Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone

• Published in: Nature neuroscience 2019-12, Vol.22 (12), p.1975-1985
• Main Authors: Frau, Roberto, Miczán, Vivien, Traccis, Francesco, Aroni, Sonia, Pongor, Csaba I., Saba, Pierluigi, Serra, Valeria, Sagheddu, Claudia, Fanni, Silvia, Congiu, Mauro, Devoto, Paola, Cheer, Joseph F., Katona, István, Melis, Miriam
• Format: Article
• Language: English
• Subjects: 631/378/1697/2602; 631/378/2571; 631/378/2591; 631/378/2629; Adolescents; Animal Genetics and Genomics; Animals; Behavioral plasticity; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cannabis; Care and treatment; Demographic aspects; Dopamine - metabolism; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - physiology; Dronabinol - adverse effects; Dronabinol - antagonists & inhibitors; Dronabinol - pharmacology; Drug use; Endophenotypes; Exposure; Female; Health aspects; Laws, regulations and rules; Marijuana; Maze Learning - drug effects; Membrane Potentials - physiology; Mental disorders; Mental illness; Morning sickness (during pregnancy); Motor Activity - drug effects; Nervous system diseases; Neural Inhibition - physiology; Neurobiology; Neuronal Plasticity - drug effects; Neurosciences; Nucleus Accumbens - metabolism; Offspring; Phenotypes; Polarity; Pregnancy; Pregnancy, Complications of; Pregnant women; Pregnenolone; Pregnenolone - pharmacology; Prenatal experience; Prenatal Exposure Delayed Effects - metabolism; Prepulse Inhibition - drug effects; Prepulse Inhibition - physiology; Rats; Regulatory agencies; Risk factors; Risk-Taking; Sensory Gating - drug effects; Sensory Gating - physiology; Sex Characteristics; Synaptic plasticity; Tetrahydrocannabinol; THC; Ventral Tegmental Area - metabolism; Ventral tegmentum
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-019-0512-2

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 Δ 9 -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. In offspring exposed to THC in utero, molecular, synaptic and circuit reorganizations lead to a hyperdopaminergic phenotype and behavioral susceptibility. The neurosteroid pregnenolone restores both dopamine function and abnormal behavior.