Elsevier

Biological Psychiatry

Volume 71, Issue 10, 15 May 2012, Pages 855-863
Biological Psychiatry

Priority Communication
Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation

https://doi.org/10.1016/j.biopsych.2011.12.004Get rights and content

Background

Magnetic resonance imaging (MRI) studies suggest that antipsychotic -treated patients with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated patients with bipolar disorder show marginal increases in gray-matter volumes. Although these clinical data are confounded by illness, chronicity, and other medications, they do suggest that typical antipsychotic drugs and lithium have contrasting effects on brain volume.

Methods

Rodent models offer a tractable system to test this hypothesis, and we therefore examined the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with clinically relevant dosing of an antipsychotic (haloperidol, HAL) or lithium (Li) on brain volume using longitudinal in vivo structural MRI and confirmed the findings postmortem using unbiased stereology.

Results

Chronic HAL treatment induced decreases in whole brain volume (−4%) and cortical gray matter (−6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast, chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray matter (+3%) without a significant effect on striatal volume. Following 8 weeks of drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated animals retained significantly greater total brain volumes, as confirmed postmortem. However, the distribution of these contrasting changes was topographically distinct: with the haloperidol decreases more prominent rostral, the lithium increases were more prominent caudal.

Conclusions

The implications of these findings for the clinic, potential mitigation strategies, and further drug development are discussed.

Section snippets

Animals

Male Sprague-Dawley rats (Charles River UK, Kent, United Kingdom), initial body weight 240 to 250 g (9 weeks of age) were housed 4 per cage under a 12-hour light–dark cycle (7 am lights on) with food and water available ad libitum. Room temperature was maintained at 21° ± 2°C and relative humidity at 55% ± 10%. Animals were habituated for 7 days before experimental procedures. Animal experiments were carried out with local ethical approval and in accordance with the Home Office Animals

Plasma Levels and Behavior

Administration of psychotropic drugs by osmotic pump achieved clinically relevant plasma levels (mean ± SD) of 4.7 ± .32 ng/mL (low HAL), 23.3 ± 1.5 ng/mL (high HAL) and .49 ± .04 mmol/L (Li). All animals increased in body weight over time irrespective of treatment group (Figure 1A; Table 1). HAL-treated animals gained less weight compared with controls, but this did not reach statistical significance. Chronic Li-treated animals displayed polyuria, but body weight was comparable to vehicle

Discussion

This is the first longitudinal in vivo MRI study in rodents to compare the effects of two commonly prescribed psychotropic medications on different brain regions. We observed contrasting effects of treatment (8 weeks) with therapeutically relevant concentrations of HAL and Li. Specifically, HAL-treatment resulted in dose-related reductions in WBV (up to −3.7%) and CTX (up to −5.9%) accompanied by hypertrophy of the STR (up to +14%) compared with vehicle controls. In contrast, Li-treatment

References (60)

  • M.H. Chakos et al.

    Striatal enlargement in rats chronically treated with neuroleptic

    Biol Psychiatry

    (1998)
  • M.J. Kempton et al.

    Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies

    Schizophr Res

    (2010)
  • E.S. Monkul et al.

    Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study

    Neurosci Lett

    (2007)
  • B. Hallahan et al.

    Structural magnetic resonance imaging in bipolar disorder: An international collaborative mega-analysis of individual adult patient data

    Biol Psychiatry

    (2011)
  • C.E. Bearden et al.

    Greater cortical gray matter density in lithium-treated patients with bipolar disorder

    Biol Psychiatry

    (2007)
  • F.M. Benes et al.

    The effects of haloperidol on synaptic patterns in the rat striatum

    Brain Res

    (1985)
  • C. Konradi et al.

    Antipsychotic drugs and neuroplasticity: Insights into the treatment and neurobiology of schizophrenia

    Biol Psychiatry

    (2001)
  • N.C. Andreasen et al.

    Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia

    Biol Psychiatry

    (2011)
  • B. Olabi et al.

    Are there progressive brain changes in schizophrenia?A meta-analysis of structural magnetic resonance imaging studies

    Biol Psychiatry

    (2011)
  • S. Kapur et al.

    Half a century of antipsychotics and still a central role for dopamine D2 receptors

    Prog Neuropsychopharmacol Biol Psychiatry

    (2003)
  • G.T. Konopaske et al.

    Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys

    Biol Psychiatry

    (2008)
  • L.D. Selemon et al.

    The reduced neuropil hypothesis: A circuit based model of schizophrenia

    Biol Psychiatry

    (1999)
  • Y. Piontkewitz et al.

    Clozapine administration in adolescence prevents postpubertal emergence of brain structural pathology in an animal model of schizophrenia

    Biol Psychiatry

    (2009)
  • J. Ashburner et al.

    Computer-assisted imaging to assess brain structure in healthy and diseased brains

    Lancet Neurol

    (2003)
  • B.C. Ho et al.

    Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia

    Arch Gen Psychiatry

    (2011)
  • J.A. Lieberman et al.

    Antipsychotic drug effects on brain morphology in first-episode psychosis

    Arch Gen Psychiatry

    (2005)
  • I.K. Lyoo et al.

    Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: A longitudinal brain imaging study

    Neuropsychopharmacology

    (2010)
  • M.H. Chakos et al.

    Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs

    Am J Psychiatry

    (1994)
  • P. Dazzan et al.

    Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study

    Neuropsychopharmacology

    (2005)
  • H. Tost et al.

    Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits

    Nat Neurosci

    (2010)
  • Cited by (0)

    Authors ACV and SN contributed equally to this work.

    View full text