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

Br J Pharmacol. 2010 Sep;161(1):103-12. doi: 10.1111/j.1476-5381.2010.00870.x.


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.

Publication types

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

MeSH terms

  • Age Distribution
  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Cyclohexanols
  • Dronabinol / administration & dosage
  • Dronabinol / pharmacology*
  • Drug Administration Schedule
  • Drug Tolerance*
  • Female
  • Male
  • Piperidines
  • Protein Binding
  • Pyrazoles
  • Rats
  • Rats, Long-Evans
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Rimonabant
  • Sex Characteristics
  • Sexual Maturation*


  • Cyclohexanols
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Dronabinol
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Rimonabant