Discrete opioid gene expression impairment in the human fetal brain associated with maternal marijuana use

Abstract

Fetal development is a period sensitive to environmental influences such as maternal drug use. The most commonly used illicit drug by pregnant women is marijuana. The present study investigated the effects of in utero marijuana exposure on expression levels of opioid-related genes in the human fetal forebrain in light of the strong interaction between the cannabinoid and opioid systems. The study group consisted of 42 midgestation fetuses from saline-induced voluntary abortions. The opioid peptide precursors (preprodynorphin and preproenkephalin (PENK)) and receptor (mu, kappa and delta) mRNA expression were assessed in distinct brain regions. The effect of prenatal cannabis exposure was analyzed by multiple regression controlling for confounding variables (maternal alcohol and cigarette use, fetal age, sex, growth measure and post-mortem interval). Prenatal cannabis exposure was significantly associated with increased mu receptor expression in the amygdala, reduced kappa receptor mRNA in mediodorsal thalamic nucleus and reduced preproenkephalin expression in the caudal putamen. Prenatal alcohol exposure primarily influenced the kappa receptor mRNA with reduced levels in the amygdala, claustrum, putamen and insula cortex. No significant effect of prenatal nicotine exposure could be discerned in the present study group. These results indicate that maternal cannabis and alcohol exposure during pregnancy differentially impair opioid-related genes in distinct brain circuits that may have long-term effects on cognitive and emotional behaviors.

At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring

“…Using a multiple regression paradigm for confounding variables that included alcohol and cigarette use, prenatal marijuana exposure was shown to significantly alter opioid receptor expression in the mesolimbic forebrain: increased µ and κ receptor levels were found in the amygdala and mediodorsal thalamic nucleus, respectively (115). These observations are strengthened by prenatal THC (0.15 mg/kg, daily)-induced reduction of preproenkephalin mRNA expression in the rat nucleus accumbens (84) during early development.…”

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

“…Pioneering studies from the Hurd laboratory have demonstrated increased heroin seeking in offspring prenatally exposed to THC 143,144 , trans-generational imprinting via epigenetic mechanisms through coincidently enhanced transcriptional repression and reduced transcriptional activation 34 , as well as misplacement of CB 1 R + hippocampal interneurons in neonatal offspring 93 . The neuronal basis for THC-induced drug-seeking behaviors in the offspring might be due to the altered neuropeptide (dynorphin, enkephalin) expression in mesocorticolimbic reward circuits 145 , and the erroneous synaptic wiring of glutamatergic cortical neurons 38 . Modifications to glutamatergic axons were shown to originate during neuronal development and be due to the CB 1 R-dependent degradation of SCG10/brain-specific stathmin-2, a determinant of microtubule elongation by sequestering tubulin dimers in a ternary T2S complex 146 .…”

Rat Models of Prenatal and Adolescent Cannabis Exposure

“…Of the developmental models, the prenatal condition has many challenges and multiple issues that must be considered that can signifi cantly impact the success of the experiment and interpretation of the data. Despite the apparent challenges, we have, for example, been able to document similar neurobiological changes in our prenatal rat model ( 39 ) to those seen in human fetuses with in utero cannabis exposure ( 54 ) . Such fi ndings support the validity of the animal models that can now be used to provide much-needed insight into the neurobiological mechanisms underlying developmental cannabis exposure that are highly related to neuropsychiatric disorders.…”