Effects of Haloperidol on Cell Proliferation in the Early Postnatal Rat Brain

Backhouse, B.; Barochovsky, O.; Malik, Corinna; Patel, Ambrish J.; Lewis, Paul D.

doi:10.1111/j.1365-2990.1982.tb00266.x

Cited by 33 publications

(12 citation statements)

References 21 publications

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“…These findings indicate that the upregulation of hippocampal BrdU labeling may be pharmacologically selective to the chemical antidepressant drugs. The lack of effect of haloperidol in this study differs from two previous studies, one reporting an increase (Dawirs et al, 1998), and one reporting a decrease (Backhouse et al, 1982) in cell proliferation. However, there are several differences between the current and these previous reports, including dose and time course of drug treatment, species and age of test animals, and the BrdU labeling protocol.…”

Section: Discussioncontrasting

confidence: 56%

Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

et al. 2000

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Recent studies suggest that stress-induced atrophy and loss of hippocampal neurons may contribute to the pathophysiology of depression. The aim of this study was to investigate the effect of antidepressants on hippocampal neurogenesis in the adult rat, using the thymidine analog bromodeoxyuridine (BrdU) as a marker for dividing cells. Our studies demonstrate that chronic antidepressant treatment significantly increases the number of BrdU-labeled cells in the dentate gyrus and hilus of the hippocampus. Administration of several different classes of antidepressant, but not non-antidepressant, agents was found to increase BrdU-labeled cell number, indicating that this is a common and selective action of antidepressants. In addition, upregulation of the number of BrdU-labeled cells is observed after chronic, but not acute, treatment, consistent with the time course for the therapeutic action of antidepressants. Additional studies demonstrated that antidepressant treatment increases the proliferation of hippocampal cells and that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal-or glial-specific markers. These findings raise the possibility that increased cell proliferation and increased neuronal number may be a mechanism by which antidepressant treatment overcomes the stress-induced atrophy and loss of hippocampal neurons and may contribute to the therapeutic actions of antidepressant treatment.Key words: proliferation; granule cell; fluoxetine; tranylcypromine; reboxetine; depression Depression is a devastating illness that is estimated to affect 12-17% of the population at some point during the lifetime of an individual (Kessler et al., 1994). Antidepressants are commonly prescribed for depression and other affective disorders, although the molecular and cellular mechanisms by which these agents exert their therapeutic effects are not well understood. Preclinical and clinical research has focused on the interactions between stress and depression and their effects on the hippocampus, among other brain regions (Duman et al., 1999;McEwen, 1999). For example, the hippocampus has been shown to undergo morphological changes in response to stress, including atrophy and loss of CA3 pyramidal neurons after exposure to physical or psychosocial stress (Watanabe et al., 1992c;Stein-Behrens et al., 1994;Margarinos et al., 1996;McEwen, 1999). In addition, brain-imaging studies demonstrate that hippocampal volume is decreased in patients with stress-related psychiatric illnesses, including depression and posttraumatic stress disorder (Sapolsky, 1996;Sheline et al., 1996).The hippocampus is one of only a few brain regions where production of neurons occurs throughout the lifetime of animals, including humans (Eriksson et al., 1998). Hippocampal neurogenesis can be influenced by several environmental factors and stimuli (Kuhn et al., 1996;Kempermann et al., 1997;Gould et al., 1999a;van Praag et al., 1999b). Importantly, it has been shown that stressful experiences, including both ph...

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Section: Discussioncontrasting

confidence: 56%

Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

et al. 2000

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“…Kippin et al (2002) reported that neither haloperidol nor clozapine (2 and 20 mg/kg, respectively, for 14 days) affected BrdU-positive cells in the DG. Yet, Dawirs et al (1998) reported that acute treatment (4 injections over 24 h at 5 mg/kg each) with haloperidol significantly increased BrdU-positive cells in the DG 7 days after BrdU administration in gerbils, whereas Backhouse et al (1982) reported that treatment with haloperidol (a single injection of 20 mg/kg in 11-day-old rat pups) decreased the number of BrdU-positive cells. However, the latter two studies examined the effects of antipsychotics in an acute rather than chronic paradigm and used either different species (gerbils rather than rats in Dawirs et al, 1998) or preadolescent rats (Backhouse et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Effects of Chronic Haloperidol and Clozapine Treatment on Neurogenesis in the Adult Rat Hippocampus

Halim

Weickert

McClintock

et al. 2004

Neuropsychopharmacol

173

109

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It has been proposed that the therapeutic benefits of treatment with antidepressants and mood stabilizers may arise partially from their ability to stimulate neurogenesis. This study was designed to examine the effects of chronic antipsychotic treatment on cell proliferation and survival in the adult rat hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU, 200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h following BrdU administration and BrdU-positive cells were quantified to assess the effects of drug treatment on cell proliferation. The remaining animals continued on antipsychotic medication for an additional 3 weeks following BrdU administration to assess the effects of antipsychotics on cell survival. Our results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus (DG) by two-fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell proliferation in DG. Moreover, neither drug at either dose had an effect on the number of newly generated neurons surviving in the DG 3 weeks following BrdU administration. These preliminary findings suggest that clozapine may influence the number of cells which divide, but antipsychotics do not promote the survival of the newly generated neurons at 3 weeks after a BrdU injection.

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“…46,47 However, either the high dose of haloperidol used or the early developmental stage chosen for testing complicates these studies. Additional studies of atypical antipsychotic drugs on either the basal rate of neurogenesis or on the down-regulation of neurogenesis in response to stress are warranted.…”

Section: Antidepressant Treatment Increases Adult Neurogenesismentioning

confidence: 99%

Synaptic plasticity and mood disorders

2002

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Recent studies demonstrate that the molecular elements known to regulate neuronal plasticity in models of learning and memory are also involved in the actions of drugs used for the treatment of depression and bipolar disorder. This includes up-regulation of transcription factors, such as the cAMP response element binding protein and neurotrophic factors, such as brain derived neurotrophic factor. These findings raise the possibility that regulation of neural plasticity in specific neuronal circuits is integrally involved in the therapeutic intervention of mood disorders. Atypical antipsychotic drugs, including clozapine and olanzapine, are also effective for the treatment of bipolar disorder, and are used as add-on medication for unipolar depression. The possibility that these atypical antipsychotic drugs also influence the molecular determinants of synaptic plasticity that are involved in the response to drugs used for the treatment of mood disorders, is discussed. Molecular Psychiatry (2002) 7, S29-S34.

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Effects of Haloperidol on Cell Proliferation in the Early Postnatal Rat Brain

Cited by 33 publications

References 21 publications

Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus

Effects of Chronic Haloperidol and Clozapine Treatment on Neurogenesis in the Adult Rat Hippocampus

Synaptic plasticity and mood disorders

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