Elsevier

Biological Psychiatry

Volume 61, Issue 4, 15 February 2007, Pages 554-563
Biological Psychiatry

Priority communication
Prenatal Cannabis Exposure Increases Heroin Seeking with Allostatic Changes in Limbic Enkephalin Systems in Adulthood

https://doi.org/10.1016/j.biopsych.2006.03.073Get rights and content

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 Δ9-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 μ 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.

Section snippets

Methods and Materials

All animal experiments were conducted in accordance with the guidelines of the European Community and The Swedish National Board for Laboratory Animals, under protocols approved by the Ethical Committee of Northern Stockholm.

Results

There was no significant group difference in the % weight gain by the pregnant females (vehicle 45.4 ± 1; THC 47.3 ± 3 g), gestational length (vehicle 21 ± .38; THC 20.8 ± .66 days), pup length at PND 2 (vehicle 6.98 ± .12; THC 7 ±.13 cm) and pup weight (vehicle 6.83 ±.18; THC 6.91 ±.16 g). There was also no significant difference (P = .565) in weight between animals pretreated with THC (317 ± 11 g) or vehicle- (330 ± 16 g) at the start of the heroin self-administration on PND 62.

Discussion

The present study provides evidence of enduring behavioral and neural impairments related to the opioid reward/stress limbic system in adult rats exposed prenatally to THC. Hyperactivity of the mesocorticolimbic enkephalinergic system was identified in adulthood that appeared a counteractive response to blunted PENK gene expression during the repeated THC exposure in early development.

The most direct experimental animal model to assess reward and reinforcement effects of drugs of abuse is the

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