Sexually Dimorphic Effects of a Single Neonatal Δ9-tetrahydrocannabinol Exposure on Neuronal Dendritic Morphology and Cognitive Functions in Rats.

A single injection of THC (5 mg/kg) given to rat pups on the third day after birth caused lasting spatial memory deficits in young adult females but not males. Anxiety-like behavior was unchanged in either sex. Both sexes showed decreased spine density, dendritic length, branching, and complexity in neurons of the frontal cortex and hippocampus (CA1, CA3, dentate gyrus). The results indicate that even brief neonatal cannabinoid exposure can produce long-lasting, sex-dependent cognitive impairment and structural brain changes, highlighting the vulnerability of the developing brain.

Study at a glance

Abstract

Cannabis consumption among adults, including pregnant and breastfeeding women, continues to rise. However, the long-term effects of early-life exposure to cannabinoids on brain development remain unclear. Δ9-tetrahydrocannabinol (THC) is the main psychoactive cannabinoid in cannabis and is an agonist of cannabinoid type 1 receptor, a critical component of the endocannabinoid system (ECS) that functions in normal pre- and postnatal brain development. We hypothesized that perinatal exposure to THC perturbs ECS-regulated neurodevelopment and leads to lasting cognitive effects in later life. Male and female Sprague Dawley rat pups received a single intraperitoneal injection of THC (5 mg/kg) or vehicle (sesame oil) at postnatal day 3. At postnatal weeks 6-8, animals were assessed for spatial memory and anxiety-like behavior using the Barnes maze, open field, and elevated plus maze. Following behavioral testing, brains were processed using Golgi-Cox staining to examine dendritic morphology and spine density in the frontal cortex and hippocampus. THC exposure during the neonatal period induced a spatial memory deficit later in young adult female, but not male, rats. Anxiety-like behavior was not altered in either sex. THC-exposed animals of both sexes exhibited decreased spine density reductions, as well as decreases in dendritic length, branching, and complexity in cortical and hippocampal (cornu ammonis 1 [CA1], CA3, dentate gyrus) neurons. These findings demonstrate that a single neonatal THC exposure induces long-lasting, sex-dependent cognitive impairment and structural alterations in cortical and hippocampal neurons in rats. Our results underscore the vulnerability of the developing brain to cannabinoid exposure.