AUTHOR=Winsauer Peter J. , Filipeanu Catalin M. , Weed Peter F. , Sutton Jessie L. TITLE=Hormonal status and age differentially affect tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on learning in female rats JOURNAL=Frontiers in Pharmacology VOLUME=6 YEAR=2015 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2015.00133 DOI=10.3389/fphar.2015.00133 ISSN=1663-9812 ABSTRACT=

The effects of hormone status and age on the development of tolerance to Δ9-THC were assessed in sham-operated (intact) or ovariectomized (OVX) female rats that received either intraperitoneal saline or 5.6 mg/kg of Δ9-THC daily from postnatal day (PD) 75–180 (early adulthood onward) or PD 35–140 (adolescence onward). During this time, the four groups for each age (i.e., intact/saline, intact/THC, OVX/saline, and OVX/THC) were trained in a learning and performance procedure and dose-effect curves were established for Δ9-THC (0.56–56 mg/kg) and the cannabinoid type-1 receptor (CB1R) antagonist rimonabant (0.32–10 mg/kg). Despite the persistence of small rate-decreasing and error-increasing effects in intact and OVX females from both ages during chronic Δ9-THC, all of the Δ9-THC groups developed tolerance. However, the magnitude of tolerance, as well as the effect of hormone status, varied with the age at which chronic Δ9-THC was initiated. There was no evidence of dependence in any of the groups. Hippocampal protein expression of CB1R, AHA1 (a co-chaperone of CB1R) and HSP90β (a molecular chaperone modulated by AHA-1) was affected more by OVX than chronic Δ9-THC; striatal protein expression was not consistently affected by either manipulation. Hippocampal brain-derived neurotrophic factor expression varied with age, hormone status, and chronic treatment. Thus, hormonal status differentially affects the development of tolerance to the disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on learning and performance behavior in adolescent, but not adult, female rats. These factors and their interactions also differentially affect cannabinoid signaling proteins in the hippocampus and striatum, and ultimately, neural plasticity.