Depression and the Glutamate/GABA-Glutamine Cycle

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 hypo- thalamic-pituitary axis in response to stress, the development of oxidative stress and neuroinflamma- tion, the dominance of cholinergic neurotransmission and the associated increase in REM sleep pres- sure. 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 de- pression. GHB is a GABAB agonist and restores the normal balance between cholinergic and mono- aminergic neurotransmission by inhibiting cholinergic neurotransmission. It relieves REM sleep pres- sure. 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 glu- tamate. In both animals and man, GHB increases the level of brain glutamate.