Abstract

There are sex differences in dopamine-dependent diseases and behaviours, and accumulating evidence suggests that estrogens are partially responsible. This thesis examines the effects of estrogens on dopamine-dependent cognitive processes. Some of these cognitive processes are affected in schizophrenia, so these experiments also examined the combined effects of estrogen and the antipsychotic drug haloperidol on these cognitive processes.
The first study in this thesis examined the effects of estrogens and haloperidol on selective attention, measured in a latent inhibition paradigm. The result of these experiments demonstrated that estrogens have detrimental effects on latent inhibition, but facilitate an acute dose of haloperidol to restore latent inhibition in female rats. The next two studies extended these findings to two other cognitive processes negatively affected in individuals with schizophrenia: perseveration and reversal learning. Estrogens alone had no effect on perseveration or reversal learning in amphetamine sensitized female rats, but did fascilitate haloperidol to reduce perseveration and improve reversal learning.
Previous research has observed very low levels of estrogen receptors in the striatum, nucleus accumbens and prefrontal cortex, regions that mediate the majority of dopamine-dependent cognitive processes. Immunoelectron microscopy was used to examine estrogen receptors in these regions to provide a mechanism for estrogens’ effects on dopamine dependent behaviour. Immunohistochemistry was used to examine the distribution of estrogen receptors, ERα, ERβ, and GPER1, demonstrating that these receptors are observed primarily at presynaptic extranuclear sites and in glia in the striatum, nucleus accumbens and prefrontal cortex. In the striatum a small proportion of ERα and GPER1 are localized to cholinergic interneurons and a larger proportion of these receptors are observed in GABAergic neurons in the striatum. In the accumbens a low proportion of ERα and GPER1 were localized to catecholaminergic neurons, and a greater proportion of these receptors were observed in GABAergic neurons. The final experiment in this thesis examined whether binding at membrane-associated estrogen receptors could rapidly affect dopamine-dependent cognition. Increasing estrogens in the prefrontal cortex rapidly biases female rats towards use of place memory, indicating that binding at membrane-associated estrogen receptors can rapidly affect dopamine-dependent cognitive processes.