Exposure to stress is a risk factor for the development of several psychiatric disorders, including posttraumatic stress disorder and depression. The results of stress exposure can be conceptualized as a shift in the set point from a positive emotional state to a negative emotional state. In adult rats, frequency-modulated 50-kHz ultrasonic vocalizations (USVs) have been shown to index positive emotional states whereas 22-kHz USVs reflect negative emotional states. A wide variety of stressors have been shown to reduce rates of hedonic 50-kHz USVs while simultaneously increasing rates of aversive 22-kHz USVs. Heterospecific rough-and-tumble play is hedonic in normal rats but aversive in stressed rats, indicating that stress shifts the set point for the induction of positive and negative emotional states. Importantly, a positive emotional state or antidepressant treatment can reverse stress effects on the emotional set point. At the physiological level, stress suppresses synaptic plasticity in the medial prefrontal cortex, a key structure for instigating the circuit for the hedonic 50-kHz USVs. These changes in plasticity could be reversed by antidepressant treatment or by a positive emotional state. At the biochemical level, hedonic rough-and-tumble play upregulates NMDA receptors as well as insulin-like growth factor-I signaling in the medial prefrontal cortex. Thus, stress shifts the threshold for the induction of a positive state and lowers the threshold for the negative emotional state, which is expressed as a suppression of synaptic plasticity in the medial prefrontal cortex positive emotional circuit. The facilitation of this form of plasticity via multiple independent mechanisms has therapeutic potential for the treatment of neuropsychiatric disorders associated with stress.