Original Article

Adolescent Exposure to Chronic Delta-9-Tetrahydrocannabinol Blocks Opiate Dependence in Maternally Deprived Rats

  • Neuropsychopharmacology 34, 24692476 (2009)
  • doi:10.1038/npp.2009.70
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Abstract

Maternal deprivation in rats specifically leads to a vulnerability to opiate dependence. However, the impact of cannabis exposure during adolescence on this opiate vulnerability has not been investigated. Chronic dronabinol (natural delta-9 tetrahydrocannabinol, THC) exposure during postnatal days 35–49 was made in maternal deprived (D) or non-deprived (animal facility rearing, AFR) rats. The effects of dronabinol exposure were studied after 2 weeks of washout on the rewarding effects of morphine measured in the place preference and oral self-administration tests. The preproenkephalin (PPE) mRNA levels and the relative density and functionality of CB1, and μ-opioid receptors were quantified in the striatum and the mesencephalon. Chronic dronabinol exposure in AFR rats induced an increase in sensitivity to morphine conditioning in the place preference paradigm together with a decrease of PPE mRNA levels in the nucleus accumbens and the caudate–putamen nucleus, without any modification for preference to oral morphine consumption. In contrast, dronabinol treatment on D-rats normalized PPE decrease in the striatum, morphine consumption, and suppressed sensitivity to morphine conditioning. CB1 and μ-opioid receptor density and functionality were not changed in the striatum and mesencephalon of all groups of rats. These results indicate THC potency to act as a homeostatic modifier that would worsen the reward effects of morphine on naive animals, but ameliorate the deficits in maternally D-rats. These findings point to the self-medication use of cannabis in subgroups of individuals subjected to adverse postnatal environment.

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References

  1. (2003). Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 27: 3–18.

  2. , (2000). Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology 153: 31–43.

  3. , , , (1995). The ontogeny of cannabinoid receptors in the brain of postnatal and aging rats. Neurotoxicol Teratol 17: 25–30.

  4. , , , , , et al (2008). Sex-dependent effects of periadolescent exposure to the cannabinoid agonist CP-55 940 on morphine self-administration behaviour and the endogenous opioid system. Neuropharmacology 54: 863–873.

  5. , , , , (2001). Behavioural sensitization after repeated exposure to delta-9-tetrahydrocannabinol and cross-sensitization with morphine. Psychopharmacology 158: 259–266.

  6. , , , , , (1998). Perinatal delta-9 tetrahydrocannabinol exposure reduces proenkephalin gene expression in the caudate–putamen of adult female rats. Life Sci 63: 843–850.

  7. , , (2007). Adolescent cannabis exposure alters opiate intake and opioid limbic neuronal populations in adult rats. Neuropsychopharmacology 32: 607–615.

  8. , (1998). Cannabinoid transmission and reward-related events. Neurobiol Disease 5: 502–533.

  9. , , , , , (1991). Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11: 563–583.

  10. (1995). Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 35: 607–634.

  11. , (2000). Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37: 71–80.

  12. , , , (2003). Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. J Neurosci 23: 4815–4820.

  13. , , (2006). Tolerance to the reinforcing effects of morphine in delta9-tetrahydrocannabinol treated mice. Behav Brain Res 173: 255–261.

  14. (1999). Opioids: first lessons from knockout mice. Trends Pharmacol Sci 20: 19–26.

  15. , , (2001). Chronic treatment with delta(9)-tetrahydrocannabinol enhances the locomotor response to amphetamine and heroine. Implications for vulnerability to drug addiction. Neuropharmacology 41: 118–129.

  16. , , , , , et al (1999). Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1, receptor knockout mice. Science 228: 401–404.

  17. , , , , , et al (2008). Dose-related differences in the regional pattern of cannabinoid receptor adaptation and in vivo tolerance development to delta9-tetrahydrocannabinol. J Pharmacol Exp Ther 324: 664–673.

  18. , , , (1995). Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18: 22–29.

  19. , , , , (2004). Cannabinoid agonist-induced sensitization to morphine place preference in mice. NeuroReport 15: 1373–1376.

  20. , , (1999). A diminution of delta-9-tetrahydrocannabinol modulation of dynorphin A(1–17) in conjunction with tolerance development. Eur J Pharmacol 381: 105–111.

  21. , , , , (1990). Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346: 561–564.

  22. , , , , , et al (2001). Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 15: 5344–5350.

  23. , , , (2003). Pre-exposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats. Eur J Pharmacol 28: 105–114.

  24. , (1997). The Rat Brain in Stereotaxic Coordinates. Academic Press: New York.

  25. (2008). The diverse CB1 and CB2 receptor pharmacology of the three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 153: 199–215.

  26. , , , , (2004). Compartment-specific localization of cannabinoid 1 (CB1) and μ opioid receptors in rat nucleus accumbens. Neuroscience 127: 101–112.

