Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone

Increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, amongst others, pregnancy-related ailments like 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 during pre-adolescence. The FDA-approved neurosteroid pregnenolone rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.