Striatal Volume Changes in the Rat Following Long-term Administration of Typical and Atypical Antipsychotic Drugs

Abstract

Caudate-putamen; Basal ganglia; Haloperidol; Clozapine; Olanzapine; Risperidone; Stereology In the last three decades, there has been a notable elucidation concerning the structure, organization and function of the basal ganglia, as well as the clinical relevance of this subcortical structure. The basal ganglia are comprised of four major structures: the striatum (made up of the caudate nucleus, the putamen, and the ventral striatum), the globus pallidus, the substantia nigra, and the subthalamic nucleus. The striatum receives inputs from the neocortex and the substantia nigra and, via the globus pallidus and substantia nigra, modulates thalamic function that, in turn, affects the frontal cortex. Although the role of the basal ganglia in movement planning and execution has been recognized for many years, we now understand that the compartmentalization and diverse chemoarchitecture of the basal ganglia, combined with complex anatomical interrelationships with thalamus and cortex, establishes this structure as a prime component in influencing executive function, emotion, and cognitive behaviors including learning and memory (Alexander et al. 1990). These findings also help explain why lesions of the basal ganglia lead to devastating movement disorders such as Parkinson's and Huntington's disease. Furthermore, due to both the complexity and functional parameters of this structure, the basal ganglia may play an important role in a number of neuropsychiatric disorders such as schizophrenia (Albin et al. 1989).Sensitive structural and functional brain imaging techniques have begun to unravel some of the complicated neuropathology present in schizophrenia. Several structural abnormalities appear to be integral to the disease process itself, including the enlargement of the lateral and third ventricles (Shenton et al. 1997;McCarley et al. 1999) as well as volumetric reductions in temporal cortex (Suddath et al. 1989;Rossi et al. 1990;DeLisi et al. 1991), hippocampus (Bogerts et al. 1985(Bogerts et al. , 1990Suddath et al. 1990), superior temporal gyrus (Barta et al. 1990;Shenton et al. 1992) and thalamus (Andreasen et al. 1994). Other anatomic abnormalities in schizophrenia, however, appear to develop secondarily to the disease process. Postmortem studies and early in vivo imaging studies have reported volumetric increases of the caudate-putamen complex in schizophrenic patients (Heckers et al. 1991;Jernigan et al. 1991). Although initially believed to be a result of a pathological neurodevelopmental process affecting the basal ganglia (Swayze et al. 1992), these structural abnormalities now appear to be probable treatment effects. In a study examining first-episode, treatment-naïve schizophrenia patients, Chakos et al. (1994) demonstrated that the volume of the caudate nucleus increased after an 18-month exposure to typical antipsychotic drugs in direct proportion to the extent of treatment, findings later confirmed by Keshavan et al. (1994). In addition, Doraiswamy et al. (1995) reported that volumetric increase...

The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeys

“…This pattern has been replicated in a recent stereological study of rats, where haloperidol exposure was associated with an increased volume of striatum and olanzapine exposure with a reduction (Andersson et al, 2002). Interestingly, a recent study of subjects with schizophrenia treated with low dosage haloperidol or atypical antipsychotics and normal comparison subjects found similar decrease in volumes of the caudate nucleus in all three groups after a 5-year follow-up (Tauscher-Wisniewski et al, 2002).…”

Caspase-3 Activation in Rat Frontal Cortex Following Treatment with Typical and Atypical Antipsychotics

“…These studies suggest that our haloperidol dose was somewhat high. However, haloperidol plasma levels for long-term dosing at 1 mg/kg/day in rats is typically around 10 ng/ml (Gao et al, 1997;Andersson et al, 2002) and 10 ng/ml is also the plasma level that has associated with better clinical response in one of the few double-blind randomized studies that targeted specific haloperidol plasma levelsF2 ng/ml vs 10 ng/mlF in acutely ill schizophrenic patients (Volavka et al, 1995). By this measure, our haloperidol dose was not unreasonably high.…”

Basal Ganglia Shape Abnormalities in the Unaffected Siblings of Schizophrenia Patients

“…The subjects in our prior study were older and had a longer duration of illness, and therefore were probably exposed to larger cumulative amounts of typical antipsychotics than subjects in our current study. The effect of typical antipsychotics, which are known to increase basal ganglia size (63,64), could have minimized a potentially greater basal ganglia structural deficit. As mentioned above, the large majority of SCZ subjects in this study were receiving atypical antipsychotic drugs.…”