Abstract

There are sex differences in the symptom manifestation of schizophrenia as well as in the response to antipsychotics. For example, women respond better to antipsychotic treatment when estrogens are used as an adjuvant therapy. This has led to the question of whether sex hormones play a role in the neurobiology of this disorder and/or the response to treatments. The earliest version of the dopamine hypothesis of schizophrenia proposed that this disorder is associated with hyperactive striatal dopamine transmission and most antipsychotics antagonize dopamine D2 receptors. Yet, estrogens themselves have been shown to enhance striatal dopamine transmission; suggesting a paradox.
This thesis examined the relationship between one estrogen, 17β-estradiol, and dopamine, and the mechanisms through which 17β-estradiol affects D2 receptors. Specifically, the effects of 17β-estradiol on tonic/phasic dorsal striatal dopamine release was measured. The effects of 17β-estradiol on specifically phasic dorsal striatal dopamine release was examined. It was shown that 17β-estradiol rapidly increases both tonic and phasic dorsal striatal dopamine release in vivo in anesthetized female rats.
The rodent model of amphetamine sensitization, which mimics in rats some of the neuronal changes thought to occur in schizophrenia, was then used for the ensuing two studies. In those experiments, the mechanisms through which 17β-estradiol and the antipsychotic, haloperidol, affect dopamine transmission were explored via their effects on dopamine D2 receptor affinity and some of its second messenger proteins (i.e., Akt, phosphorylated Akt, and β-arrestin). Both 17β-estradiol and haloperidol increase the affinity of D2High and D2Low receptors. Additionally, the combination of 17β-estradiol and haloperidol together decrease the proportion of dopamine D2 receptors in the high affinity state. However, there were no observed effects on second messenger proteins.
These studies provide one potential mechanism, i.e., via dopamine D2 receptor affinity state, through which 17β-estradiol in conjunction with the antipsychotic, haloperidol, may enhance its effects on reducing striatal dopamine transmission despite increasing dopamine release. These data have implications for the beneficial effects of estrogens in the treatment of schizophrenia in women.