Haloperidol alters rat CNS cholinergic system: Enzymatic and morphological analyses

Dhandapani

et al. 2007

Neuropsychopharmacol

Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia). Additional studies indicate that haloperidol has other deleterious effects on the brain (eg increased apoptosis). Despite such limitations, haloperidol remains one of the more commonly prescribed antipsychotic agents worldwide due to its efficacy for the positive symptoms of schizophrenia and its low cost. Interestingly, the hematopoietic hormone, erythropoietin, in its recombinant human form rhEPO has been reported to increase the expression of BDNF in neuronal tissues and to have neuroprotective effects. Such observations provided the impetus for us to investigate in the present study whether co-treatment of rhEPO with haloperidol could sustain the normal levels of BDNF in vivo in rats and in vitro in cortical neuronal cultures and further, whether BDNF could prevent haloperidol-induced apoptosis through the regulation of key apoptotic/antiapoptotic markers. The results indicated that rhEPO prevented the haloperidol-induced reduction in BDNF in both in vivo and in vitro experimental conditions. The sustained levels of BDNF in rats with rhEPO prevented the haloperidol-induced increase in caspase-3 (po0.05) and decrease in Bcl-xl (po0.01) protein levels. Similarly, in vitro experiments showed that rhEPO prevented (po0.001) the haloperidol-induced neuronal cell death as well as the decrease in Bcl-xl levels (po0.01). These findings may have significant implications for the development of neuroprotective strategies to improve clinical outcomes when antipsychotic drugs are used chronically.

Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

Dhandapani

et al. 2007

Neuropsychopharmacol

“…Thus, important cholinergic pathways in the brain including the basal forebrain-cortical pathway, septo-hippocampal pathway, and striatum were analyzed. The procedure used (ie the perfusion, fixation, and tissue processing conditions) was developed (Mahadik et al, 1988) based on several reports that used monoclonal antibody to ChAT for analysis of cholinergic neurons (Eckenstein and Thoenen, 1982;Houser et al, 1983;Borges and Iversen, 1986;Connaughton et al, 1986). Staining was carried out by the modified original immunofluorescence method (Sternberger, 1979).…”

Section: Cholinergic Activity By Chat-immunohistochemical Methodsmentioning

confidence: 99%

“…Representative animals from the 90-day treatment group were subsequently tested in the water maze procedure and then killed as described above. The HAL dose (2 mg/kg/day) was chosen based on previous studies (Mahadik et al, 1988) to obtain plasma levels, which are relevant to standard doses in humans and based on the fact that HAL is metabolized over 3 times faster in rats than in humans. The RISP (2.5 mg/kg/day) and CLOZ (20 mg/kg/day) doses were selected based on the published reports (Skarsfeldt, 1996;Didriksen, 1995) that have demonstrated significant (acute) behavioral effects in rodents.…”

Section: Chronic Drug Administrationmentioning

confidence: 99%

“…Although most of the focus to explain these effects is still on the differential affinity binding (Kapur et al, 1999;Wadenberg et al, 2001) and receptor mechanisms (Moore et al, 1993;Bymaster et al, 1996;Skarsfeldt, 1996) of several neurotransmitters, HAL may also interfere with mitochondrial electron transport and protein synthesis and potentially generate oxidative metabolites, which are structurally similar to the known neurotoxins, MPTP, and MPP + (Barrientos et al, 1998;Prince et al, 1997;Subramanyam et al, 1991). Furthermore, HAL has been observed to decrease ChAT enzyme activity in the striatum and hippocampus and decrease ChAT immunoreactivity as indicated by an apparent reduction in the intensity and number of stained neurons and their processes (Mahadik et al, 1988). This finding could be of particular significance in the light of the well-documented role of septo-hippocampal cholinergic pathways in cognitive function.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Effects of Haloperidol, Risperidone, and Clozapine Exposure on Cholinergic Markers and Spatial Learning Performance in Rats

Terry

Hill

Parikh

et al. 2002

Neuropsychopharmacol

Haloperidol (HAL), a potent typical antipsychotic, continues to be a frequently prescribed medication for behavioral disturbances associated particularly with schizophrenia despite well-documented adverse effects associated with its chronic use. Animal experiments have even indicated that HAL can damage cholinergic pathways and thus could be especially deleterious to those experiencing cognitive deficits. However, several recent clinical studies indicate that atypical antipsychotics may actually improve cognitive function in some patients, although this assertion requires further investigation. The purpose of this study was to compare the effects of prior chronic (45-or 90-day) oral exposure to HAL and the atypical antipsychotics risperidone (RISP) and clozapine (CLOZ) on cognitive performance and central cholinergic markers in rats. All analyses were done after 4 days of drug washout in order to minimize direct drug effects. Learning performance and choline acetyltransferase (ChAT) levels were assessed in a water maze task and with immunofluorescence staining, respectively. HAL significantly impaired learning performance after 90 but not after 45 days of treatment when compared to both vehicle controls and the atypical agents, while RISP slightly improved task performance. Both 45 and 90 days of previous HAL exposure reduced ChAT staining in several brain regions, including the cortex, caudate-putamen, and hippocampus. ChAT staining in the caudate-putamen and hippocampus was also decreased after 90 days of RISP exposure, raising the possibility of deleterious cognitive effects after exposure to this dosage for longer periods of time. The results suggest that antipsychotic drugs exert differential and temporally dependent effects on central cholinergic neurons and learning performance.

Pharmacological actions of the atypical antipsychotic drug clozapine: A review

Ashby

Wang

1996

Synapse

167

Clozapine [8-chloro- 11-(4-methyl- 1-piperazinyl)-3H-dibenzo (b,e)(1,4) diazepine], or clozaril, is a member of the dibenazepine class of antipsychotic drugs. Initially, studies in animals using a number of neurochemical, biochemical, electrophysiological, and behavioral paradigms indicated that clozapine was markedly different from various typical antipsychotic drugs such as haloperidol and chlorpromazine. Subsequently, clinical studies have shown that clozapine is effective in ameliorating the core symptoms, as well as the negative symptoms, in schizophrenia. However, clozapine has a much lower propensity for inducing neurological side effects after acute or repeated administration compared to various typical neuroleptics. Furthermore, clozapine is therapeutically effective in treating about 30% of schizophrenic patients who are resistant to standard antipsychotic drugs. Based on the above information, clozapine has been designated an atypical antipsychotic drug. However, at this time, it is not entirely clear why clozapine is such a unique antipsychotic drug. To date, there has not been a comprehensive review regarding clozapine's pharmacological profile. Therefore, we will review clozapine's profile in the following areas: 1) affinity for neurotransmitter receptors in the brain; 2) electrophysiology (in vivo, single-cell recording and iontophoresis; in vitro studies); 3) in vivo microdialysis and voltammetry; 4) monoamine turnover or metabolism; 5) intermediate early gene expression; 6) positron emission tomography studies; and 7) molecular biological studies. We will also compare and contrast clozapine's acute and chronic effects, and discuss the merits of various hypotheses that have been put forward to explain clozapine's unique profile.