Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments

Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Brain Research (Impact Factor: 2.84). 06/2008; 1211:37-43. DOI: 10.1016/j.brainres.2008.03.023
Source: PubMed


Antidepressant treatments have been proposed to produce their therapeutic effects, in part, through increasing neurotrophin levels in the brain. The current experiments investigated the effects of acute and chronic treatment with different pharmacologic and somatic antidepressant treatments on protein levels of BDNF in several brain regions associated with depression in the rat. Repeated applications (10 days) of electroconvulsive shock (ECS), but not a single treatment (1 day), produced 40-100% increases of BDNF protein in the hippocampus, frontal cortex, amygdala, and brainstem. Chronic (21 days), but not acute (1 day), treatment with the tricyclic antidepressant (TCA) desipramine (10 mg/kg), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10 mg/kg), and the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg) increased BDNF protein levels in the frontal cortex (10-30%), but not in the hippocampus, amygdala, olfactory bulb, and brain stem. To determine whether the regulation of BDNF was unique to antidepressant treatments, drugs used to treat schizophrenia and anxiety were also studied. Chronic administration of the typical antipsychotic haloperidol (1 mg/kg) and the atypical antipsychotic clozapine (20 mg/kg) increased BDNF levels by only 8-10% in the frontal cortex. Haloperidol also elevated BDNF levels in the amygdala, while clozapine decreased BDNF in the olfactory bulb. Acute or chronic treatment with the benzodiazepine chlordiazepoxide (10 mg/kg) did not alter BDNF levels. These results suggest that diverse pharmacologic and somatic antidepressant treatments, as well as antipsychotics, increase levels of BDNF protein in the frontal cortex, even though they have different mechanisms of action at neurotransmitter systems.

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Available from: Jessica E Malberg, May 27, 2014
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    • "For example, tricyclic antidepressants act by blocking the reuptake of monoamine transmitters e noradrenaline and serotonin e from the synaptic cleft, leading to increases in their levels [18]. A wide body of research work has examined how psychotropics affect individual transmitters [19], receptors [20], second messengers [21], genes [22], and other key components involved in intra-and inter-cellular signalling [23]. Recently, it has been found that antidepressants have the ability to improve connectivity (synaptic plasticity) between neurons [24]. "
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    ABSTRACT: Psychotropic medications are widely used to treat a variety of mental disorders, but a unifying explanation of their modes of action remains obscure.
    04/2015; 4. DOI:10.1016/j.pmu.2015.03.001
    • "In line with our results, an acute administration of conventional antidepressants is reported to cause no alteration on hippocampal and/ or cerebrocortical BDNF levels (Balu et al., 2008). Conversely, chronic treatment with zinc, similar to conventional antidepressants, (Balu et al., 2008; De Foubert et al., 2004) was reported to increase BDNF mRNA and protein levels in the hippocampus (Cieslik et al., 2011; Sowa-Kucma et al., 2008) or cerebral cortex (Nowak et al., 2004) of rats. "
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    ABSTRACT: Considering that intracellular signaling pathways that modulate brain BDNF are implicated in antidepressant responses, this study investigated whether signaling pathway inhibitors upstream to BDNF might influence the antidepressant-like effect of zinc, a metal that has been shown to display antidepressant properties. To this end, the influence of i.c.v. administration of H-89 (1 μg/site, PKA inhibitor), KN-62 (1 μg/site, CAMKII inhibitor), chelerythrine (1 μg/site, PKC inhibitor), PD98059 (5 μg/site, MEK1/2 inhibitor), U0126 (5 μg/site, MEK1/2 inhibitor), LY294002 (10 nmol/site, PI3K inhibitor) on the reduction of immobility time in the tail suspension test (TST) elicited by ZnCl2 (10 mg/kg, p.o.) was investigated. Moreover, the effect of the combination of sub-effective doses of ZnCl2 (1 mg/kg, p.o.) and AR-A014418 (0.001 μg/site, GSK-3β inhibitor) was evaluated. The occurrence of changes in CREB phosphorylation and BDNF immunocontent in the hippocampus and prefrontal cortex of mice following ZnCl2 treatment was also investigated. The anti-immobility effect of ZnCl2 in the TST was prevented by treatment with PKA, PKC, CAMKII, MEK1/2 or PI3K inhibitors. Furthermore, ZnCl2 in combination with AR-A014418 caused a synergistic anti-immobility effect in the TST. None of the treatments altered locomotor activity of mice. ZnCl2 treatment caused no alteration in CREB phosphorylation and BDNF immunocontent. The results extend literature data regarding the mechanisms underlying the antidepressant-like action of zinc by indicating that its antidepressant-like effect may be dependent on the activation of PKA, CAMKII, PKC, ERK, and PI3K/GSK-3β pathways. However, zinc is not able to acutely increase BDNF in the hippocampus and prefrontal cortex.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 01/2015; 59. DOI:10.1016/j.pnpbp.2015.01.008 · 3.69 Impact Factor
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    • "Behavioral despair was assessed using a modified version of the forced swim test (FST) [18] [19]. The forced swim paradigm is a well-validated test for behavioral despair that has been widely used to investigate depression-like behavioral responses in rodents [18] [19] [20]. Male WT (n = 18) and BDNF-tg (n = 16) mice were tested at 14 – 16 months of age. "
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    ABSTRACT: Evidence from clinical studies suggests that abnormal activity of brain derived neurotrophic factor (BDNF) contributes to the pathogenesis of autism spectrum disorders (ASDs). A genetically modified line of mice over-expressing a BDNF transgene in forebrain neurons was used to investigate if this mutation leads to changes in behavior consistent with ASD. The mice used in these experiments were behaviorally tested past 5 months of age when spontaneous seizures were evident. These seizures were not observed in age-matched wildtype (WT) mice or younger mice from this transgenic line. The BDNF mice in these experiments weighed less than their WT littermates. The BDNF transgenic (BDNF-tg) mice demonstrated similar levels of sociability in the social approach test. Conversely, the BDNF-tg mice demonstrated less obsessive compulsive-like behavior in the marble burying test, less anxiety-like behavior in the elevated plus maze test, and less depressive-like behavior in the forced swim test. Changes in behavior were found in these older mice that have not been observed in younger mice from this transgenic line, which may be due to the development of seizures as the mice age. These mice do not have an ASD phenotype but may be useful to study adult onset epilepsy.
    Behavioural brain research 04/2014; 268. DOI:10.1016/j.bbr.2014.04.025 · 3.03 Impact Factor
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