Stress response and depression have a crucial impact on modern society. Although the symptoms are well characterized, the molecular mechanisms underlying depression are largely unknown. Currently, the monoaminergic systems, especially serotonergic systems, have received the most attention in the research of depression. Accumulating evidence suggests that the glutamatergic and GABAergic system play an important role in the neurobiology and treatment of this disease. Multiple studies have shown that serotonin (5-HT) could modulate the neurotransmission of glutamic acid (Glu) and gamma-aminobutyric acid (GABA). The orbitofrontal cortex (OFC), which is involved in the pathophysiology and treatment of depression, plays a critical role in the control of higher brain functions and it mainly receives a dense 5-HT innervation from the dorsal raphe nucleus. There exist some 5-HT1A receptors on glutamatergic neurons and GABAergic neurons in the OFC. The purpose of this research was to elucidate the modulatory action of 5-HT1A receptor on the functions of Glu and GABA, which are the principal neurotransmitters mediating excitatory and inhibitory signals in the OFC respectively, in a well-established animal model of depression induced by chronic unpredictable mild stress (CUMS).
We used CUMS in rat to mimic the core symptoms in human. Using the pharmacology approaches by microinjecting of 5-HT1A receptor agonist 8-OH-DPAT and its antagonist WAY100635 to the OFC, we detected behavioral changes by using behavior tests including sucrose preference test, open field test and tail suspension test. In addition, high-performance liquid chromatography (HPLC) was used to detect the level of neurotransmitters such as 5-HT, Glu and GABA in the OFC, respectively.
CUMS group showed a variety of behavioral characteristics of depression, including a significant reduction in the sucrose preference, and locomotion, rearing and grooming in the open field test, and a significant increase in immobility time in the tail suspension test compared with control group. In addition, CUMS group showed that a significant increase in the concentration of Glu, but no significant difference in the levels of 5-HT and GABA in the OFC. Depression-like behaviors of CUMS rats were obviously ameliorated after being treated with 8-OH-DPAT, while the concentration of Glu was decreased. Rats received WAY100635 in control group showed similar depression-like behaviors and similar increased Glu levels. However, 5-HT level and GABA concentration were not altered in both groups received 8-OH-DPAT or WAY100635.
These findings indicated that the mechanism through which CUMS could induce depression-like behaviors, probably is not due to the decrease of 5-HT level within the OFC, but because of excessive release of Glu that resulted from that 5-HT could not regulate glutamatergic neurons or the decrease of 5-HT1A receptor function on glutamatergic neurons within the OFC during stress. Our data suggested that 5-HT1A receptor in the OFC plays an important role in modulating the synthesis and release of Glu during CUMS. This study provided insights on modulation of glutamate transmission in depression.