Activation of 5-HT4 receptors reverses stress-induced dopamine system dysregulation

Stress can profoundly impact brain function, particularly in circuits regulating dopamine transmission. Increased mesolimbic dopamine activity is a well-documented consequence of stress exposure, contributing to maladaptive behavioral and cognitive outcomes. Previous studies have identified a multisynaptic circuit that modulates dopamine neuron population activity in the ventral tegmental area (VTA), highlighting potential intervention points for mitigating stress-induced dopamine dysregulation. One such target is the 5-hydroxytryptamine-4 receptor (5-HT4R), which is expressed in key brain regions involved in dopamine system regulation, making it a promising candidate for pharmacological intervention. Here, we demonstrate that the 5-HT4R agonist BIMU8 effectively restores normal dopamine system function following stress exposure without altering baseline dopamine population activity in control male rats. Interestingly, in female rats, BIMU8 increased dopamine neuron population activity specifically during proestrus and estrus, suggesting that estrogen may play a role in serotoninergic modulation of mesolimbic dopamine function. Intracranial administration of BIMU8 into multiple brain regions indicates that its effects may be mediated through modulation of activity in the nucleus accumbens (NAc). These findings highlight 5-HT4R activation as a potential strategy for normalizing stress-induced alterations in dopamine system function.