Effects of delta-9-tetrahydrocannabinol administration on the functionality of schedule-induced behaviour and time estimation

Abstract

Cannabis is a highly popular recreational drug globally. Its main psychoactive compound, ∆-9-Tetrahydrocannabino (THC), can impair learning and memory, especially with prolonged usage. Nonetheless, there is growing interest in its potential clinical applications. Schedule-indiced drinking (SID) is an experimental procedure that induces persistent and excessive water consumption in animals through intermittent reinforcement, making it a valuable animal model for studying behaviours within the compulsive spectrum. Moreover, the distinctive temporal pattern of behaviour observed in animals during SIF suggest they can discriminate time based on reinforcer delivery. These features make the SID procedure useful for studying the therapeutic effects of THC in compulsive behaviour, as well as its impact on temporal patterns. Therefore, the main aims addressed in this thesis were: i) investigate the effects of chronic and acute administration of THC on the acquisition, maintenance, and temporal adjusment of SID in adult and adolescent rats (chapter 3 and 4), ii) explore the effects of the repeated administration of THC on previously established SID (chapter 5), and iii) assess more specifically the effects of chronic and acute administration of THC on time estimation, using two widely-used tasks in the study of time estimation: the peak procedure and peak procedure with gaps (chapter 6). The results of the experiment presented in chapters 3 and 4 showed that chronic THC administration delayed the adquisition of SID in animals treated in adulthood but not in those treated in adolescence and evaluated later in adulthood. Acute THC administration increased variability in SID performance, particularly at doses of 5 and 10 mg/kg in all animals. Sensitization effects were observed when animals were re-exposed to acute THC after a certain time without drug exposure in rats previously treated in adulthood. The experiment presented in chapter 5, which investigated the potential therapeutic effects of THC on previously established SID, showed that repeated administration of THC may not be an effective pharmacological treatment to reduce complusive-like behaviour as a result of the SID procedure, and may even increase it. The capacity of THC to alter the temporal distribution of SID was more pronounced under acute administration and the experiments consistently showed a rightward shift of the licking peak, indicating a slower timing in animals due to THC. Regarding the study discussed in chapter 6, which examined the chronic and acute effects of THC on time estimation using the peak procedure, showed that prolonged chronic THC administration did not result in long-lasting effects on time estimation. However, acute THC administration resulted in an overstimation of time intervals only in animals without previous drug experience, suggesting the presence of tolerance effects that did not alter timing in animals that had previously experienced chronic admnistration of THC. This PhD thesis is the first to investigate the long-term effects of chronic THC administration on SID and time estimation in animals. The results indicate that THC has diverse effects on both SID and time estimation depending on the mode of administration and previous drug experience. These findings have important implications for four understanding of the potential therapeutic and harmful effects of THC on learning, compulsive behaviour, and temporal processing. Further research in this area is needed to fully understand the effects of THC on these processes and to identify potential therapeutic applications of the drug.