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Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.
Eur Neuropsychopharmacol 2017; 27(2):132-145EN

Abstract

The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive.

Authors+Show Affiliations

Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia.Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia.Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia.Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia.Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia; The Lambert Initiative of Cannabinoid Therapeutics, University of Sydney, Sydney, Australia.Brain and Mind Centre, University of Sydney, Sydney, Australia; Discipline of Pharmacology, School of Medical Science, University of Sydney, Sydney, Australia; The Lambert Initiative of Cannabinoid Therapeutics, University of Sydney, Sydney, Australia. Electronic address: jonathon.arnold@sydney.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28043732

Citation

Todd, Stephanie M., et al. "Interactions Between Cannabidiol and Δ9-THC Following Acute and Repeated Dosing: Rebound Hyperactivity, Sensorimotor Gating and Epigenetic and Neuroadaptive Changes in the Mesolimbic Pathway." European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology, vol. 27, no. 2, 2017, pp. 132-145.
Todd SM, Zhou C, Clarke DJ, et al. Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. Eur Neuropsychopharmacol. 2017;27(2):132-145.
Todd, S. M., Zhou, C., Clarke, D. J., Chohan, T. W., Bahceci, D., & Arnold, J. C. (2017). Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology, 27(2), pp. 132-145. doi:10.1016/j.euroneuro.2016.12.004.
Todd SM, et al. Interactions Between Cannabidiol and Δ9-THC Following Acute and Repeated Dosing: Rebound Hyperactivity, Sensorimotor Gating and Epigenetic and Neuroadaptive Changes in the Mesolimbic Pathway. Eur Neuropsychopharmacol. 2017;27(2):132-145. PubMed PMID: 28043732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interactions between cannabidiol and Δ9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway. AU - Todd,Stephanie M, AU - Zhou,Cilla, AU - Clarke,David J, AU - Chohan,Tariq W, AU - Bahceci,Dilara, AU - Arnold,Jonathon C, Y1 - 2016/12/31/ PY - 2016/05/19/received PY - 2016/12/07/revised PY - 2016/12/16/accepted PY - 2017/1/4/pubmed PY - 2018/1/16/medline PY - 2017/1/4/entrez KW - Behaviour KW - Cannabidiol KW - Epigenetic KW - Mesolimbic pathway KW - Neuroadaption KW - THC SP - 132 EP - 145 JF - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology JO - Eur Neuropsychopharmacol VL - 27 IS - 2 N2 - The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive. SN - 1873-7862 UR - https://www.unboundmedicine.com/medline/citation/28043732/Interactions_between_cannabidiol_and_Δ9_THC_following_acute_and_repeated_dosing:_Rebound_hyperactivity_sensorimotor_gating_and_epigenetic_and_neuroadaptive_changes_in_the_mesolimbic_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-977X(16)32012-0 DB - PRIME DP - Unbound Medicine ER -