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
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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