Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) in adult female rats

Pharmacol Biochem Behav. 2012 Sep;102(3):442-9. doi: 10.1016/j.pbb.2012.06.008. Epub 2012 Jun 15.


Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ⁹-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ⁹-THC, OVX/saline, and OVX/Δ⁹-THC). These groups were then trained to discriminate Δ⁹-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ⁹-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ⁹-THC lower than the training dose, and 3) the OVX/Δ⁹-THC group was significantly less sensitive to the rate-decreasing effects of Δ⁹-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ⁹-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ⁹-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ⁹-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Conditioning, Operant / drug effects
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Data Interpretation, Statistical
  • Discrimination Learning / drug effects
  • Discrimination, Psychological / drug effects*
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Gonadal Steroid Hormones / pharmacology*
  • Hallucinogens / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Ovariectomy
  • Ovary / physiology*
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Long-Evans
  • Receptor, Cannabinoid, CB1 / drug effects
  • Reinforcement Schedule


  • Cyclic AMP Response Element-Binding Protein
  • Gonadal Steroid Hormones
  • Hallucinogens
  • Receptor, Cannabinoid, CB1
  • Dronabinol
  • Extracellular Signal-Regulated MAP Kinases