Chronic cannabinoid agonist (WIN 55,212-2) exposure alters hippocampal dentate gyrus spine density in adult rats

Brain Res. 2014 Jan 13;1542:104-10. doi: 10.1016/j.brainres.2013.10.039. Epub 2013 Oct 30.


Chronic abuse of drugs can result in vast negative repercussions on behavioral and biological systems by altering underlying neurocircuitry. Long-term cannabinoid administration in rats leads to detrimental cellular and dendritic morphology changes. Previous studies have found that chronic treatment with delta-9-THC selectively decreases dendritic morphology and spine density in the dentate gyrus of adolescent rats (Rubino et al., 2009); however, whether these changes are specific to a particular developmental age is not known. The present study evaluated the effects of chronic exposure (7 or 21 days) to WIN 55,212-2 (i.p., 3.7 mg/kg), a potent cannabinoid agonist, on dendritic morphology of dentate gyrus neurons in adult rats. Upon completion of treatment brains were processed for Golgi-Cox staining. No significant effects of WIN 55,212-2 exposure were observed for dendritic branching or length. Spine density was quantified in the inner (proximal), middle, and outer (distal) thirds of the dendritic fields selected to approximate the spatial loci of afferents comprising the associational-commissural pathway, medial perforant path, and lateral perforant path, respectively. Compared to vehicle controls there was a significant reduction in spine density (~1 spine/10 μm) in the inner and middle dendritic segments. The spine density reduction was significant in inner segments following 7 days of treatment. These results suggest that chronic cannabinoid treatment specifically alters spine density in the dendritic targets of the associational-commissural afferents and medial perforant path projections, but not lateral perforant path. The resulting loss of dendritic spine density may be an important factor underlying cannabinoid induced memory impairments.

Keywords: Cannabinoid; Dendritic spine; Dentate gyrus; Golgi–Cox; Hippocampus; Synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Benzoxazines / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Dendrites / drug effects*
  • Dentate Gyrus / cytology*
  • Male
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Neurons / ultrastructure*
  • Rats
  • Rats, Long-Evans
  • Silver Staining
  • Time Factors


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