Mesolimbic dopaminergic activity responding to acute stress is blunted in adolescent rats that experienced neonatal maternal separation.

Neonatal maternal separation (MS), stressful experience early in life, leads to the development of depression-like behaviors in the offspring later in life. This study was conducted to define the neural basis of depression-like behaviors observed in our MS model. Sprague-Dawley pups were separated from dam for 3 h daily during the first 2 weeks of birth (MS) or left undisturbed (NH). All pups were sacrificed on postnatal day 41 with/without 1 h of restraint stress. Restraint stress significantly increased c-Fos expression in the nucleus accumbens (NAcb) of NH pups, but not in MS. In NH pups, restraint stress increased dopamine levels not only in the NAcb but also in the midbrain dopamine neurons; however, these increases were not observed in MS. Gene expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was increased by acute restraint in NH pups, but not in MS pups. The raphe serotonin level was lower in MS than in NH, and not significantly changed by acute restraint neither in NH nor in MS. Results reveal that experience of neonatal MS may lead to a long-term suppression in the mesolimbic dopamine system of the offspring later in life, in which an epigenetic control may be implicated, such as suppressed gene expression of TH in the midbrain. We conclude that a decreased activity of the mesolimbic dopamine system may play a role in the pathophysiology of depression-like behaviors by neonatal MS, in addition to a decreased serotonin level in the raphe nucleus.