Neurobiological mechanisms underlying individual differences in responses to addictive drugs in rats: with special focus on dopamine.

Abstract

This thesis addresses the intriguing question why some individuals easily become addicted to drugs, while others do not. A key player in this phenomenon is the neurotransmitter dopamine. Several studies have indicated that there are differences in the dopaminergic system of rats that are more or less prone to addiction. In this thesis we describe neurobiological differences in the dopaminergic system of the so-called apomorphine-susceptibe (APO-SUS) and unsusceptible (APO-UNSUS) rats. These rats have a different vulnerability to the dopamine D2 agonist apomorphine and show behavioural, physiological, endocrinological and genetical differences. Most importantly, they show a difference in drug self-administration (alcohol, cocaine) and drug sensitivity. The aim of this thesis was to investigate the neurobiological differences between these two rat lines that might underlie their difference in drug sensitivity. Thus, two types of research were conducted. First, the dopaminergic system was investigated using in vivo microdialysis, measuring extracellular levels of dopamine, and in vitro immunocytochemistry for the enzyme tyrosine hydroxylase (TH), which is the rate-limiting enzyme in dopamine synthesis. Second, the response of the dopaminergic system to in vivo administration of amphetamine and cocaine was investigated with prepulse inhibition as read-out parameter. The main finding of these studies was that there are pronounced differences in the basic structure of the dopaminergic system between APO-SUS and APO-UNSUS rats. In addition, the response of their dopaminergic system to environmental and drug challenges was different. Finally, the underlying cellular mechanism that mediates the response to amphetamine was also different between the rat lines. In conclusion, individuals that have a different drug sensitivity have a different make-up of the dopaminergic system and this system also responds differently to environmental and drug challenges. Thus, addiction has a clear neurobiological basis that awaits further investigation in order to understand the mechanisms underlying individual differences in drug sensitivity.