Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Laviolette, Steven R

2nd Supervisor

Rushlow, Walter J

Co-Supervisor

Abstract

The developing brain is especially vulnerable to the schizophrenia-inducing effects of tetrahydrocannabinol (THC), the psychoactive chemical in cannabis. Although the mechanisms underlying schizophrenia remains unclear, aberrant mesocorticolimbic signaling and brain omega-3 deficiency may be involved. This study investigated chronic prenatal THC’s effects on schizophrenia-associated behaviour as well as the neuronal activity states and omega-3 levels in the mesocorticolimbic system. Behaviourally, THC induced social memory impairments in male offspring whereas female exposure increased anxiety and anhedonia. Electrophysiology revealed ventral tegmental area dopamine hyperactivity and ventral hippocampus glutamate hyperactivity in male offspring whereas female exposure induced glutamate hyperactivity in the prefrontal cortex and ventral hippocampus. Lastly, matrix-assisted laser desorption/ionization imaging mass spectrometry showed that THC induces omega-3 deficiency in the prefrontal cortex, nucleus accumbens, and ventral hippocampus. These findings suggest that prenatal THC may induce different schizophrenia-associated effects on male and female offspring which calls for sex-specific treatments to counter THC’s effects.

Summary for Lay Audience

Cannabis is commonly used by pregnant women for morning sickness relief. Unfortunately, cannabis use during pregnancy may endanger their children’s brain development. Cannabis contains a chemical called tetrahydrocannabinol that causes adverse neurological effects. Evidence suggests that tetrahydrocannabinol exposure during early stages of brain development such as adolescence induces symptoms associated with schizophrenia, a disorder characterized by hallucinations, delusions, emotional instability, and intellectual decline. However, the consequences of fetal tetrahydrocannabinol are unclear; this is especially concerning since the concentration of THC have dramatically increased over the last decade. Moreover, this lack of knowledge may contribute to the widespread cannabis use by unknowing pregnant women. Therefore, using pregnant rats, we examined the schizophrenia-associated effects of maternal tetrahydrocannabinol exposure on the offspring and the neurological changes associated with these behavioural abnormalities. Pregnant rats received daily tetrahydrocannabinol injections (17 days) and their adult offspring underwent behavioural tests that examined schizophrenia-associated symptoms such as anxiety, locomotion, memory, sociability, depression-like behaviour, and propensity for addiction. We found that tetrahydrocannabinol decreased memory in male offspring only and induced anxiety and depression-like behaviour in only females. Next, we examined tetrahydrocannabinol’s effects on schizophrenia-implicated brain regions such as the ventral tegmental area, prefrontal cortex, and the ventral hippocampus. As seen in schizophrenia patients, male offspring displayed increased ventral tegmental area activity as well as decreased ventral hippocampus activity that is characteristic of the late stages of schizophrenia. In contrast, female offspring displayed increased prefrontal cortex and ventral hippocampus activity which are typical of schizophrenia patients. Finally, we measured brain levels of omega-3, a nutrient essential for proper brain function, in schizophrenia-related brain regions since decreased brain omega-3 is associated with schizophrenia. In males, tetrahydrocannabinol decreased omega-3 levels at 3-weeks and 6-months of age which suggests that tetrahydrocannabinol induces persistent omega-3 deficits. In female offspring, only the 3-week old offspring displayed omega-3 deficits which suggests that unlike males, females can recover from these omega-3 deficits. Altogether, these findings suggest that fetal tetrahydrocannabinol exposure leads to schizophrenia-associated effects. These findings also raise the need for male and female-specific treatments to counter the schizophrenia-inducing effects of tetrahydrocannabinol.

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