Supervisors: Prof. Jaanus Harro
Prof. Ivo Leito
Opponent: Prof. Artur Swiergiel
The present dissertation focuses on the neurochemical mechanisms associated with behaviour in depression-related states using different analytical methods and animal models of depression.
Inter-individual differences, that are probably caused by variations in the regulation of neurochemical pathways, exist between organisms, and are likely to be significant in the pathogenesis of affective disorders. Depression is a highly prevalent psychopathological condition. In order to investigate depression the tests based on exploratory behaviour of rats are mostly used. Exploratory behaviour is very much dependent on the function of the noradrenergic projections of the locus coeruleus. All rats with near complete denervation of these projections behave in the exploration box test like the spontaneous LE-phenotype that has been associated with less efficient dopaminergic neurotransmission. It appeared that extensive denervation of the noradrenergic projections from locus coeruleus indeed reduced the effect of cocaine-induced place preference and locomotor activation.
Early life experiences may also affect neurochemical mechanisms and thereby influence the behavioural pattern later in life. Thus, the effect of maternal separation (as the early life stress) on alcohol consumption was studied. It appeared that animals that experienced maternal separation had low serotonin levels in amygdala and responded with an increase in serotonin after ethanol intake, which is a key area in addiction processes.
Studies in the present dissertation indicate that rats with different exploratory phenotype differ, in addition to catecholaminergic mechanisms, also with regard to regulation of serotonergic and glutamatergic systems. Serotonergic neurotransmission in hippocampus and prefrontal cortex was found to be regionally differentially regulated in HE- and LE-rats. In prefrontal cortex, the LE-rats had higher extracellular serotonin levels induced by citalopram and higher levels of serotonin transporter binding. In dentate gyrus, contrary, the HE-rats had higher levels of extracellular serotonin. Additionally, HE-rats had increased levels of glutamate after blockade of glutamate transporter in striatum.
Predisposition to express positive affect at low levels had previously been linked to vulnerability to depression. We could confirm the higher sensitivity of the LC-rats that produce less 50-kHz vocalizations to chronic stress: they gained weight more slowly and had higher corticosterone levels measured from full blood after stress. LC-rats have also differences in serotonergic mechanisms after chronic stress was supported by the finding that stressed LC-rats had higher extracellular serotonin levels induced by citalopram in hippocampus, where serotonergic system has been known to mediate response to anxious stimuli. These findings support the notion that male rats with low 50-kHz USVs response to tickling, having lower positive emotionality, are behaviourally more vulnerable to stress.
Taken together, the consideration of these neurobiological differences between individuals could lead to novel approaches to more personalized medical treatment of depression-related states.
Keywords: depression, negative and positive affect, exploratory behaviour, noradrenaline, serotonin, glutamate, inter-individual differences, ultrasonic vocalization, stress, alcohol consumption.