Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra. There is a need for genetic animal models of PD for screening and in vivo testing of novel restorative therapeutic agents. Although current genetic models of PD produce behavioral impairment and nigrostriatal dysfunction, they do not reproduce the loss of midbrain dopaminergic neurons and 3,4-dihydroxyphenylalanine (L-DOPA) reversible behavioral deficits. Here, we demonstrate that Pitx3-deficient aphakia (ak) mice, which have been shown previously to exhibit a major loss of substantia nigra dopaminergic neurons, display motor deficits that are reversed by L-DOPA and evidence of "dopaminergic supersensitivity" in the striatum. Thus, ak mice represent a novel genetic model exhibiting useful characteristics to test the efficacy of symptomatic therapies for PD and to study the functional changes in the striatum after dopamine depletion and L-DOPA treatment.

These results indicate that asenapine has region-specific and dose-dependent effects on dopamine receptor subtypes in rat forebrain, which may contribute to asenapine's unique psychopharmacological properties.

The atypical antipsychotic risperidone is often prescribed to pediatric patients with neuropsychiatric disorders, though its effects on the developing brain remain unclear. Accordingly, we studied the effects of repeated treatment of risperidone on dopamine receptors in brain regions of juvenile rat. Levels of dopamine receptors (D 1 , D 2 , D 3 , D 4 ) in forebrain regions of juvenile rats were quantified after 3 weeks of treatment with three different doses of risperidone (0.3, 1.0 and 3.0 mg/kg) and compared findings to those in adult rats treated with risperidone (3.0 mg/kg/day) previously. Risperidone (at 1.0 and 3.0 mg/kg/day) increased levels of D 1 receptors in nucleus accumbens and caudate-putamen of juvenile, but not adult rats. Conversely, all three doses of risperidone dosedependently increased D 2 labeling in medial prefrontal cortex and hippocampus, and D 4 receptor in nucleus accumbens, caudate-putamen and hippocampus of juvenile animals as well as in adults. Only the high dose of risperidone (3.0 mg/kg) increased D 2 receptors in caudate-putamen in both juvenile and adult brain. D 3 receptors were not altered by risperidone in any brain region at any dose or age. The findings indicate dose-dependent effects of risperidone on dopamine receptors in developing animals, and that juvenile animals are more sensitive than adults to the cerebral effects of risperidone.

Antipsychotic drugs are often prescribed to juvenile psychiatric patients, though their cerebral effects during development are incompletely described. Accordingly, we studied the effects of repeated treatment with dissimilar antipsychotic drugs on dopamine (DA) receptors in juvenile vs. adult rats. Tissue levels of DA receptor types (D1, D2, D3, and D4) in forebrain regions of juvenile rats were quantified after 3 weeks of daily treatment with representative first- (fluphenazine) and second-generation (clozapine and olanzapine) antipsychotics, and compared with similarly treated adult rats examined in previous studies. Fluphenazine, clozapine, and olanzapine all decreased D1 receptors in dorsolateral frontal and medial prefrontal cortex (MPC) of juvenile, but not adult rats. Conversely, all three test agents increased D2 labeling in MPC of adult, but not young animals. Fluphenazine and olanzapine, but not clozapine, also increased D2 receptor levels in hippocampus, and D4 levels in nucleus accumbens (NAc) and caudate-putamen (CPu) in both juvenile and adult brain. D3 receptors were not altered by any treatment in any brain region at either age. Only some DA receptor adaptations to antipsychotic treatment are shared by developing and mature animals. Developmental differences in DA receptor responses may account for differences in clinical effects of antipsychotic drugs between young and adult psychiatric patients.