Prenatal cannabis exposure increases heroin seeking with allostatic changes in limbic enkephalin systems in adulthood

Biol Psychiatry. 2007 Feb 15;61(4):554-63. doi: 10.1016/j.biopsych.2006.03.073. Epub 2006 Jul 28.


Background: Prenatal cannabis exposure is a growing concern with little known about the long-term consequences on behavior and neural systems relevant for reward and emotional processing.

Methods: We used an animal model to study the effects of prenatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin self-administration behavior and opioid neural systems in adult males (postnatal day 62). Rats were exposed to THC (.15 mg/kg) or vehicle from gestational day 5 to postnatal day 2.

Results: Both pretreatment groups showed similar heroin intake, but THC-exposed rats exhibited shorter latency to the first active lever press, responded more for low heroin doses, and had higher heroin-seeking during mild stress and drug extinction. THC exposure reduced preproenkephalin (PENK) mRNA expression in the nucleus accumbens during early development, but was elevated in adulthood; no adult striatal changes on preprodynorphin mRNA or PENK in caudate-putamen. PENK mRNA was also increased in the central and medial amygdala in adult THC-exposed animals. THC animals had reduced heroin-induced locomotor activity and nucleus accumbens mu opioid receptor coupling.

Conclusions: This study demonstrates enduring effects of prenatal THC exposure into adulthood that is evident on heroin-seeking behavior during extinction and allostatic changes in mesocorticolimbic PENK systems relevant to drug motivation/reward and stress response.

Publication types

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

MeSH terms

  • Analysis of Variance
  • Animals
  • Autoradiography / methods
  • Behavior, Animal
  • Cannabis*
  • Conditioning, Operant / drug effects
  • Dynorphins / genetics
  • Dynorphins / metabolism
  • Enkephalins / genetics
  • Enkephalins / metabolism*
  • Female
  • Guanosine 5'-O-(3-Thiotriphosphate) / pharmacokinetics
  • Heroin Dependence / etiology*
  • In Situ Hybridization / methods
  • Limbic System / metabolism*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Protein Binding / drug effects
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Rats
  • Rats, Long-Evans
  • Reaction Time / drug effects


  • Enkephalins
  • Protein Precursors
  • pre-prodynorphin
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Dynorphins