Lactating rats exhibit stable individual differences in pup licking/grooming. We used in vivo voltammetry to monitor changes in extracellular dopamine (DA) in the nucleus accumbens (n. Acc) shell of lactating rats interacting with pups and found that (1) the DA signal increased significantly with pup licking/grooming; (2) the onset of such increases preceded pup licking/grooming; and (3)

While many experiment with drugs, relatively few individuals develop a true addiction. We hypothesized that, in rats, such individual differences in the actions of addictive drugs might be determined by postnatal rearing conditions. To test this idea, we investigated whether stimulant- and stress-induced activation of nucleus accumbens dopamine transmission and dopamine-dependent behaviours might differ among adults rats that had been either repeatedly subjected to prolonged maternal separation or a brief handling procedure or left undisturbed (non-handled) during the first 14 days of life. We found that, in comparison with their handled counterparts, maternally separated and non-handled animals are hyperactive when placed in a novel setting, display a dose-dependent higher sensitivity to cocaine-induced locomotor activity and respond to a mild stressor (tail-pinch) with significantly greater increases in nucleus accumbens dopamine levels. In addition, maternally separated animals were found to sensitize to the locomotor stimulant action of amphetamine when repeatedly stressed under conditions that failed to sensitize handled and non-handled animals. Finally, quantitative receptor autoradiography revealed a lower density of nucleus accumbens-core and striatal dopamine transporter sites in maternally separated animals. Interestingly, we also found greatly reduced D(3) dopamine receptor binding and mRNA levels in the nucleus accumbens-shell of handled animals. Together, these findings provide compelling evidence that disruptions in early postnatal rearing conditions can lead to profound and lasting changes in the responsiveness of mesocorticolimbic dopamine neurons to stress and psychostimulants, and suggest a neurobiological basis for individual differences in vulnerability to compulsive drug taking.

Parental care influences development across mammals. In humans such influences include effects on phenotypes, such as stress reactivity, which determine individual differences in the vulnerability for affective disorders. Thus, the adult offspring of rat mothers that show an increased frequency of pup licking/grooming (ie, high LG mothers) show increased hippocampal glucocorticoid receptor (GR) expression and more modest hypothalamic-pituitary-adrenal responses to stress compared with the offspring of low LG mothers. In humans, childhood maltreatment associates decreased hippocampal GR expression and increased stress responses in adulthood. We review the evidence suggesting that such effects are mediated by epigenetic mechanisms, including DNA methylation and hydroxymethylation across GR promoter regions. We also present new findings revealing associated histone post-translational modifications of a critical GR promoter in rat hippocampus. Taken together these existing evidences are consistent with the idea that parental influences establish stable phenotypic variation in the offspring through effects on intracellular signaling pathways that regulate the epigenetic state and function of specific regions of the genome.

Maternal care in the rat influences the development of cognitive function in the offspring through neural systems known to mediate activity-dependent synaptic plasticity. The offspring of mothers that exhibit increased levels of pup licking/grooming (high-LG mothers) show increased hippocampal N-methyl-D-aspartate (NMDA) subunit mRNA expression, enhanced synaptogenesis and improved hippocampal-dependent spatial learning in comparison with animals reared by low-LG mothers. The effects of reduced maternal care on cognitive function are reversed with peripubertal environmental enrichment; however, the neural mechanisms mediating this effect are not known. In these studies we exposed the offspring of high- and low-LG mothers to environmental enrichment from days 22 to 70 of life, and measured the expression of genes encoding for glutamate receptor subunits and synaptophysin expression as a measure of synaptic density. Environmental enrichment reversed the effects of maternal care on synaptic density and this effect was, in turn, associated with a reversal of the effect of maternal care on the NR2A and NR2B subunits of the NMDA receptor, as well as effects on (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. Finally, direct infusion of an NR2B-specific NMDA receptor antagonist into the hippocampus eliminated the effects of maternal care on spatial learning/memory in the Morris water maze. These findings suggest that: (1) the effects of maternal care are mediated by changes in NR2B gene expression; and (2) that environmental enrichment reverses the effects of reduced maternal care through the same genomic target, the NR2B gene, and possibly effects on other subunits of the NMDA and AMPA receptors.