Article

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. "
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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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    • "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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