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Nat Neurosci. 2019 Oct 14. doi: 10.1038/s41593-019-0512-2. [Epub ahead of print]

Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone.

Author information

1
Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy.
2
Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
3
Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary.
4
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
5
Nikon Center of Excellence for Neuronal Imaging, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
6
Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy. myriam@unica.it.

Abstract

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.

PMID:
31611707
DOI:
10.1038/s41593-019-0512-2

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