The depressive phenotype induced in adult female rats by adolescent exposure to THC is associated with cognitive impairment and altered neuroplasticity in the prefrontal cortex

Neurotox Res. 2009 May;15(4):291-302. doi: 10.1007/s12640-009-9031-3. Epub 2009 Feb 28.


We recently demonstrated that Delta(9)-tetrahydrocannabinol (THC) chronic administration in female adolescent rats induces alterations in the emotional circuit ending in depressive-like behavior in adulthood. Since cognitive dysfunction is a major component of depression, we assessed in these animals at adulthood different forms of memory. Adolescent female rats were treated with THC or its vehicle from 35 to 45 post-natal days (PND) and left undisturbed until their adulthood (75 PND) when aversive and spatial memory was assessed using the passive avoidance and radial maze tasks. No alteration was found in aversive memory, but in the radial maze THC pre-treated animals exhibited a worse performance than vehicles, suggesting a deficit in spatial working memory. To correlate memory impairment to altered neuroplasticity, level of marker proteins was investigated in the hippocampus and prefrontal cortex, the most relevant areas for learning and memory. A significant decrease in synaptophysin and PSD95 proteins was found in the prefrontal cortex of THC pre-treated rats, with no alterations in the hippocampus. Finally, proteomic analysis of the synapses in the prefrontal cortex revealed the presence of less active synapses characterized by reduced ability in maintaining normal synaptic efficiency. This picture demonstrates the presence of cognitive impairment in THC-induced depressive phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Area Under Curve
  • Avoidance Learning / drug effects
  • Cognition Disorders / chemically induced*
  • Cognition Disorders / complications*
  • Depression / chemically induced*
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Dronabinol / toxicity*
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Maze Learning / drug effects
  • Membrane Proteins / metabolism
  • Neuronal Plasticity / drug effects*
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / physiopathology
  • Proteomics / methods
  • Psychotropic Drugs / toxicity
  • Rats
  • Rats, Sprague-Dawley
  • Reaction Time / drug effects
  • Synaptophysin / metabolism
  • Tubulin / metabolism


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Glial Fibrillary Acidic Protein
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Psychotropic Drugs
  • Synaptophysin
  • Tubb3 protein, rat
  • Tubulin
  • Dronabinol