This study aims to investigate the molecular mechanisms of acupuncture in the remission of depression. A depressive disorder model was induced by exposing Sprague-Dawley rats to chronic unpredictable stress. The rats were divided into five groups: healthy (blank group) and stressed rats (model group), and stressed rats treated with acupuncture (acupuncture group), riluzole (riluzole group), acupuncture combined with botulinum toxin A (BTX-A) injection (acupuncture + BTX-A group) or riluzole combined with BTX-A injection (riluzole + BTX-A group). Behavioral analysis showed significant differences in sucrose consumption, weight, and horizontal or vertical movements between the model and both the riluzole and acupuncture groups. No obvious differences between the riluzole + BTX-A and acupuncture + BTX-A groups were found. Moreover, no significance differences in glutamate content in the hippocampus were found among the riluzole + BTXA, acupuncture + BTX-A and model groups (p > 0.05). Western blots and reverse transcription polymerase chain reactions were employed to detect protein and mRNA expressions of VGLUT2, SNAP25, VAMP1, VAMP2, VAMP7, and syntaxin1; no obvious differences among the riluzole + BTX-A, acupuncture + BTX-A and model groups were found. These data suggest that soluble N-ethylmaleimide-sensitive factor attachment receptor proteins are involved in the remission of depression in rats treated with acupuncture.