Suboptimal maternal diets alter mu opioid receptor and dopamine type 1 receptor binding but exert no effect on dopamine transporters in the offspring brain.

Birthweight is a marker for suboptimal fetal growth and development in utero. Offspring can be born large for gestational age (LGA), which is linked to maternal obesity or excessive gestational weight gain, as well as small for gestational age (SGA), arising from nutrient or calorie deficiency, placental dysfunction, or other maternal conditions (hypertension, infection). In humans, LGA and SGA babies are at an increased risk for certain neurodevelopmental disorders, including Attention Deficit/Hyperactivity Disorder, schizophrenia, and social and mood disorders. Using mouse models of LGA (maternal high fat (HF) diet) and SGA (maternal low protein (LP) diet) offspring, our lab has previously shown that these offspring display alterations in the expression of mesocorticolimbic genes that regulate dopamine and opioid function, thus indicating that these brain regions and neurotransmitter systems are vulnerable to gestational insults. Interestingly, these two maternal diets affected dopamine and opioid systems in somewhat opposing directions (e.g., LP offspring are generally hyperdopaminergic with reduced opioid expression, and the reverse is found for the HF offspring). These data largely involved evaluation at the transcriptional level, so the present experiment was designed to extend these analyses through an assessment of receptor binding. In this study, control, SGA and LGA offspring were generated from dams fed control, low protein or high fat diet, respectively, throughout pregnancy and lactation. At weaning, mice were placed on the control diet and sacrificed at 12 weeks of age. In vitro autoradiography was used to measure mu-opioid receptor (MOR), dopamine type 1 receptor (D1R), and dopamine transporter (DAT) binding level in mesolimbic brain regions. Results showed that the LP offspring (males and females) had significantly higher MOR and D1R binding than the control animals in the regions associated with reward. In HF offspring there were no differences in MOR binding, and limited increases in D1R binding, seen only in females in the nucleus accumbens core and the dorsomedial caudate/putamen. DAT binding revealed no differences in either models. In conclusion, LP but not HF offspring show significantly elevated MOR and D1R binding in the brain thus affecting DA and opioid signaling. These findings advance the current understanding of how suboptimal gestational diets can adversely impact neurodevelopment and increase the risk for disorders such as ADHD, obesity and addiction.

Knockout of p11 attenuates the acquisition and reinstatement of cocaine conditioned place preference in male but not in female mice.

Cocaine's enhancement of dopamine signaling is crucial for its rewarding effects but its serotonergic effects are also relevant. Here we examined the role of the protein p11, which recruits serotonin 5HT1B and 5HT4 receptors to the cell surface, in cocaine reward. For this purpose we tested wild-type (WT) and p11 knockout (KO) male and female mice for cocaine conditioned place preference (CPP) and its cocaine-induced reinstatement at different abstinence times, after 8 days of extinction and 28 days of being home-caged. All mice showed significant cocaine CPP. Among males, p11KO showed lower CPP than WT; this difference was also evident after 28 days of home-cage abstinence. In contrast, in females there were no CPP differences between p11KO and WT mice at any time point tested. Cocaine priming after the 28-day home-cage abstinence period also resulted in lower cocaine conditioned motor activity in both male and female p11KO mice. These results suggest that cocaine CPP and its persistence during extinction and reinstatement are modulated in a sex-differentiated manner by p11. The lack of protein p11 confers protection from CPP on male, but not female mice, immediately after cocaine conditioning as well as after prolonged abstinence, but not after short-term withdrawal. Synapse 70:293-301, 2016. © 2016 Wiley Periodicals, Inc.