Alpha₁-adrenergic receptor blockade in the VTA modulates fear memories and stress responses

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha₁-adrenergic receptor (α₁-AR) signaling in the VTA affects conditioned fear. The role of α₁-AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α₁-AR blockade in the mammillary bodies (MB) - a brain region with α₁-AR expression adjacent to the VTA. Intra-VTA but not intra-MB α₁-AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α₁-AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α₁-AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α₁-AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α₁-AR signaling in the regulation of stress responsiveness and fear memory.