Drug- and cue-induced reinstatement of cannabinoid-seeking behaviour in male and female rats: influence of ovarian hormones

Br J Pharmacol. 2010 Jun;160(3):724-35. doi: 10.1111/j.1476-5381.2010.00734.x.


Background and purpose: Animal and human studies have shown that sex and hormones are key factors in modulating addiction. Previously, we have demonstrated that self-administration of the cannabinoid CB(1) receptor agonist WIN55,212-2 (WIN; 12.5 microg.kg(-1) per infusion) is dependent on sex, intact female rats being more sensitive than males to the reinforcing properties of cannabinoids, and on the oestrous cycle, ovariectomized (OVX) females being less responsive than intact females.

Experimental approach: This follow-up study investigated whether sex and ovarian function also affect reinstatement of cannabinoid-seeking in rats after exposure to drug or cue priming.

Key results: After priming with 0.15 or 0.3 mg.kg(-1) WIN, intact female rats exhibited stronger reinstatement than males and OVX females. Responses of intact female rats were higher than those of male and OVX rats even after priming with a drug-associated visual (Light) or auditory (Tone) cue, or a WIN + Light combination. However, latency to the first response did not differ between intact and OVX female rats, and males showed the longest latency to initiate lever-pressing activity.

Conclusions and implications: Our study provides compelling evidence for a pivotal role of sex and the oestrous cycle in modulating cannabinoid-seeking, with ovariectomy diminishing drug and cue-induced reinstatement. However, it is possible that sex differences during self-administration training are responsible for sex differences in reinstatement. Finding that not only drug primings but also acute exposure to drug-associated cues can reinstate responding in rats could have significant implications for the development of pharmacological and behavioural treatments of abstinent female and male marijuana smokers.

MeSH terms

  • Animals
  • Behavior, Addictive / psychology
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacology*
  • Conditioning, Operant / physiology
  • Cues
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Female
  • Male
  • Morpholines / administration & dosage
  • Morpholines / pharmacology*
  • Naphthalenes / administration & dosage
  • Naphthalenes / pharmacology*
  • Ovariectomy / psychology*
  • Rats
  • Rats, Inbred Strains
  • Receptor, Cannabinoid, CB1 / agonists
  • Self Administration
  • Sex Characteristics
  • Time Factors


  • Benzoxazines
  • 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