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

Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies

“…Thus, one may postulate that instead of provoking a gross neurodevelopmental phenotype (“direct hit”), pharmacological or genetic manipulation of select molecular constituents in endocannabinoid signaling networks will induce subtle changes in many neurons and synapses, only manifesting as disease upon a secondary stressor (“double hit”). This concept is compatible with recent studies showing that pre- or perinatal administration (from embryonic day 10 to postnatal day 7) of URB597, a FAAH inhibitor 138 or GPR55 deletion 139 does not markedly affect neurogenesis or axonal development (Table 1). Yet both strategies induced long-lasting behavioral deficits, particularly indices of depression-like symptoms and memory impairment enduring into the adulthood of affected offspring.…”

Decreased anxiety in juvenile rats following exposure to low levels of chlorpyrifos during development

“…Previous work demonstrated the long term effects caused by developmental exposure to the FAAH inhibitor URB597 (Marco et al, 2009; Macri et al, 2012; Wu et al, 2014), making this a plausible hypothesis. However, this mechanism does not take the elevated OEA and PEA levels into consideration.…”

“…Exposure to the FAAH inhibitor URB597 during adolescence altered the levels of the CB1 receptor in adult rat brain (Marco et al, 2009) and led to increased anhedonia in adults (Macri et al, 2012). Gestational exposure to URB597 led to subtle behavioral deficits in the offspring after they reached adult ages (Wu et al, 2014). However, the dosages used in those developmental studies were also designed to produce substantial FAAH inhibition.…”

The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

“…Lack of efficacy is an important reason for drug discontinuation, but others include clinical safety, toxicology and commercial considerations (Kola and Landis 2004). Little is known about the long-term consequences of treatment with eCB-modulating agents of the sort discussed here, other than a study investigating the effects of perinatal treatment with URB597 upon behavioural patterns of the offspring (Wu et al 2014). It is thus prudent to be cautious in considering the therapeutic value of compounds with global effects on the breakdown not only of the eCBs but on related endogenous substrates with biological actions of their own.…”