Mu-opioid receptor agonism differentially alters social behaviour and immediate early gene expression in male adolescent rats prenatally exposed to valproic acid versus controls

Mu-opioid receptors (MOPs) mediate and modulate social reward and social interaction. However, few studies have examined the functionality of this system in rodent models of social impairment. Deficits in social motivation and cognition are observed in rodents following pre-natal exposure to the anti-epileptic valproic acid (VPA), however it is not known whether MOP functionality is altered in these animals. The present study examined the effects of acute administration of the prototypical MOP agonist morphine (1 mg/kg) on social behavioural responding in the 3-chamber test and immediate early gene expression in adolescent rats (postnatal day 28-43) prenatally exposed to VPA vs saline-exposed controls. Pharmacokinetic analysis of morphine concentration, MOP binding and expression were also examined. The data revealed that sociability and social novelty preference in the 3-chamber test were reduced in rats prenatally exposed to VPA compared to salineexposed control counterparts. Morphine reduced both sociability and social novelty preference behaviour in saline-, but not VPA-, exposed rats. Analysis of immediate early gene expression revealed that morphine reduced the expression of cfos in the prefrontal cortex of both saline- and VPA-exposed rats and reduced expression of cfos and junb in the hippocampus of VPA-exposed rats only. Pharmacokinetic analysis revealed similar concentrations of morphine in the plasma and brain of both saline- and VPA-exposed rats and similar thalamic MOP occupancy levels. Gene and protein expression of MOP in prefrontal cortex and hippocampus did not differ between saline and VPA-exposed rats. These data indicate differential effects of morphine on social responding and immediate early gene expression in the hippocampus of VPA-exposed rats compared with saline-exposed controls. This study provides support for altered MOP functionality in rats prenatally exposed to VPA, which may underlie the social deficits observed in the model.