Differential effects of long-term treatment with typical and atypical antipsychotics on NGF and BDNF levels in rat striatum and hippocampus

Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, USA.
Schizophrenia Research (Impact Factor: 4.43). 03/2006; 82(1):95-106. DOI: 10.1016/j.schres.2005.11.021
Source: PubMed

ABSTRACT The results of mostly short-term treatment studies in human patients and animals suggest that second-generation antipsychotics (SGAs) such as risperidone (RISP) and olanzapine (OLZ) compared to first-generation antipsychotics (FGAs) such as haloperidol (HAL) and chlorpromazine (CPZ) have neuroprotective effects. The animal studies indicate that these effects are probably mediated through increased expression of neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). However, since antipsychotics are commonly used for very long-term treatment periods, particularly in schizophrenic patients, it is important to measure the effects of chronic administration of antipsychotic drugs on the aforementioned growth factors. This study determined the effects of 90- and 180-day treatments with two FGAs, HAL and CPZ, and two SGAs, RISP and OLZ, on the levels of NGF and BDNF protein in hippocampus and striatum of rat. Furthermore, since a preliminary study showed that 90-day treatment of HAL caused significant reductions in the expression of both NGF and BDNF the HAL-treated animals were then switched to SGAs for the next 90 days to assess the potential for restoration of trophic factor levels. After the 90-day treatment, NGF levels in the hippocampus were reduced by 60-70% with HAL or CPZ, and by only 25-30% with RISP or OLZ compared to levels with vehicle only. After the 180-day treatment, NGF levels were further reduced with HAL, RISP, and OLZ, but not with CPZ. The magnitude of the NGF decreases in the striatum was larger (70-90%) with all the antipsychotics compared to the hippocampus. However, the pattern of BDNF changes in the hippocampus differed significantly from the striatum after 90- or 180-day treatment with the antipsychotics. In hippocampus, compared to controls, BDNF levels remained unchanged with OLZ both after 90 and 180 days of treatment. Whereas, larger decreases in BDNF levels were observed with HAL or CPZ and intermediate decreases were observed with RISP after 90 days of treatment that continued to decline up to 180 days. Furthermore, switching HAL animals after 90 days of treatment to either RISP or OLZ for the next 90 days significantly restored levels of both NGF and BDNF in both the brain regions. These data indicate that SGAs compared to FGAs induce less deleterious effects on neurotrophic factor levels in the brain and may also offer ability to reverse the more pronounced negative effects of FGAs as well. These data may have significant clinical implications for long-term antipsychotic selection as well as the common practice of antipsychotic switchover.

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    • "Paliperidone (5 mg/kg/day) or vehicle (saline) was administered via continuous subcutaneous infusion (ALZET) in order to mimic the profile of LAI paliperidone ER in clinical studies (Marchese et al., 2010). The dose and duration of drug treatment were selected based on previous studies (Pillai et al., 2006; McNamara et al., 2011). Risperidone and paliperidone were provided by Janssen Scientific Affairs, LLC. "
    Schizophrenia Research 10/2013; 151(1-3). DOI:10.1016/j.schres.2013.09.027 · 4.43 Impact Factor
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    • "BDNF and CREB are used as molecular markers of neuronal survival and neurogenesis (Calabrese et al. 2011; Hashimoto 2010). Haloperidol-induced catalepsy was shown to be associated with a decrease of BDNF signaling in the brain (Bai et al. 2003; Chlan-Fourney et al. 2002; Lipska et al. 2001; Parikh et al. 2004; Pillai et al. 2006; 2008; Ukai et al. 2004). On the other hand, chronic antidepressant treatment increased expression of BDNF and/or CREB in the hippocampus (Balu et al. 2008; Castren 2004; Nibuya et al. 1995; Thome et al. 2000). "
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    ABSTRACT: The creation of effective psychotropic drugs is the key problem of psychopharmacology. Natural compounds and their synthetic analogues attract particular attention. The effect of a new synthetic analogue of varacin, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), on the behavior and the expression of the genes coding BDNF (Brain-Derived Neurotrophic Factor, Bdnf) and CREB (cAMP response element-binding protein, Creb) implicated in the mechanism of psychotropic drug action as well as gp130 (Il6st) implicated in the mechanism of hereditary catalepsy in the brain of mice of ASC (Antidepressant Sensitive Catalepsy) strain was studied. Acute per os administration of 20 or 40 mg/kg, but not 10 mg/kg of TC-2153 significantly decreased catalepsy. At the same time, in the open field test, 10 or 20 mg/kg of TC-2153 did not influence the locomotor activity, grooming or time spent in the center, while the highest dose of the drug (40 mg/kg) significantly reduced time in the center without any effect on locomotion and grooming. Chronic TC-2153 treatment (10 mg/kg for 12-16 days) did not influence the behavior in the open field but significantly attenuated catalepsy, increased Bdnf mRNA and decreased Il6st mRNA levels in the hippocampus. The results suggest: 1) TC-2153 as a new drug with potential psychotropic and anticataleptic activities and 2) the involvement of BDNF and gp130 in the molecular mechanism of TC-2153 action.
    Psychopharmacology 11/2011; 221(3):469-78. DOI:10.1007/s00213-011-2594-8 · 3.99 Impact Factor
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    • "Although the mechanism of olanzapine effects on these measures is uncertain, atypical antipsychotics may have neuroprotective effects, through an increase in the expression of neurotrophic factors, stimulating neurogenesis, or increasing the activity of the glutamate NMDA receptor (Vita and De Peri, 2007). Treatment with olanzapine reverses the lowered brain derived neurotrophic factor (BDNF) and TrK receptor caused by haloperidol in the rat hippocampus (Parikh et al., 2004), and olanzapine restores levels of nerve growth factor reduced by haloperidol treatment in the rat hippocampus (Pillai et al., 2006). In addition, blocking selective 5HT2A receptors may increase BDNF production (Vaidya et al., 1997). "
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    ABSTRACT: Abnormalities in connectivity are thought to contribute to the symptoms of schizophrenia. Accumulating evidence suggests that antipsychotic medication affects both subcortical and cortical grey and white matter volumes. The goal of this study was to investigate the effects of antipsychotic medication on two white matter tracts: a subcortical-cortical tract, the anterior and posterior limbs of the internal capsule; and a cortical-cortical tract, the corpus callosum. Magnetic resonance imaging was conducted on 10 chronic schizophrenia patients treated with typical antipsychotics and 20 healthy controls at baseline. Patients were switched to olanzapine and both groups were rescanned after 1 year. At baseline, the volume of the anterior limb of the internal capsule was 24% smaller in typical-treated patients than controls (p = 0.009). Patients treated with greater amounts of chlorpromazine-equivalent daily dosage had smaller anterior internal capsule volumes at baseline (r = -0.65, p = 0.04). At follow-up, after being switched to olanzapine, there were no significant differences between patients and controls. Patients with schizophrenia had a significant 25% increase in anterior internal capsule volume from baseline to follow-up compared with controls (p = 0.04). These effects were most prominent in the anterior limb of the internal capsule, which consists of fronto-thalamic pathways, and were not statistically significant in the posterior limb of the internal capsule or corpus callosum. Olanzapine may be effective in normalizing fronto-thalamic structural connectivity in schizophrenia.
    Journal of Psychopharmacology 04/2010; 25(5):621-9. DOI:10.1177/0269881110363314 · 2.81 Impact Factor
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