Long-term behavioral and pharmacodynamic effects of delta-9-tetrahydrocannabinol in female rats depend on ovarian hormone status

Abstract

Abuse of Δ 9 -THC by females during adolescence may produce long-term deficits in complex behavioral processes such as learning, and these deficits may be affected by the presence of ovarian hormones. To assess this possibility, 40 injections of saline or 5.6 mg/kg of Δ 9 -THC were administered i.p. daily during adolescence to gonadally intact or ovariectomized (OVX) female rats, yielding 4 treatment groups (intact/saline, intact/THC, OVX/saline, and OVX/THC). Δ 9 -THC (0.56-10 mg/kg) was then re-administered to each of the 4 groups during adulthood to examine their sensitivity to its disruptive effects. The behavioral task required adult subjects to both learn (acquisition component) different response sequences and repeat a known response sequence (performance component) daily. During baseline (no injection) and control (saline injection) sessions, ovariectomized subjects had significantly higher response rates and lower percentages of error in both behavioral components than the intact groups irrespective of saline or Δ 9 -THC administration during adolescence; the intact group that received Δ 9 -THC had the lowest response rates in each component. Upon re-administration of Δ 9 -THC, the groups that received adolescent ovariectomy alone, adolescent Δ 9 -THC administration alone, or both treatments were found to be less sensitive to the rate-decreasing effects, and more sensitive to the error-increasing effects of Δ 9 -THC than the control group (i.e., intact subjects that received saline during adolescence). Neurochemical analyses of the brains from each adolescent-treated group indicated that there were also persistent effects on cannabinoid type-1 (CB-1) receptor levels in the hippocampus and striatum that depended on the brain region and the presence of ovarian hormones. In addition, autoradiographic analyses of the brains from adolescent-treated, but behaviorally-naïve, subjects indicated that ovariectomy and Δ 9 -THC administration produced effects on receptor coupling in some of the same brain regions. In summary, chronic administration of Δ 9 -THC during adolescence in female rats produced long-term effects on operant learning and performance tasks and on the cannabinoid system that were mediated by the presence of ovarian hormones, and that altered their sensitivity to Δ 9 -THC as adults.

Chronic 9-Tetrahydrocannabinol during Adolescence Differentially Modulates Striatal CB1 Receptor Expression and the Acute and Chronic Effects on Learning in Adult Rats

“…In the hippocampus, CB1R levels were increased in female rats that received 5.6 mg/kg of THC during adolescence, whereas the opposite was true in the male rats. This finding systematically replicates the previous findings of Winsauer et al (2011) for gonadally intact females. In the striatum, both male and female rats that received this dose during adolescence had more CB1R than rats that received saline.…”

“…Researchers have typically used rodents to characterize the long-term effects of chronic cannabinoid administration during adolescence in both males and females (Biscaia et al, 2003;Rubino et al, 2008Rubino et al, , 2009Harte and Dow-Edwards, 2010;Llorente-Berzal et al, 2011;Mateos et al, 2011;Winsauer et al, 2011Winsauer et al, , 2012Harte-Hargrove and Dow-Edwards, 2012). Male rats that received D 9 -tetrahydrocannabinol (THC) during adolescence made more errors during the acquisition of a radial-arm maze task than males that received vehicle (Rubino et al, 2009).…”

“…In addition, adult female rats chronically administered THC during adolescence were differentially sensitive to the rate-decreasing and error-increasing effects of THC on responding under a complex learning task, and these effects depended on ovarian hormone status Winsauer and Sutton, 2014). Studies investigating the long-term effects of THC administration have also correlated these behavioral changes with changes in cannabinoid type-1 receptor (CB1R) expression in regions of the brain such as the hippocampus and striatum (Burston et al, 2010;Winsauer et al, 2011;Lopez-Gallardo et al, 2012). For These data were adapted from the dissertation of Peter F. Weed: Effects of Chronic D example, Lopez-Gallardo et al (2012) found that the administration of CP 55,940 (a cannabinoid receptor agonist) to adolescent rats produced sexually dimorphic changes in CB1R expression in several regions of the hippocampus.…”

Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

“…In a rodent study, for example, a within-subject design was used to show that estradiol administration can attenuate the disruptive effects of Δ 9 -THC in ovariectomized (OVX) female rats responding in a complex learning task (Daniel et al 2002). Along with these purely behavioral data, there are biochemical data indicating that ovarian hormones can either inhibit or antagonize cannabinoid signaling in areas of the brain important for cognitive functioning, such as the hippocampus and striatum (Winsauer et al 2011a). Moreover, estrogens are capable of producing the attenuation of cannabinoid signaling in multiple ways, including reducing guanosine-5'-O-(3-thio)triphosphate (GTPγS) binding or coupling of CB1 receptors to signaling pathways, modification of CB1 receptor mRNA and protein expression, altering the relative affinity of agonists for CB1 receptors, and affecting co-chaperones such as the activator of heat-shock 90kDa protein ATPase homolog 1 (AHA-1) that move CB1 receptors to the cell surface from subcellular locations (Filipeanu et al 2011; Gonzalez et al 2000; Mize and Alper 2000; Riebe et al 2010; Rodriguez de Fonseca et al 1994).…”

Scientific Opinion on the risks for human health related to the presence of tetrahydrocannabinol (THC) in milk and other food of animal origin

“…per day i.p. for 40 days) induces alterations in operant learning that are dependent on the oestrous cycle and are reversed by ovariectomy in adolescent rat females (Winsauer et al, 2010).…”