The Mechanisms of Plasticity in Mesolimbic DA Function Underlying Behavioural and Neurochemical Sensitisation

Background: Repeated psychostimulant exposure results in progressive and enduring behavioural sensitisation modelling increased drug craving observed in human psychostimulant abusers. Aims: This project aimed to evaluate mechanisms underlying sensitisation-related neuroadaptations during repeated nicotine or amphetamine administration, and to investigate whether behavioural sensitisation to each drug employed the same or different processes. Methods: Behavioural sensitisation during repeated daily nicotine (0.6 mg/kg) or amphetamine (1 mg/kg) administration was measured, compared to saline control (1 ml/kg). Male Lister-hooded rats received five daily injections of drug or saline and locomotor activity was recorded. Ten days later, rats were challenged with the same doses of drug/saline and their locomotor activity was measured. Using immunohistochemistry, we measure expression of immediate early genes (IEG), activity-regulated cytoskeleton-associated protein (Arc) and c-fos, and of Methy1-CpG-binding-protein 2 (MeCp2) and brain-derived neurotrophic factor (BDNF), in nucleus accumbens (NAc) sub-regions, and ventral tegmental area (VTA). Finally, effects of drug pre-treatment on dopamine receptor gene expression in NAc and VTA, and on dopamine release in NAc shell and core subregions were investigated. Results: Nicotine and amphetamine increased locomotor activity, during daily treatment and challenge ten days later. Behavioural sensitization, was accompanied by increased in Arc and MeCp2 expression in NAc, which differed between nicotine and amphetamine treatment, but no changes in either c-fos, or BDNF were observed. Although there was evidence of behavioural and immunohistochemistry cross-sensitisation from amphetamine to nicotine, no evidence for either behavioural or immunohistochemistry cross-sensitisation from nicotine to amphetamine was seen. Dopamine receptor gene expression increased in VTA after nicotine pre-treatment and NAc after amphetamine pre-treatment, but treatment history did not affect dopamine release in NAc shell or core. Conclusions: Behavioural sensitization was accompanied by increases in IEG, MeCp2, and dopamine receptors gene expression, which differed between nicotine and amphetamine suggesting that sensitisation to the two drugs occurs through separate mechanisms, perhaps involving increased neuronal plasticity within different sub-regions of NAc and VTA.