Cannabinoid self-administration in rats: sex differences and the influence of ovarian function

Br J Pharmacol. 2007 Nov;152(5):795-804. doi: 10.1038/sj.bjp.0707465. Epub 2007 Sep 24.


Background and purpose: We recently demonstrated the existence of strain differences in self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) by Long Evans (LE) and Lister Hooded (LH) but not Sprague-Dawley (SD) male rats. This follow-up study is aimed at verifying whether sex and ovarian hormones might also be critical factors in the initiation, retention and extinction of WIN self-administration.

Experimental approach: LE, LH and SD male and female rats, the latter either intact or bilaterally ovariectomized (OVX), were trained to self-administer WIN (12.5 microg kg(-1) per infusion) under a FR1 reinforcement schedule, using lever-pressing.

Key results: Data showed that contrary to the findings in SD rats, LE and LH rats developed robust cannabinoid intake, with rates of responding for WIN being constantly higher in intact females than in males (+45 and +42% for LE and LH strains, respectively). In comparison with intact females, OVX females of both strains acquired self-administration at lower rates, displaying slower acquisition, lower drug intake (-42 and -52% for LE and LH, respectively) and longer extinction.

Conclusions and implications: These findings provide the first evidence of significant sex differences in cannabinoid self-administration, females acquiring stable WIN intake at higher rates and more rapidly than males. Moreover, when compared to intact females, a lower percentage of LE and LH OVX rats acquired and maintained stable drug intake, suggesting that ovarian hormones might represent a critical factor in modulating the reinforcing effect of cannabinoids.

MeSH terms

  • Age Factors
  • Analgesics / administration & dosage
  • Analgesics / pharmacology
  • Analysis of Variance
  • Animals
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacology*
  • Cannabinoids / administration & dosage
  • Cannabinoids / pharmacology*
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Extinction, Psychological / drug effects
  • Female
  • Infusions, Intravenous
  • Male
  • Morpholines / administration & dosage
  • Morpholines / pharmacology*
  • Naphthalenes / administration & dosage
  • Naphthalenes / pharmacology*
  • Ovarian Function Tests
  • Ovariectomy / methods
  • Ovary / drug effects*
  • Ovary / physiology
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / agonists
  • Retention, Psychology / drug effects
  • Self Administration
  • Sex Characteristics
  • Sex Factors
  • Time Factors


  • Analgesics
  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptor, Cannabinoid, CB1
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone