Long-Term Treatment of Rats with Haloperidol: Lack of an Effect on Brain N-Acetyl Aspartate Levels

Bustillo, Juan; Barrow, Ranee; Paz, Rodrigo D.; Tang, Jennifer; Seraji‐Bozorgzad, Navid; Moore, Gregory J.; Bolognani, Federico; Lauriello, John; Perrone‐Bizzozero, Nora I.; Galloway, Matthew P.

doi:10.1038/sj.npp.1300874

Cited by 42 publications

(37 citation statements)

References 26 publications

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“…Similarly, following a 6-week exposure to haloperidol and clozapine, we detected no reductions in NAA (Bustillo et al, 2004). Recently two studies with 6 months exposures to haloperidol failed to identify NAA reductions in various cortical regions or hippocampus (Harte et al, 2005;Bustillo et al, 2006), consistent with our current findings. However, Harte et al (2005) did find striatal NAA elevations with haloperidol.…”

Section: Discussionsupporting

confidence: 91%

Proton Magnetic Resonance Spectroscopy During Initial Treatment With Antipsychotic Medication in Schizophrenia

Bustillo

Rowland

Jung

et al. 2007

Neuropsychopharmacol

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Reduced brain N-acetyl-aspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. We studied 32 minimally treated schizophrenia patients and 21 healthy subjects with single-voxel proton magnetic resonance spectroscopy ( 1 H-MRS) of the frontal and occipital lobes, caudate nucleus, and cerebellum. Concentrations of NAA, Choline, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind manner with either haloperidol or quetiapine. 1 H-MRS was repeated every 6 months for up to 2 years. There was a group main effect for baseline NAA with lower global NAA in schizophrenia subjects before treatment compared to healthy controls. Global NAA was directly related to measures of global cognitive performance in the whole subject sample. Following treatment with haloperidol or quetiapine, there were no changes in NAA in any of the regions studied. Early in the illness, schizophrenia patients already demonstrate subtle reductions in NAA. Treatment with typical or atypical antipsychotic medications for several months does not result in NAA changes.

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Section: Discussionsupporting

confidence: 91%

Proton Magnetic Resonance Spectroscopy During Initial Treatment With Antipsychotic Medication in Schizophrenia

Bustillo

Rowland

Jung

et al. 2007

Neuropsychopharmacol

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“…Fourth, antipsychotic treatment was not standardized for enrolled subjects. Several studies have suggested that antipsychotic treatment or withdrawal of treatment may raise or reduce cortical NAA levels, respectively (Bertolino Furthermore, a 6-month longitudinal MRS study in haloperidol-treated rats found no effect of antipsychotic treatment on NAA or choline in cortical brain regions (Bustillo et al, 2006). In summary, 12 weeks of davunetide was associated with a modest increase in choline/Cr and a suggestive increase in NAA/Cr in DLPFC in clinically stable people with schizophrenia taking antipsychotic medication.…”

Section: Discussionmentioning

confidence: 93%

Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia

Jarskog

Dong

Kangarlu

et al. 2013

Neuropsychopharmacol

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Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy ( 1 H-MRS) was conducted to explore the effects of davunetide on change in NAA/ creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed 1 H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high-and low-dose davunetide groups (N ¼ 11). NAA/Cr in the high-dose davunetide group (N ¼ 8) suggested a trend increase of 8.0% (P ¼ 0.072) over placebo (N ¼ 7). Choline/Cr for combined high-and low-dose davunetide groups suggested a 6.4% increase (P ¼ 0.069), while the high-dose group showed a 7.9% increase (P ¼ 0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R ¼ 0.52, P ¼ 0.033), as did individual cognitive domains of attention/ vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.

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“…No changes were observed in other brain areas. Reports from another group did not support these results, and instead these researchers detected no changes in NAA levels in frozen rat brain micro-punches after haloperidol treatment using HPLC (Bustillo et al, 2004) or high field MRS (Bustillo et al, 2005). Further studies are required to determine the effects of haloperidol on brain NAA levels.…”

Section: Magnetic Resonance Spectroscopy and Imaging Of Naamentioning

confidence: 90%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Long-Term Treatment of Rats with Haloperidol: Lack of an Effect on Brain N-Acetyl Aspartate Levels

Cited by 42 publications

References 26 publications

Proton Magnetic Resonance Spectroscopy During Initial Treatment With Antipsychotic Medication in Schizophrenia

Proton Magnetic Resonance Spectroscopy During Initial Treatment With Antipsychotic Medication in Schizophrenia

Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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