Insensitivity to anorexigenic effects of naltrexone in the VPA rat model of autism

Abstract

Autism spectrum disorder (ASD) is a complex disorder whose etiology lies in, among others, abnormal neural processing, and improper neural circuitry development. This results in a plethora of aberrant behaviors, including those driven by the brain’s reward system and by the endogenous mediators of reward, for example opioids. One of the maladaptive consequences of pathophysiology of the reward system is excessive consumption of palatable foods in people with autism and in ASD model animals, such as valproic acid (VPA)-induced ASD rats. Here, I hypothesized that overconsumption of palatable diets in the VPA ASD rat is caused by abnormal functioning of the opioid circuitry. To investigate this, first I determined sensitivity of sucrose liquid-fed or high?fat high-sugar chow (HFHS)-fed VPA vs non-VPA control rats to the anorexigenic properties of the opioid receptor antagonist, naltrexone (NTX), a drug that reduces eating for palatability, but does not affect feeding for calories. In the follow up immunohistochemical study involving a marker of neuronal activity, c-Fos, I examined differences in brain activation after an injection of the same dose of NTX in VPAs vs non-VPA controls. As expected, NTX did not affect energy-driven consumption of bland chow in non-VPA controls or VPAs. NTX did, however, decrease intake of palatable sucrose water and HFHS chow. Importantly, while 1 mg/kg NTX was sufficient to reduce eating for palatability in non-VPA controls, a 10-mg NTX dose was needed to achieve the same effect in VPAs. c-Fos analysis in the non–VPA controls showed significant differences in neuronal activation in the paraventricular nucleus (PVN), supraoptic nucleus (SON), arcuate nucleus (ARC), Dorsomedial hypothalamus (DMH), central nucleus of the amygdala (CeA), and nucleus accumbens shell (NAc – shell). The VPA animals showed a difference only in the CeA. Collectively these data show different responsiveness to NTX at the behavioural (feeding) and brain activation iii (c-Fos) level, likely indicative of dysregulation of the opioid signaling and – more broadly – reward processing, in the autistic brain.