Investigation of long-term behavioural, neurochemical and molecular changes in morphine preferring rats
Creators: name: Joshi, Dipesh
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Drug addiction is a chronic relapsing disorder and the study of chronic vulnerability to relapse remains a compelling challenge for the treatment of drug addiction. There is a growing emphasis on research that advances knowledge about predisposing factors for compulsive drug use and relapse taking into consideration the observation that not all individuals develop addiction when exposed to addictive drugs. The aim of the present work was to investigate the long-term adaptations (neurochemical and molecular) that result following development of morphine preference in rats. The project also included behavioural studies utilizing the open field test, the elevated plus maze and prepulse inhibition of the acoustic startle response to determine if a behavioural phenotype exists for rats showing morphine preference behaviour. A previously well-validated voluntary oral morphine self-administration animal model was used for all the studies presented. Following chronic compulsory morphine consumption and withdrawal, 17-35% of rats display preference to consume morphine in their drinking water sufficient to re-establish their dependence. The rats displaying preference to morphine were termed high morphine preferring (HMP) and those that chose not to consume morphine were termed low morphine preferring (LMP). Though no behavioural phenotypes could be identified from the behavioural tests performed, an interesting observation was made in that some HMP rats displayed a shift in morphine preference from being HMP to LMP when presented with a second choice phase following a prolonged drug free period (4 weeks). Such a change in preference was observed only in LMP rats. Subsequently, the effect of morphine preference on the relative expression of the phosphorylated form of cAMP response element binding protein (pCREB), opioid receptors (mu [MOR] and delta [DOR]), dopamine receptors (D2 and D3), the cannabinoid CB1 receptor, and the enzyme fatty acid amide hydrolase (FAAH) was investigated. Immunohistochemical results revealed a significant reduction in the long-term expression of MOR, DOR, D2, D3, CB1 receptors and FAAH in the reward related brain regions of HMP compared to LMP rats. In contrast, in HMP rats there was an increased pCREB expression in reward-related brain regions of compared to LMP rats. There was a significant effect of the length of the drug free period between the two choice phases on morphine preference and long-term neuroprotein expression. A shorter drug free period (1 week) between the two choice phases did not result in a shift in preference from HMP to LMP as observed following a 4 week drug free period. In HMP rats that had a shorter drug free period, there was a significant increase in the expression of neuroproteins examined (except CB1 receptors) in the reward-related brain regions. These changes were observed only in rats which voluntarily self-administered morphine. These results suggested that the changes in neuroprotein expression were related to morphine preference and not a consequence of high morphine intake over time. A microarray study identified several genes related to long-term synaptic plasticity which may impact morphine preference and/or vulnerability to drug abuse. In addition, genes related to the response to glucocorticoid stimulus and glucocorticoid-mediated signalling were identified which may have a crucial role in the development of morphine preference or vulnerability to opioid abuse. Taken together, these studies provide a useful insight into the relationship between morphine preference and subsequent neurochemical and molecular changes in reward related brain regions. The current work therefore provides a starting point for future studies to explore the role of genes related to the response to glucocorticoid stimulus and glucocorticoid-mediated signalling in the development of morphine preference and subsequent long term neuroadaptations.