Paternal THC exposure before conception caused lasting cholinergic brain deficits in rat offspring through middle age

After 28 days of THC exposure (0, 2, or 4 mg/kg/day) in male rats, followed by mating with drug-naive females, offspring showed dose-dependent decreases in hemicholinium-3 binding (presynaptic acetylcholine activity) with regionally selective increases in choline acetyltransferase. This produced a persistent decrease in impulse activity per nerve terminal from adolescence (PND 30) through middle age (PND 150). At low doses, compensatory nicotinic receptor upregulation partially offset deficits; at high doses, receptors were subnormal, worsening the impairment. THC also accelerated age-related nicotinic receptor decline.

Male rats received THC (0, 2, or 4 mg/kg/day) for 28 days, then mated with drug-naive females 2 days later. Offspring brain acetylcholine systems assessed at PND 30, 60, 90, 120, and 150 across multiple brain regions.

This demonstrates that a father cannabis use before conception can cause lifelong brain changes in offspring. The cholinergic system is critical for attention, memory, and learning, and its impairment from adolescence through middle age represents a persistent neurodevelopmental injury.

Combined with sperm epigenetics data from the same research group, this provides compelling evidence that paternal cannabis exposure before conception can program lifelong brain changes in offspring, through a mechanism that does not involve the fetal chemical environment.

Rat model; THC doses may not match human recreational use; behavioral outcomes not assessed (only biochemical markers); limited to cholinergic system; cannot determine if effects are reversible with longer abstinence before conception.