| Autor: |
Ruiz CM; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Torrens A; Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA., Castillo E; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Perrone CR; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA.; Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA., Cevallos J; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Inshishian VC; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA.; Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA., Harder EV; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Justeson DN; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Huestis MA; Institute of Emerging Health Professions, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Swarup V; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA., Piomelli D; Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.; Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu.; Department of Biological Chemistry, University of California, Irvine, CA, 92697, USA. piomelli@uci.edu., Mahler SV; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA. mahlers@uci.edu. |
| Abstrakt: |
Δ 9 -tetrahydrocannabinol (THC) is the intoxicating constituent of cannabis and is responsible for the drug's reinforcing effects. Retrospective human studies suggest that cannabis use during adolescence is linked to long-term negative psychological outcomes, but in such studies it is difficult to distinguish the effects of THC from those of coexisting factors. Therefore, translationally relevant animal models are required to properly investigate THC effects in adolescents. However, though the relevance of these studies depends upon human-relevant dosing, surprisingly little is known about THC pharmacology and its effects on behavior and brain activity in adolescent rodents-especially in females. Here, we conducted a systematic investigation of THC pharmacokinetics, metabolism and distribution in blood and brain, and of THC effects upon behavior and neural activity in adolescent Long Evans rats of both sexes. We administered THC during an early-middle adolescent window (postnatal days 27-45) in which the brain may be particularly sensitive to developmental perturbation by THC. We determined the pharmacokinetic profile of THC and its main first-pass metabolites (11-hydroxy-THC and 11-nor-9-carboxy-THC) in blood and brain following acute injection (0.5 or 5 mg/kg, intraperitoneal). We also evaluated THC effects on behavioral assays of anxiety, locomotion, and place conditioning, as well as c-Fos expression in 14 brain regions. Confirming previous work, we find marked sex differences in THC metabolism, including a female-specific elevation in the bioactive metabolite 11-hydroxy-THC. Furthermore, we find dose-dependent and sex-dependent effects on behavior, neural activity, and functional connectivity across multiple nodes of brain stress and reward networks. Our findings are relevant for interpreting results of rat adolescent THC exposure studies, and may lend new insights into how THC impacts the brain in a sex-dependent manner. |
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