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Symposia

Sex Differences in Response to Neuroleptic Exposure
Douglas O. Frost, Ph.D.
School of Medicine, University of Maryland, Baltimore

Antipsychotic drugs (APDs) are taken by people suffering from schizophrenia or other psychiatric diseases with a psychotic component. Sadly, many people have these diseases: schizophrenia, alone, afflicts about 1% of the world's population, and of those, about 1/3 are women. Despite the unknown risks for their children, many pregnant or nursing women must take APDs because interruption of pharmacotherapy would severly jeopardize the women's ability to carry on their daily lives and to care for their children. APDs modulate communication among nerve cells (neurons) in the brain that is mediated by the neurotransmitters serotonin and dopamine. Serotonin and dopamine also regulate many important ontogenetic processes in the brain, including the development of "axons" and "dendrites"-neuronal appendages that are connected together to form brain circuitry and thus, are key determinants of neuronal function. APDs can cross the placental barrier or be transferred to nursing infants in breast milk. Therefore, we hypthesized that APD exposure during brain development causes long-lasting, behaviorally significant changes in brain circuitry.

We conducted preliminary studies of male mice treated with therapeutic doses of representative members of the two major families of antipsychotic drugs-haloperidol, a classical (typical) APD, and olanzapine, a commonly prescribed second generation (atypical) APD. Drug treatment was at developmental stages after the interval when sexual dimorphism is induced in the brain by a surge of testosterone production in males and during an epoch when the circuitry of the cerebral cortex is being assembled. This epoch is largely prenatal in humans. The mice appear to be impaired in the performance of sets of behavioral tasks that assess the functions of the medial prefrontal (MPC) and anterior cingulate (ACC) cortices. We also conducted preliminary quantitative studies of the normal development of dendrites on neurons of the MPC, ACC and the primary somatosensory cortex (S1) of male mice, as well as the effects on dendritic development of early exposure to haloperidol or olanzapine. During normal ontogeny, the dendrites of different populations of cortical neurons in these 3 areas develop by distinct combinations of constructive and regressive events. Early APD exposure can accelerate, retard or inhibit the developmental growth and "pruning" of immature dendrites and thus change the pattern and functionality of cortical circuitry. These changes appear to underlie the observed behavioral changes.

Our initial, pilot studies used only male mice for two reasons: 1) In addition to gender differences in behavior, there are numerous examples of sexual dimorphism in dendritic structure and function and in dendritic responses to lesions and experience. Thus, pooling data from mice of both sexes could obscure the effects of APD treatment in one or both sexes. Because our studies are labor intensive it was not feasible to conduct parallel studies in mice of both sexes. 2) Studies of female mice are complicated by the fact that dendritic form in many brain regions is constantly remodeled with the progression of the estrus cycle. Thus, we chose to simplify our preliminary experiments by using male mice, in which this complicating factor is absent.

Now that the effects of early APD exposure on behavior and cortical circuitry have begun to emerge in our relatively simpler studies of male mice, we wish to compare the effects of APDs in females and males. These studies impact women's health in that they determine the relative risk of women of early APD exposure and they provide new information on effects of a previously understudied, widely used class of drugs on pregnancy outcomes.