Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone

Nat Neurosci. 2019 Dec;22(12):1975-1985. doi: 10.1038/s41593-019-0512-2. Epub 2019 Oct 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine / metabolism
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / physiology
  • Dronabinol / adverse effects*
  • Dronabinol / antagonists & inhibitors
  • Dronabinol / pharmacology*
  • Endophenotypes
  • Female
  • Maze Learning / drug effects
  • Membrane Potentials / physiology
  • Motor Activity / drug effects
  • Neural Inhibition / physiology
  • Neuronal Plasticity / drug effects
  • Nucleus Accumbens / metabolism
  • Pregnancy
  • Pregnenolone / pharmacology*
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prepulse Inhibition / drug effects
  • Prepulse Inhibition / physiology
  • Rats
  • Risk-Taking
  • Sensory Gating / drug effects
  • Sensory Gating / physiology
  • Sex Characteristics
  • Ventral Tegmental Area / metabolism


  • Pregnenolone
  • Dronabinol
  • Dopamine