Regional enhancement of cannabinoid CB₁ receptor desensitization in female adolescent rats following repeated Delta-tetrahydrocannabinol exposure

Abstract

Background and purpose: Disruption of the substantial re-organization of the brain during adolescence may be induced by persistent abuse of marijuana. The aim of this study was to determine whether adolescent and adult rats exhibit differential adaptation of brain cannabinoid (CB(1)) receptors after repeated exposure to Delta(9)-tetrahydrocannabinol (THC).

Experimental approach: Rats of both ages and sexes were dosed with 10 mg kg(-1) THC or vehicle twice daily for 9.5 days. Subsequently, CB(1) receptor function and density were assessed.

Key results: In all brain regions, THC treatment produced desensitization and down-regulation of CB(1) receptors. While the magnitude of down-regulation did not differ across groups, greater desensitization was evident in the brains of THC-treated female adolescent rats for most regions. Adolescent females showed greater desensitization than adult females in the prefrontal cortex, hippocampus, periaqueductal gray (PAG) and ventral midbrain. In contrast, adolescent males exhibited less desensitization in the prefrontal cortex, hippocampus and PAG, an effect opposite to that seen in females. With the exception of the PAG, sex differences were seen only in adolescents, with greater desensitization in the prefrontal cortex, striatum, hippocampus, PAG, and ventral midbrain of females.

Conclusions and implications: These results suggest that the brains of adolescent females may be particularly vulnerable to disruption of CB(1) receptor signalling by marijuana abuse. Alternatively, increased desensitization may reflect protective adaptation. Given the extensive re-organization of the brain during adolescence, this disruption has potential long-term consequences for maturation of the endocannabinoid system.

Figure 1

Concentration effect curves for CP55,940-stimulated [³⁵S]GTPγS binding in tissues from cerebellum (top panels) and hippocampus (bottom panels) of adolescent and adult rats (left and right panels, respectively) of both sexes that had received vehicle or THC treatment. E_max values for vehicle-treated rats are presented in Table 1.

Figure 2

Desensitization, defined as decrease in maximal stimulation (E_max) of CP55,940-stimulated [³⁵S]GTPγS binding in THC-treated tissue. Data are expressed as a percent decrease in the E_max value, compared with vehicle-treated tissue from rats of the corresponding age and sex, in membrane homogenates derived from THC-treated female and male adolescent and adult Long-Evans rats treated twice daily with 10 mg kg⁻¹ THC for 9.5 days. (A–G) Desensitization in the prefrontal cortex, striatum, hypothalamus, periaqueductal gray (PAG), hippocampus, ventral midbrain and cerebellum, respectively. Values represent mean (±SEM) percent desensitization for each group. * Significant (P < 0.05) age difference for adolescents versus adults of the same sex (based on age–sex interaction). # Significant (P < 0.05) sex difference within a single age group (based on age–sex interaction). $ Significant (P < 0.05) main effect for age or sex without an accompanying significant interaction.