Early exposure to haloperidol or olanzapine induces long-term alterations of dendritic form

Abstract

Exposure of the developing brain to a wide variety of drugs of abuse (e.g., stimulants, opioids, ethanol, etc.) can induce life-long changes in behavior and neural circuitry. However, the long-term effects of exposure to therapeutic, psychotropic drugs have only recently begun to be appreciated. Antipsychotic drugs are little studied in this regard. Here, we quantitatively analyzed dendritic architecture in adult mice treated with paradigmatic typical- (haloperidol) or atypical (olanzapine) antipsychotic drugs at developmental stages corresponding to fetal or fetal plus early childhood stages in humans. In layer 3 pyramidal cells of the medial and orbital prefrontal cortices and the parietal cortex and in spiny neurons of the core of the nucleus accumbens, both drugs induced significant changes (predominantly reductions) in the amount and complexity of dendritic arbor and the density of dendritic spines. The drug-induced plasticity of dendritic architecture suggests changes in patterns of neuronal connectivity in multiple brain regions that are likely to be functionally significant.

Fig. 1

Camera lucida drawings of typical pyramidal cells in the parietal and medial prefrontal cortices of mice treated with saline or haloperidol on P3-10. The insets immediately adjacent to each cell are drawings of terminal apical (upper) or third order basal (lower) dendritic segments that were used to calculate spine densities. The cells shown were selected because they were close to the group averages for our 3 measures of dendritic form.

Fig. 2

Total dendritic arbor, number of dendritic segments and dendritic spine density in adult, female mice treated from P3-10 or P3-20 with haloperidol, olanzapine or (as a control) saline. Data from apical and basal dendritic arbors are calculated separately for each cortical area. 5 neurons were measured in each region of interest in each hemisphere. n =6 hemispheres/treatment group-duration. Asterisks indicate measures in APD treated mice that differ significantly (p<0.05) from those obtained in saline treated mice. OPC, MPC, Par and NAc indicate the orbital and medial prefrontal cortices, parietal cortex and nucleus accumbens core, respectively.