  27. , , , , , (2004). Adolescent exposure to cannabinoids induces long-lasting changes in the response to drugs of abuse of rat midbrain dopamine neurons. Biol Psychiatry 56: 86–94.

  28. , , (2006). μ opioid and CB1 cannabinoid receptors interactions: reciprocal inhibition of receptor signaling and neuritogenesis. Br J Pharmacol 148: 387–395.

  29. , , (2001). Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat caudate putamen nucleus. J Neurosci 24: 1673–1679.

  30. , , , (1993). Presence of cannabinoid binding sites in the brain from early postnatal ages. Neuroreport 4: 135–138.

  31. , (2009). Modulation of excitatory synaptic transmission by Δ9-tetrahydrocannabinol switches from agonist to antagonist depending on firing rate. Mol Pharmacol 75: 892–900.

  32. , , , , , et al (1998). Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to delta-9-tetrahydrocannabinol. Synapse 30: 298–308.

  33. , , , , , (2000). Chronic delta-9-tetrahydrocannabinol treatment increases cAMP levels and cAMP-dependent protein kinase activity in some rat brain regions. Neuropharmacology 39: 1331–1336.

  34. , , , (2006). Interactions between CB1 cannabinoid and μ opioid receptors mediating inhibition of neurotransmitter release in rat nucleus accumbens core. Neuropharmacology 51: 773–781.

  35. , , (1993). of the neurochemical substrates mediating the motivational effects of opioids: role of the mesolimbic dopamine system and D-1 vs D-2 dopamine receptors. J Pharmacol Exp Ther 265: 53–59.

  36. (2003). Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol 15: 91–119.

  37. , , (2005). Repeated exposure to delta9-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity. Neuropharmacology 49: 1189–1200.

  38. , , (2006). Perinatal exposure to delta-9 tetrahydrocannabinol alters heroin-induced place conditioning and Fos-immunoreactivity. Neuropsychopharmacology 31: 58–69.

  39. , , , , (1999). Altered gene expression in striatal projection neurons in CB1 cannabinoid receptor knockout mice. Proc Natl Acad Sci USA 96: 5786–5790.

  40. , (2003). Cannabinoids: reward, dependence, and underlying neurochemical mechanisms- a review of recent preclinical data. Psychopharmacology 169: 115–134.

  41. , , , , , (2001). Δ9—tetrahydrocannabinol releases and facilitates the effects of endogenous enkephalins: reduction in morphine withdrawal syndrome without change in rewarding effect. Eur J Neurosci 13: 1816–1824.

  42. , , , , , et al (2000). Endogenous opioids and reward. Eur J Pharmacol 405: 89–101.

  43. , , , , (2007). Maternal deprivation and handling modify the effect of the dopamine D3 receptor agonist, BP 897 on morphine-conditioned place preference in rats. Psychopharmacology 193: 475–486.

  44. , , , , , (2005). Maternal deprivation increases vulnerability to morphine dependence and disturbs the enkephalinergic system in adulthood. J Neurosci 25: 4453–4462.

  45. , , (2006). Maternal deprivation specifically enhances vulnerability for opiate dependence. Behav Pharmacol 17: 715–724.

  46. , , , , , (2006). Adenosine A2a blockade prevents synergy between μ-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats. Proc Natl Acad Sci USA 103: 7877–7882.

  47. , (1995). From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav Brain Res 70: 77–94.

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Acknowledgements

This study was supported by grants from the French Institut National de la Recherche Scientifique et Médicale (INSERM). LM has a fellowship supported by the French Mission Interministérielle de la Lutte contre la Drogue et la Toxicomanie (MILDT).

Author information

Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U952, Université Pierre et Marie Curie, 9 quai Saint Bernard, Paris, Ile de France, France

    • Lydie J Morel
    • , Bruno Giros
    •  & Valérie Daugé
  2. Centre National de la Recherche Scientifique (CNRS), UMR 7224, Université Pierre et Marie Curie, 9 quai Saint Bernard, Paris, Ile de France, France

    • Lydie J Morel
    • , Bruno Giros
    •  & Valérie Daugé
  3. UMPC Université Paris 06, 9 quai Saint Bernard, Paris, Ile de France, France

    • Lydie J Morel
    • , Bruno Giros
    •  & Valérie Daugé
  4. Department of Psychiatry, Douglas Hospital Research Center, McGill University, boulevard Lasalle, Verdun, QC, Canada

    • Bruno Giros
  5. Université Paris Descartes, 12 rue de l’Ecole de médecine, Paris, Ile de France, France

    • Lydie J Morel

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Corresponding author

Correspondence to Valérie Daugé.

DISCLOSURE/CONFLICT OF INTEREST

The authors declare no conflict of interest.