It has long been recognized that the amygdala is involved in the expression of fear in mammals, and that vasopressin and oxytocin can modulate this response. Huber and colleagues have now shown, for the first time, that two distinct neuronal populations in the amygdala are excited by either vasopressin or oxytocin, and that their interactions might represent a neurophysiological mechanism for regulation of the fear response.

The central amygdala (CeA) triggers autonomic fear expression by signalling to the brainstem and hypothalamus, and is known to express various neuropeptide receptors, including those for vasopressin and oxytocin. Vasopressin enhances aggression, anxiety and stress levels, and the consolidation of fear memory. Conversely, oxytocin decreases stress and anxiety, and facilitates maternal care and other social interactions. Both neuropeptides increase neuronal activity in the CeA, but, until now, their mechanism of action was unclear.

The authors first determined the positions of vasopressin and oxytocin receptors within previously defined regions of the CeA — vasopressin receptors in the medial part and oxytocin receptors in the lateral and capsular areas — using autoradiography of rat brain sections. Next, by applying different oxytocin and vasopressin receptor agonists, they discovered two types of responsive neuron: those excited by oxytocin-receptor activation, and those inhibited by oxytocin-receptor activation but excited by a specific vasopressin-receptor type, V1a.

Using sharp-electrode intracellular recordings, the authors determined the precise locations of these neurons in the CeA, and found that vasopressin-excited cells were restricted to the medial CeA whereas oxytocin-excited cells were found in the lateral CeA. This correlated with the autoradiographic map of the receptors. The inhibitory effects of oxytocin on vasopressin-excited cells were caused by the enhanced excitability of neurons in the lateral CeA areas, which led to an increase in GABA (γ-aminobutyric acid) release in the medial region of the CeA.

These findings show that, in the medial CeA, oxytocin and vasopressin modulate activity in opposite ways. Through the activation of distinct elements of this inhibitory network, the two neuropeptides can integrate the different signals entering the CeA into a single output to the autonomic nervous system, thereby regulating the expression of fear. The authors argue that the distribution of oxytocin and vasopressin receptors throughout the larger, extended amygdala indicates that this system might also be involved in the control of anxiety, stress, motivation and addiction in mammals. Furthermore, they suggest that these neuropeptide receptors could be future targets for the pharmacological treatment of stress and anxiety in humans.