Supervisors: professor Eero Vasar, MD, dr. med. ja juhtivteadur Vallo Volke, MD, dr. med. (Füsioloogia instituut),
Opponent: Vootele Võikar, MD, PhD (Närviteaduste keskuse projektijuht, Helsingi Ülikool, Soome)
Neuronal cholecystokinin (CCK) is involved in neurobiology of several physiological and behavioural processes like regulation of feeding, anxiety, pain processing, perception, motivation, learning and memory. CCK closely interacts with various neuromediator systems in the brain and, therefore, the genetic invalidation of CCK type 2 receptors (CCK2R) could have versatile impact on the behaviour of mice. In order to extend our pool of knowledge about the role of CCK in the regulation of behaviour the following specific tasks were put forward in this study on CCK2R knockout mice: 1. To study the impact of CCKergic mechanisms on functional, neurochemical and molecular characteristics of brain dopaminergic neurons; 2. To describe whether invalidation of CCK2R in mice changes the activity of endopioid system and adaptive behaviour in mice; 3. To determine the functional role of eCBs in the development of amphetamine induced sensitization and possible involvement of CCK2R. Genetic deletion of CCK2R in mice increases the activity of the midbrain dopaminergic neurons. Although the concentration of DA and its metabolites in the brain tissue was not changed, the gene expression studies were in line with the pharmacological and behavioural experiments indicating enhanced activity of dopaminergic projections. The pharmacological testing demonstrated that lack of CCK2R leads to the functional augmentation of endopioid system and, therefore, changes the adaptation of mice in a novel environment. The CCK and eCBs play a role in the development of amphetamine induced sensitization and intact CCK2R are necessary for the mediation of eCBs effect on the development amphetamine-induced sensitization. The genetic invalidation of CCK2R demonstrates that CCK plays in the brain a distinct role in the regulation of behaviours; it includes the regulation of motor, emotional and motivational mechanisms. Therefore, this animal model has potential to be applied for the pre-clinical screening of drugs targeting psychopharmacology.