Long-term consequences of perinatal fatty acid amino hydrolase inhibition.

Abstract

BACKGROUND AND PURPOSE:

Fatty acid amide hydrolase inhibitors show promise as a treatment for anxiety, depression and pain. Here we investigated whether perinatal exposure to URB597, a fatty acid amide hydrolase inhibitor, alters brain development and affects behaviour in adult mice.

EXPERIMENTAL APPROACH:

Mouse dams were treated daily from gestational day 10.5 to 16.5 with 1, 3 or 10 mg kg−1 URB597. MS was used to measure a panel of endocannabinoids and related lipid compounds and brain development was assessed at embryonic day 16.5. Separate cohorts of mouse dams were treated with 10 mg kg−1 URB597, from gestational day 10.5 to postnatal day 7, and the adult offspring were assessed with a battery of behavioural tests.

KEY RESULTS:

Perinatal URB597 exposure elevated anandamide and related N-acyl amides. URB597 did not induce signs of toxicity or affect dam weight gain, neurogenesis or axonal development at embryonic day 16.5. It did lead to subtle behavioural deficits in adult offspring, manifested by reduced cocaine-conditioned preference, increased depressive behaviours and impaired working memory. Anxiety levels, motor function and sensory-motor gating were not significantly altered.

CONCLUSIONS AND IMPLICATIONS:

Taken together, the present results highlight how exposure to elevated levels of anandamide and related N-acyl amides during brain development can lead to subtle alterations in behaviour in adulthood.

LINKED ARTICLES:

This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6

• Authors: Chia-Shan Wu, Daniel Morgan, Chris P Jew, Chris Haskins, Mary-Jeanette Andrews, Emma Leishman, Corinne M Spencer, Traci Czyzyk, Heather Bradshaw, Ken Mackie, Hui-Chen Lu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 6 Pg. 1420-34 (Mar 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24730060 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Benzamides
• Carbamates
• Enzyme Inhibitors
• cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Amidohydrolases (antagonists & inhibitors)
• Animals
• Behavior, Animal (drug effects)
• Benzamides (pharmacology)
• Carbamates (pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Mice
• Mice, Inbred ICR
• Pregnancy