Clinical work on the mother-child relationship shows that the quality of maternal care from women with schizophrenia is generally inferior to that from healthy mothers. One important contributing factor recognized by both patients and their clinicians is antipsychotic medications. Both typical and atypical antipsychotics are reported to adversely affect maternal care. The PI's long-term goal is to understand the neurobiological and behavioral mechanisms of action of antipsychotic drugs. The objective of this R03 application is to determine the behavioral and neurochemical mechanisms underlying the adverse effects of both typical and atypical antipsychotics on maternal behavior using a rat model. The project hypothesis is that at the clinical relevant dose, the disruptive effect of antipsychotics on maternal behavior primarily reflects a suppressive effect on maternal motivation and is mediated via the dopamine D2 receptor system. Rat maternal behavior is chosen as a model system because it is an ecologically valid and complex behavior that cuts across mammalian species and shares many direct features with human mothering behaviors.
Aim 1 will examine the motivational mechanism underlying the disruptive effect of antipsychotics on rat maternal behavior.
Aim 2 will identify the neurochemical basis (dopamine versus serotonin) of clozapine-induced maternal behavior deficits. Specifically, the PI will seek to determine (1) whether haloperidol and clozapine at the therapeutic relevant doses (~50%-80% D2 occupancy in rodents) produce a disruption of active maternal behaviors by decreasing mother rats' motivation, as opposed to motor function or sedation; (2) to what extent clozapine (as the representative of atypical antipsychotic drugs) disrupts maternal behavior via the blocking of dopamine D2 receptors and/or 5-HT2A receptors. This project is innovative in that both behavioral (mother-pup separation, repeated drug administration and testing) and pharmacological means (chlordiazepoxide) will be employed to tease apart the specific antipsychotic effects on various distinct behavioral processes involved in rat maternal behavior. . This preclinical project is designed to determine the important psychological and neurochemical mechanisms underlying the adverse side effects of antipsychotic medication on human mothering behavior. Knowledge gained from this project is expected to enhance understanding of the extent to which antipsychotic drugs impact the quality of maternal care and the nature of such impact. Project outcomes are expected to increase the effectiveness of the evaluation of psychotropic drug uses in mothers, future drug development and clinical practice and, ultimately, positively impact the health and well-being of children of mothers with schizophrenia. ? ? ?
