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Updated: Dec 28, 2025
Preclinical Model of Prenatal Delta-9-Tetrahydrocannabinol Exposure to Assess Its Impact on Neurodevelopmental Outcomes
Published on: February 28, 2025
Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the
Theodore A Slotkin1, Samantha Skavicus1, Edward D Levin2
1Department of Pharmacology & Cancer Biology.
Abstract:
Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.
Insights
Paternal exposure to THC, the active compound in marijuana, can negatively impact offspring brain development. This study shows THC affects acetylcholine systems, crucial for brain function, in offspring rats.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Paternal drug use is an understudied factor in offspring neurodevelopment.
- Marijuana use during pregnancy is known to affect fetal development.
- The impact of paternal marijuana exposure on offspring brain development requires further investigation.
Purpose of the Study:
- To investigate the effects of paternal Δ9-tetrahydrocannabinol (THC) exposure on the development of acetylcholine (ACh) systems in offspring rats.
- To assess the impact of paternal THC on offspring neurodevelopment from adolescence to middle age.
- To determine if paternal pre-conception exposure to THC has lasting adverse effects on offspring brain function.
Main Methods:
- Male rats were administered varying doses of THC (0, 2, or 4 mg/kg/day) for 28 days.
- Following THC treatment, males were mated with drug-naïve females.
- Offspring were assessed for changes in ACh systems, including hemicholinium-3 binding and choline acetyltransferase activity, across different life stages.
Main Results:
- Paternal THC exposure led to dose-dependent deficits in presynaptic ACh activity (hemicholinium-3 binding).
- Regionally selective increases in choline acetyltransferase activity were observed, indicating altered ACh terminal numbers.
- The ratio of hemicholinium-3 binding to choline acetyltransferase, an index of nerve impulse activity, was persistently decreased.
- Nicotinic ACh receptor levels showed complex changes, with partial compensation at low doses and exacerbation of defects at high doses.
- THC exposure accelerated age-related decline in nicotinic ACh receptors in offspring.
Conclusions:
- Paternal THC administration adversely affects offspring neurodevelopment, specifically impacting the cholinergic system.
- The findings highlight that paternal pre-conception drug exposure can negatively influence offspring brain development.
- Vulnerability to drug-induced neurodevelopmental effects can be established through paternal exposure prior to conception.
