Individual differences in motivational imparment following nerve injury and their relationships to neurochemical changes in the Nucleus Accumbens of the rat

Abstract

A loss of motivation for, and enjoyment of previously pleasurable activities characterises some, but not all, chronic neuropathic pain patients who seek treatment. Pleasure & motivation are primary components of reward, and the nucleus accumbens (NAcc) is a pivotal brain region involved in reward processing. The neurotransmitters dopamine, glutamate, orexin and endogenous opioids each play important roles in reward processing and are each found within the NAcc. Thus, it was hypothesised that the diminished pleasure & motivation of neuropathic pain patients may reflect neural adaptations of these pathways in the NAcc. In chapter 3, a modified sucrose preference test was developed to measure individual differences in motivation towards a naturally rewarding sucrose solution in rats. It was observed that some rats consumed more sucrose than others. Following chronic constriction injury (CCI) of the sciatic nerve, changes from baseline sucrose consumption identified a subpopulation of behaviourally affected rats that had reduced sucrose drinking. It is reported in this thesis that high sucrose consumers were more likely to become affected rats after nerve-injury than low sucrose consumers. Following sucrose testing, the NAcc was removed post-mortem from all rats and real-time RT-PCR and western blotting, or immunohistochemical procedures were used to measure RNA and protein abundance and localisation. It was hypothesised that the varying motivational drives for sucrose would be reflected in NAcc neurochemistry. Chapter 4 describes investigations of the expression, abundance and distribution of dopamine D1 receptor, dopamine D2 receptor, µ-opioid receptor, tyrosine hydroxylase, vesicular glutamate transporter 3 (VGLUT3) and orexin in the NAcc of sucrose-drinking, uninjured rats compared to water-only drinking controls. Specific, lateralised changes in the neurochemistry of NAcc of sucrose drinking rats, particularly in the NAcc medial shell subregion, are reported. The effects of CCI on sucrose drinking and NAcc adaptations are reported in chapter 5. Again, lateralised changes in the expression and distribution of neurochemical components of reward processing were identified in specific NAcc subregions – in particular along the rostrocaudal axis of the NAcc medial shell. After nerve injury, high and low sucrose consumers could be characterised by significant correlations with the expression of dopamine D2 receptor, µ-opioid receptor and VGLUT3 at specific rostral and caudal levels of the NAcc shell that corresponded to the “hedonic hotspot” and “hedonic coldspot” respectively. Collectively, these changes contribute to understanding the diminished pleasure & motivation of some chronic neuropathic pain patients. The NAcc medial shell has emerged as a critical region that encodes the individual differences in reward and pain experience. A vast array of neurochemical adaptations in the NAcc following long-term sucrose drinking and nerve-injury suggests that a rostrocaudal functional gradient through the NAcc shell contributes to motivational behaviours and may underpin individual differences in the response to neuropathic pain. The observation that high sucrose consumers are most vulnerable to nerve injury may have important, as yet unappreciated, clinical significance.