression. GHB is a GABAB agonist and restores the normal balance between cholinergic and monoaminergic neurotransmission by inhibiting cholinergic neurotransmission. It relieves REM sleep pressure. GHB's metabolism generates NADPH, a key antioxidant cofactor. Its metabolism also generates succinate, the tricarboxylic acid cycle intermediate, to provide energy to the cell and to synthesize glutamate. In both animals and man, GHB increases the level of brain glutamate.