Behavioral and molecular changes elicited by acute administration of SR141716 to Δ9-tetrahydrocannabinol-tolerant rats: An experimental model of cannabinoid abstinence

Sara González, Javier Fernández-Ruiz*, Vincenzo Di Marzo, Mariluz Hernández, Cristina Arévalo, Cristina Nicanor, Maria Grazia Cascio, Emilio Ambrosio, José A. Ramos

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)


Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB 1 receptor) in Δ9-tetrahydrocannabinol (Δ9-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Δ9-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion - these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Δ9-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Δ9-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Δ9-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Δ9-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Δ9-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Δ9-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB1 receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats.

Original languageEnglish
Pages (from-to)159-170
Number of pages12
JournalDrug and Alcohol Dependence
Issue number2
Early online date26 Feb 2004
Publication statusPublished - 10 May 2004


  • Δ-Tetrahydrocannabinol
  • Cannabinoid CB receptor
  • Dependence
  • Endocannabinoids
  • Precipitated-withdrawal
  • SR141716
  • Tolerance


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