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

ArticleinSchizophrenia Research 82(1):95-106 · March 2006with12 Reads
DOI: 10.1016/j.schres.2005.11.021 · Source: PubMed
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.
    • "Antipsychotics have been used to treat SCZ for over 40 years [4]. Presently, pharmacological management of SCZ involves the use of one or more antipsychotics, which are classified as first-generation or typical such as haloperidol (HAL) and second-generation or atypical such as clozapine (CLZ), risperidone (RIS), olanzapine (OLZ), quetiapine (QTP) and ziprasidone (ZPS) [5]. It remains controversial the impact that typical vs. atypical antipsychotics could have on the oxidative stress status in SCZ patients [4]. "
    [Show abstract] [Hide abstract] ABSTRACT: Although the etiopathogenic mechanisms of schizophrenia (SCZ) are unknown, evidences suggest that excessive free radical production or oxidative stress may be involved in the pathophysiology of SCZ. Antipsychotics are the drugs used in the treatment of SCZ but it remains controversial the impact that typical vs. atypical antipsychotics has on the oxidative stress status in SCZ patients. In vitro, the antioxidant capacity of six antipsychotics was assessed by their ability to: decrease or scavenge reactive oxygen species in the neutrophil respiratory burst; donate hydrogen and stabilize the free radical 2,2-diphenyl-1-picryl-hydrazyl (DPPH); and scavenge 2,2'-azino-di-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS+). This study demonstrated that both clozapine and olanzapine have antioxidant effects, in vitro, by scavenging superoxide anion on the respiratory burst, donating electron in the ABTS+ assay and stabilizing the radical DPPH. Ziprasidone significantly scavenged ABTS+ and stabilized the radical DPPH whereas risperidone significantly reduced the respiratory burst. Haloperidol and quetiapine lacked antioxidant effects. The chemical structure-related antioxidant capacity suggests a possible neuroprotective mechanism of these drugs on the top of their antipsychotic mechanism of action.
    Full-text · Article · Jul 2016
    • "However, augmentation of HAL with ORM significantly increased striatal BDNF vs. SIR controls in this study. This finding correlates with that of Pillai et al. (2006), who demonstrated that reduced striatal BDNF levels following long term (90-180 days) HAL treatment could be partially reversed by co-administered risperidone or olanzapine, both showing much higher α 2C /D 2 ratios compared to HAL (Kalkman and Loetscher, 2003). Chronic HAL use is associated with excess dopamine release in the striatum (Moghaddam and Bunney, 1990; Westerink et al., 2001), with associated degenerative effects, while postsynaptic α 2C -ARs (extensively expressed in rat striatum) are proposed to be subtly stimulated by dopamine (Zhang et al., 1999a). "
    [Show abstract] [Hide abstract] ABSTRACT: Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10,921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10,921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10,921 (0.01 mg/kg), clozapine (5 mg/kg), haloperidol (0.2 mg/kg), haloperidol (0.2 mg/kg) + ORM-10,921 (0.01 mg/kg) or vehicle once daily for 14 days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10,921 and haloperidol + ORM-10,921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10,921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol + ORM-10,921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.
    Full-text · Article · Jul 2016
    • "Due to its involvement in neuronal growth, maintenance and survival (specifically of dopaminergic neurons (Hyman et al., 1991)), BDNF may produce a neuroprotective mechanism against MA (Matsuzaki et al., 2004), and may thus contribute to the observed morphological abnormalities in MA-dependent individuals. It may be hypothesized that, in MAP, treatment with typical antipsychotics reduces inflammation or lowers BDNF (Pillai et al., 2006). Longitudinal studies are needed to determine whether MA dependence is associated with neuroplastic changes and higher gray matter thickness, and whether MAP in particular leads to a more Table 5Correlations between cortical thickness and Emotion Reactivity Scale scores. "
    [Show abstract] [Hide abstract] ABSTRACT: Methamphetamine (MA) has been shown to have neurotoxic effects associated with brain structure changes and schizophrenia-like psychotic symptoms. Although these abnormalities may in turn be related to cognitive impairment and increased aggression, their association with affect dysregulation is less well studied. We investigated cortical thickness and subcortical volumes in 21 participants with MA dependence, 19 patients with MA-associated psychosis (MAP), and 19 healthy controls. Participants' affect regulation abilities were assessed through self-report scales on emotion reactivity (ERS) and difficulties in emotion regulation (DERS) and correlated with differences in cortical thickness. MAP patients showed thinner cortices in the fusiform and inferior temporal gyrus (ITG), orbitofrontal (OFC) and inferior frontal gyrus (IFG), and insula, compared to the MA group. MAP also showed significantly lower hippocampal volumes relative to MA and CTRL. Both clinical groups showed impairment in affect regulation, but only in MAP was this dysfunction associated with thinner cortices in ITG, OFC and IFG. Our findings suggest significant differences in cortical thickness in MA dependence with and without psychosis. Lower fronto-temporal cortical thickness and smaller hippocampal volumes in MAP are consistent with neuroimaging findings in other psychotic disorders, supporting the notion of MAP being a useful model of psychosis.
    Article · Jan 2016
Show more