Campion, MichelleMichelleCampion2022-06-302022-06-302022 the A2022http://hdl.handle.net/10197/12939In Chapter 1, we treated primary embryonic hippocampal neurons with acute cocaine exposure and subsequent psychedelic or CBD treatment. For this study we used the psychedelics 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), lysergic acid diethylamide (LSD), psilocybin, 2,5-dimethoxy-4-iodoamphetamine (DOI) and the cannabinoid cannabidiol (CBD). We examined the expression of a transcription factor associated with driving cocaine addiction gene expression, known as FosB proto-oncogene, AP-1 transcription factor subunit (FosB) and an epigenetic marker associated with inhibiting cocaine addiction gene expression, known as histone deacetylase 5 (HDAC5). In the presence of cocaine FosB accumulates in the nucleus of neuronal cells. We found that cocaine induced nuclear accumulation of FosB was reduced by 5-MeO-DMT and psilocybin. We then investigated the role of 5-MeO-DMT, LSD, psilocybin, DOI and CBD in treating chronic cocaine addiction in vivo. We used a rat model of cocaine addiction where cocaine was administered by intraperitoneal (i.p.) injection daily over a two-week period followed by a single administration of 5-MeO-DMT, LSD, psilocybin, DOI or CBD. We discovered molecular markers associated with repeated cocaine exposures. We demonstrated the reversal of a significant array of these molecular adaptations associated with repeated cocaine exposure and subsequent 5-MeO-DMT, LSD, psilocybin, DOI or CBD treatment. In vivo we have shown that 5-MeO-DMT, LSD, psilocybin, DOI and CBD are capable of reversing cocaine addiction associated gene and protein expression change in the hippocampus and nucleus accumbens (NAc) of rats. In Chapter 2, we used a rat model of environmental stress known as isolation rearing (IR), we raised rodent pups in isolation from post-natal day 25 (P25) to post-natal day 80 (P80) followed by a single administration of 5-MeO-DMT and assessed proteins associated with environmental stress and behaviours associated with anxiety, cognitive deficits, and sensorimotor gating deficits. We conducted an extensive battery of behavioural assessments including the open field test (OFT), novel object recognition (NOR) and prepulse inhibition (PPI) of startle response. Our molecular readout demonstrated that 5-MeO-DMT can reverse environmental stress induced protein change in the hippocampus and PFC of isolated rats. We found that isolation induced anxiety and cognitive deficit behaviours in animals. Isolated animals administered 5-MeO-DMT did not improve symptoms, but notably, did not worsen symptoms either. Overall, we have shown that 5-MeO-DMT, LSD, psilocybin, DOI and CBD can effectively reverse cocaine addiction molecular alterations in the hippocampus and NAc of animals and 5-MeO-DMT is capable of reversing environmental stress-associated protein alterations in hippocampus and prefrontal cortex (PFC) of animals. Our findings underpin the role of synaptic plasticity disruption in cocaine addiction and environmental stress and the ability of psychedelics to reverse these molecular alterations. We conducted a separate project in chapter 3, where we examined the role of interleukin-4 (IL-4) and interleukin-13 (IL-13) in acute itch (pruritus) in mice. After injection of IL-4, IL-13 alone or in combination there was a significant increase of scratching bouts compared to vehicle. The combination treatment produced acute pruritus at an earlier time point than the two treatments administered alone. Together, our results suggest that IL-4 and IL-13 produce a clear, acute pruritic effect immediately after i.d. injection and are involved in acute pruritus in vivo. This finding expands our understanding of cytokines as pruritogens, how targeted anti-cytokine medications act in AD, and about neuroimmune communication in the skin.en5MEODMTPsychedelicsCocaine addictionIsolation rearingDoctoral Thesis2022-06-04https://creativecommons.org/licenses/by-nc-nd/3.0/ie/