Development of Anxiety-Like Behavior via Hippocampal IGF-2 Signaling in the Offspring of Parental Morphine Exposure: Effect of Enriched Environment

Abstract

Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxietylike behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

“…On the basis of deficits in hippocampal LTP, it is likely that opioid‐sired offspring would display deficits in hippocampal learning and memory. It is worth noting that to our knowledge only one study (Li et al ., ) assessed potential deficits in learning and memory in opioid‐sired offspring and found no difference using the Morris water maze. Importantly, the Morris water maze was assessed in Sprague Dawley rats, whereas the differences in hippocampal LTP were assessed in Wistar rats.…”

Exposure to opiates in female adolescents alters mu opiate receptor expression and increases the rewarding effects of morphine in future offspring

“…For example, adolescent cannabinoid exposure causes alterations in both opioid-induced CPP and heroin self-administration in future adult offspring; effects that occur despite a prolonged period of abstinence prior to conception (Byrnes et al, 2012; Szutorisz et al, 2014). Moreover, adolescent opioid exposure has been shown to have effects on anxiety-like behavior and hippocampal dendritic retraction, an effect that is mitigated by environmental enrichment of the offspring (Byrnes, 2005; Li et al, 2014). With growing rates of use and abuse in adolescent populations, it is critical to better understand the possible effects this use could have on future generations.…”

Epigenetic Risk Factors for Diseases: A Transgenerational Perspective

“…These effects need to be confi rmed and maternal effects need to be better controlled. Finally, 10 days of morphine exposure in male and female rats leads to strong anxiety behavior in the offspring that is transmitted through both the matriline and patriline (Li et al 2014 ). This effect is dependent on reduced IGF-2 signaling in the hippocampus and can be rescued by IGF-2 overexpression and by exposing the offspring to enriched environmental conditions after weaning.…”