Pharmacokinetic, behavioral, and brain activity effects of Δ9-tetrahydrocannabinol in adolescent male and female rats
Autor: | Erik Castillo, Jenny Cevallos, Vivek Swarup, Alexa Torrens, Marilyn A. Huestis, Victoria C. Inshishian, Stephen V. Mahler, Christina R Perrone, Drew N Justeson, Christina M. Ruiz, Daniele Piomelli, Eden V Harder |
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Rok vydání: | 2020 |
Předmět: |
Male
Drug Pediatric Research Initiative Brain activity and meditation media_common.quotation_subject Physiology Basic Behavioral and Social Science Medical and Health Sciences Substance Misuse 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Behavioral and Social Science mental disorders medicine Animals 2.2 Factors relating to the physical environment Distribution (pharmacology) Dronabinol Aetiology Retrospective Studies media_common Pediatric Psychiatry Pharmacology biology business.industry organic chemicals Functional connectivity Psychology and Cognitive Sciences Neurosciences Brain Long-Evans biology.organism_classification Rats 030227 psychiatry Psychiatry and Mental health Mental Health Good Health and Well Being Hallucinogens Anxiety Female Cannabis medicine.symptom Δ9-tetrahydrocannabinol Drug Abuse (NIDA only) business 030217 neurology & neurosurgery |
Zdroj: | Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, vol 46, iss 5 |
ISSN: | 1740-634X 0893-133X |
Popis: | Δ9-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. |
Databáze: | OpenAIRE |
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