Hormone Influence on the Mesocortical Dopaminergic System: An Integrated Behavioral, Anatomical and In Vivo Physiological Characterization in Adult Male Rats

Abstract

The prefrontal cortices (PFC) are linked to highest-order executive functions such as working memory, planning and decision making. These complex constructs are strongly dependent on local signaling via the neurotransmitter dopamine (DA). Stimulated by male over female sex differences in PFC function and especially by the significantly greater vulnerability of males to symptoms of PFC dysfunction in disorders such as schizophrenia, the experiments of this dissertation explored behavioral and biochemical effects of gonadal hormones on PFC DA systems using adult male rats that were gonadectomized (GDX) and supplemented with either androgens or estrogens as animal models. The first studies extended previous evidence that GDX disrupts performance in DA-dependent PFC behavioral tasks to the novel object recognition paradigm, which enabled the first identification of GDX effects on working memory independent of any effects on the animals' motivational state. Next, using in vivo microdialysis, it was found that resting PFC DA levels were nearly two-fold higher than normal in GDX animals. In searching for anatomical substrates for these androgen-sensitive, estrogen-insensitive effects of GDX, it was considered that fewer than 25% of the DA neurons that innervate the PFC contained androgen receptors, i.e. were androgen sensitive. Thus, the next study combined anatomical track-tracing and immunohistochemistry for androgen receptors to see whether neurons projecting to these DA cells might be the locus of hormone sensitivity. These studies revealed the surprising result that perhaps the most likely targets of androgen actions were neurons in the PFC itself that use glutamate as neurotransmitter. Thus, the final experiment again used in vivo microdialysis, but this time paired with glutamate receptor-selective drugs. These studies revealed that GDX caused striking androgen-sensitive deviations from expected drug-stimulated changes in PFC DA levels. Taken together, these findings thus extend understanding of androgen's regulation of PFC function in males and identify DA/glutamate interactions as prime targets for this gonadal hormone influence. Because DA/glutamate interactions are central to contemporary etiological theories for disorders including schizophrenia, autism and ADHD, these findings may not only bring us closer to understanding the neurobiological bases for these devastating disorders, but closer to overcoming them as well