Cannabinoid treatment during development and evaluation of behavioral and neurobiological indices in adulthood (Doctoral thesis)

Πούλια, Ναυσικά

The study of escalating low-dose Δ9-tetrahydrocannabinol (Δ9-THC) administration – the main psychoactive component of the plant cannabis - during adolescence focusing on behavioral, neurochemical and neurobiological indices of adult rats.Methodology: In the present study escalating low-dose adolescent Δ9-THC was used (between post-natal days 35-45) in male rats (0.3 mg/kg, 1 mg/kg, 3 mg/kg) in order to better simulate the human adolescent cannabis abuse and its effects on adulthood. Behavioral studies aimed to pattern an endophenotype providing information on spontaneous motor activity of adult rats, their habituation profile in the open field, their object location discrimination ability and the spatial memory and learning through the evaluation of the Morris Water Maze test, and their higher-order cognitive functions through the attentional set-shift test. In parallel, we assessed the filtering of the sensorimotor information through the pre-pulse inhibition test and the impact of acute d-amphetamine (1 mg/kg) hyperlocomotion on the motor response of adult rats. The neurochemical–neurobiological studies aimed to evaluate Δ9-THC effects concerning dopaminergic and serotonergic activity in specific brain regions (prefrontal cortex, hippocampus, dorsal striatum, nucleus accumbens) using High Performance Liquid Chromatography, while in the aforementioned regions DAT and SERT protein expression levels were measured. Further neurobiological evaluation aimed to study protein expression levels of specific markers and to correlate them with the observed behavioral and neurochemical changes (BDNF pathway and evaluation of cannabinoid receptors CB1 and CB2).Results: The escalating low-dose Δ9-ΤΗC treatment during adolescence induced major changes in behavioral parameters. In particular, our pharmacological model led to increased spontaneous horizontal and vertical activity and affected the pattern of behavioral habituation of adult rats in the open-field test. Moreover, escalating low-dose Δ9-ΤΗC treatment led to impairment in adult short-term spatial recognition memory and learning. On the contrary, our protocol did not affect either the execution of higher-order cognitive tasks or the filtering of sensorimotor gating during adulthood. Moreover, we observed a reduction in motor parameters of adult Δ9-ΤΗC-treated rats that received an acute dose of d-amphetamine. Regarding the neurochemical evaluation of dopaminergic and serotonergic activity in specific brain regions of adult rats, an opposing pattern of changes between the two neurotransmitter systems was found in adult rats treated with Δ9-THC. These changes were accompanied with increased protein expression levels of serotonin transporter in the hippocampus, while unaffected DAT protein expression levels were observed. Finally, we observed decreased expression levels of the neuroplasticity marker BDNF in the hippocampus as well as in the prefrontal cortex of Δ9-THC-treated rats in adulthood, while increased CB1 receptor levels were measured in the prefrontal cortex.Conclusions: Adolescent low-dose Δ9-THC treatment induced a «cognitive deranged» phenotype regarding alterations in specific indices that could be related to psychotic-like symptomatology.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Subject classification: Κάνναβη -- Θεραπευτική χρήση
Keywords: Δ9-τετραϋδροκανναβινόλη,Χαμηλές-κλιμακούμενες δόσεις,Εφηβεία,Ενηλικίωση,Κινητικότητα,Γνωστικές λειτουργίες,Αμφεταμίνη,Νευροχημεία,Νευροβιολογικοί δείκτες,Ιππόκαμπος,Προμετωπιαίος φλοιός,Ψυχωτικού τύπου συμπτωματολογία,Δ9-tetrahydrocannabinol,Εscalating low doses,Αdolescence,Αdulthood,Μotor response,Cognitive functions,Amphetamine,Neurochemistry,Neurobiological indices,Hippocampus,Prefrontal cortex,Psychotic-like symptomatology
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