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

Abstract

The purpose of this study was to determine whether chronic administration of D 9-tetrahydrocannabinol (THC) during adolescence would (1) modify any sex-specific effects of THC on learning and (2) affect the development of tolerance to THC as an adult. Male and female rats received daily injections of saline or 5.6 mg/kg of THC from postnatal day 35-75, yielding four groups (female/saline, female/THC, male/saline, and male/THC). Rats were then trained on a procedure that assayed both learning and performance behavior and administered 0.32-18 mg/kg of THC acutely as adults (experiment 1). THC produced rate-decreasing and error-increasing effects in both sexes; however, female rats were more sensitive than male rats were to the rate-decreasing effects. Rats were then chronically administered 10 mg/kg of THC (experiment 2). Rats that received THC during adolescence developed tolerance to the rate-decreasing effects more slowly and less completely than did rats that received saline; in addition, females developed tolerance to the error-increasing effects of THC slower than males did. Western blot analysis of brain tissue indicated long-term changes in hippocampal and striatal cannabinoid type-1 receptor (CB1R) levels despite levels that were indistinguishable immediately after chronic treatment during adolescence. Striatal CB1R levels were increased in adult rats that received THC during adolescence; hippocampal CB1R levels varied by sex. In summary, female rats were more sensitive than male rats were to the acute and chronic effects of THC, and chronic administration of THC during adolescence produced long-term changes in CB1R levels that correlated with decreased tolerance development to the rate-decreasing effects of THC.

Tolerance to hypothermic and antinoceptive effects of Δ9-tetrahydrocannabinol (THC) vapor inhalation in rats

“…Prior work has shown that female mice develop tolerance to locomotor stimulant effects of THC (i.p.) under conditions under which males do not (Wiley, 2003), that female rats develop tolerance to THC-induced errors on a learning task more slowly than males during chronic injection of 10 mg/kg THC, i.p., (Weed, Filipeanu, Ketchum & Winsauer, 2016) and that female rats develop a greater degree of nociceptive tolerance to THC even when the repeated dose is only 71% as large as the male dose (Wakley, Wiley & Craft, 2014). The study also demonstrated, as in our prior reports (Javadi-Paydar, Nguyen, Grant, Vandewater, Cole & Taffe, 2017;, that so long as intervals of at least 7 days are maintained between THC administration sessions, there is no detectable plasticity of the hypothermic response.…”

Mechanisms Underlying Sex Differences in Cannabis Use

“…Preclinical cannabinoid exposure in adolescence largely induces a sex-independent, widespread reduction in CB1-R density [41, 61–63], although enhancement in hippocampus in female animals [64–66], and striatum in both sexes [64], has been observed. Chronic THC exposure during adolescence led to a reduction in CB1-R density in the amygdala [61], caudate, putamen, nucleus accumbens, and substantia nigra [41] of adult male rats.…”

Lasting effects of repeated Δ9-tetrahydrocannabinol (THC) vapor inhalation during adolescence in male and female rats

“…The present findings are likely mechanistically attributable, in part, to plasticity in the expression and/or function of the endogenous cannabinoid receptor subtype 1 (CB 1 ). One prior study of repeated adolescent THC exposure found decreased CB 1 receptor expression in the hippocampus of female, but not male rats (Weed et al, 2016). Another study found greater CB 1 receptor desensitization in adolescents, compared with adults, and in female adolescents compared with male adolescents, following repeated THC injection.…”