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1.
Psychol Med ; 46(15): 3081-3093, 2016 11.
Article in English | MEDLINE | ID: mdl-27516217

ABSTRACT

BACKGROUND: One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear. METHOD: We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group. RESULTS: Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes. CONCLUSIONS: Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.


Subject(s)
Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Gray Matter/drug effects , Haloperidol/pharmacology , Hippocampus/drug effects , Animals , Brain/diagnostic imaging , Brain/drug effects , Brain/pathology , Female , Gray Matter/diagnostic imaging , Gray Matter/pathology , Hippocampus/diagnostic imaging , Hippocampus/pathology , Magnetic Resonance Imaging , Male , Olanzapine , Organ Size , Rats
2.
Neuropharmacology ; 62(3): 1359-70, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21521646

ABSTRACT

Neuroanatomical, electrophysiological and behavioural abnormalities following timed prenatal methylazoxymethanol acetate (MAM) treatment in rats model changes observed in schizophrenia. In particular, MAM treatment on gestational day 17 (E17) preferentially disrupts limbic-cortical circuits, and is a promising animal model of schizophrenia. The hypersensitivity of this model to the NMDA receptor antagonist-induced hyperactivity has been proposed to mimic the increase in sensitivity observed in schizophrenia patients following PCP and Ketamine administration. However, how this increase in sensitivity in both patients and animals translates to differences in EEG oscillatory activity is unknown. In this study we have shown that MAM-E17 treated animals have an increased response to the hyperlocomotor and wake promoting effects of Ketamine, PCP, and MK801 but not to the competitive antagonist SDZ 220,581. These behavioural changes were accompanied by altered EEG responses to the NMDAR antagonists, most evident in the gamma and high frequency (HFO) ranges; altered sensitivity of these neuronal network oscillations in MAM-exposed rats is regionally selective, and reflects altered interneuronal function in this neurodevelopmental model.


Subject(s)
Brain Waves/drug effects , Cerebral Cortex/embryology , Disease Models, Animal , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Schizophrenia/physiopathology , Animals , Biphenyl Compounds/pharmacology , Cerebral Cortex/drug effects , Cross-Over Studies , Excitatory Amino Acid Antagonists/pharmacology , Female , Male , Methylazoxymethanol Acetate/toxicity , Pregnancy , Propionates/pharmacology , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/physiology , Schizophrenia/chemically induced
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