Summary: Prenatal exposure to THC makes dopamine neurons hyperactive and increases the sensitivity to the behavioral effects of the compound during pre-adolescence. This may increase the risk of developing schizophrenia later in life. However, treatment with pregnenolone, a drug under clinical trials for ASD, cannabis use disorder, and schizophrenia, appears to correct the brain abnormalities and behavioral problems associated with prenatal cannabis exposure.
Source: University of Maryland School of Medicine
As a growing number of U.S. states legalize the medicinal and recreational use of marijuana, an increasing number of American women are using cannabis before becoming pregnant and during early pregnancy often to treat morning sickness, anxiety, and lower back pain. Although emerging evidence indicates that this may have long-term consequences for their babies’ brain development, how this occurs remains unclear.
A University of Maryland School of Medicine study using a preclinical animal model suggests that prenatal exposure to THC, the psychoactive component of cannabis, makes the brain’s dopamine neurons (an integral component of the reward system) hyperactive and increases sensitivity to the behavioral effects of THC during pre-adolescence. This may contribute to the increased risk of psychiatric disorders like schizophrenia and other forms of psychosis later in adolescence that previous research has linked to prenatal cannabis use, according to the study published today in journal Nature Neuroscience.
The team of researchers, from UMSOM, the University of Cagliari (Italy) and the Hungarian Academy of Sciences (Hungary), found that exposure to THC in the womb increased susceptibility to THC in offspring on several behavioral tasks that mirrors the effects observed in many psychiatric diseases. These behavioral effects were caused, at least in part, by hyperactivity of dopamine neurons in a brain region called the ventral tegmental area (VTA), which regulates motivated behaviors.
More importantly, the researchers were able to correct these behavioral problems and brain abnormalities by treating experimental animals with pregnenolone, an FDA-approved drug currently under investigation in clinical trials for cannabis use disorder, schizophrenia, autism, and bipolar disorder.
“This is an exciting finding that suggests a therapeutic approach for children born to mothers who used cannabis during pregnancy,” said Joseph Cheer, PhD, a Professor of Anatomy & Neurobiology and Psychiatry at the University of Maryland School of Medicine. “It also raises important questions that need to be addressed such as how does pregnenolone exert its effects and how can we improve its efficacy? Do these detrimental effects persist into adulthood, and if so, could they also be treated in a similar way?”
The researchers concluded that as physicians caution pregnant women against alcohol and cocaine intake because of their detrimental effects to the fetus, they should also, based on these new findings, advise them on the potential negative consequences of using cannabis specifically during pregnancy.
Funding: The study was funded by an international collaborative program on marijuana research issued by the U.S. National Institute on Drug Abuse, the National Research, Development and Innovation Office of Hungary and the University of Cagliari as well as private European foundations.
Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone
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.