Efekti anestezije indukovane propofolom na sinaptičku plastičnost, aktivnost dopaminskog sistema i ponašanje juvenilnih pacova
The effects of propofol induced anesthesia on synaptic plasticity, dopaminergic system activity and behaviour of juvenile rats
Doctoral thesis (Published version)
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Propofol is a commonly used anesthetic in modern medicine. Addictive potential of propofol is observed, as well as the impact on the memory process. However, both phenomena are still insufficiently explored. Bearing in mind that adolescence is a period of extreme sensitivity to addictive substances and intense maturation of the mnemonic potential, the aim of this study was to examine the effect of a single exposure to propofol anesthesia, which is a typical method of its clinical application, on dopaminergic signaling, synaptic and neuronal activity in different brain regions and behavior of juvenile/peripubertal rats, as a model system of human periadolescencent development. The effects were analyzed 4, 24 and 48 hours after the treatment, in male Wistar rats aged 35 days. The obtained findings for the first time showed that exposure to propofol anesthesia caused changes in the expression/phosphorylation of signal molecules that are already recognized as significant for the action of the addictive substances. Of all the analyzed dopaminoceptive brain regions (medial prefrontal cortex, striatum and thalamus), significant changes in the expression of the phosphorylated/activated form of DARPP-32 protein, indicator of postsynaptic dopaminergic signalling, were observed only in the thalamus, 4 and 24 hours after the treatment, and were accompanied by increased expression of FosB/ΔFosB protein, a biochemical indicator of neuronal activity. The alterations were localized in the paraventricular thalamic nucleus and the mid-dorsal thalamus. An increase in the expression of the phosphorylated form of CaMKIIα, a biochemical sensor of synaptic activity that has an important role in memory on addictive substances exposure, was detected in striatum and medial prefrontal cortex. Reduction in the intensity of anxiety (estimated in accordence to the data obtained in the light/dark box and elevated plus maze tests) was observed 24 hours after the treatment, along with the decrease in the expression of FosB protein in striatum, which can be interpreted as a sensation seeking due to decreased activity of brain region important for a pleasure/motivation. An enhanced motor response to d-amphetamine and phencyclidine was observed 24 hours after the treatment (cross sensitization), as confirmation that despite the different primary mechanisms of action, propofol and these two drugs use the same neuronal pathways to achieve psychomotor effects. The results of the study also indicated that in peripubertal rats exposed to propofol anesthesia, there were some difficulties in memory retrieval and acquisition of new learning in non-aversive memory tests (spatial habituation, novel object recognition), 24 hours after the treatment. These effects were accompanied by changes in the expression of molecules involved in retrieval and reconsolidation of episodic memory (BDNF/TrkB, Egr-1, ERK1/2, CaMKIIα, FosB/ΔFosB) in the dorsal hippocampus. Detected difficulties in recognizing the novelty are consistent with a few clinical studies that emphasize the importance of controlling basic cognitive functions in older children after exposure to propofol anesthesia. Also, in all investigated brain regions, except the thalamus, an increase in the expression of the phosphorylated form of Adducinβ protein was observed, which is an indication of the cytoskelet destabilization and synaptic reorganization. Overall, the results of this study accentuated that a better understanding of the biological consequences of the use of propofol in juvenile/puberty period could contribute to the undestanding of age-dependent health risks of the treatment, which have been extensively investigated so far only at the extremes of age, i.e. during early postnatal period and in aging.