Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats

Abstract

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e., during a 14 day drug-free washout period) of chronic treatment (i.e., ranging from 45 days to six months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme linked immunosorbant assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared to vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to two weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphoTrkA protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 NTR levels. These data indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects

The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs

“…Animals received once a day sterile 0.9% saline or drug between 9:00 a.m. and 10:00 a.m. for either 1 day or 28 consecutive days (n=7/group). Drug dosing, route of administration, and duration of treatment were selected based on previous studies showing the regulation of NGF mRNA and BDNF or fibroblast growth factor protein by psychotropic medications (Angelucci et al 2000;Alvin et al 2007;Dias et al 2003;Vinay et al 2004). In case of NGF or eCB alteration by any psychotropic medication, the CB 1 receptor neutral antagonist AM4113 (N-piperidin-1-yl-2,4-dichlorophenyl-1H-pyrazole-3-carboxamide analog, Center for Drug Discovery, Northeastern University, USA) was dissolved in dimethylsulfoxide (Sigma-Aldrich, Germany), Tween-80 (Sigma-Aldrich, Germany), and 0.9% saline in a 1:1:8 ratio and injected i.p.…”

“…All drugs were injected at a total volume of 1 ml/kg. NGF quantification Brain regional levels of NGF were measured at three time points (24, 48, and 72 h) after the last injection of drug or vehicle (Alvin et al 2007;Angelucci et al 2000;Dias et al 2003;Gwinn et al 2002;Vinay et al 2004). Animals were decapitated without anesthesia, and the brain of each animal was quickly and carefully removed from the skull.…”

“…NGF is a neurotrophin that is critical for the survival and maintenance of neurons in the peripheral and central nervous systems (Ebendal 1992); it is trophic for cholinergic neurons (Lad et al 2003) which are important for cognition (Browne et al 2001) and is regulatory in stress in rodents and humans (Alleva et al 1996). However, in contrast to BDNF, few studies have measured NGF content in multiple brain regions following the administration of different classes of psychotropic drugs and most have been limited in scope, examining a single drug class or brain region (Alvin et al 2007;Angelucci et al 2000;Vinay et al 2004). In addition, the mechanism(s) by which psychotropic drugs regulate NGF level remain elusive.…”

Differential Long-Term Effects of Haloperidol and Risperidone on the Acquisition and Performance of Tasks of Spatial Working and Short-Term Memory and Sustained Attention in Rats

“…Other possible sources of the disparate results could include differences in intramaze and extramaze cues and differences in the strain of rats tested (Fisher 344 in the Rosengarten and Quartermain study compared with Wistar rats in our study). It is important to note, however, that in a previous study in our laboratory using a 12-arm RAM with arms 10 cm wide and 70 cm long (with testing begun during washout after a 90-day drug exposure period in Wistar rats), neither haloperidol nor risperidone affected the number of working or reference memory errors compared with vehicle-treated controls (Terry et al, 2007a).…”

“…In a rat study in which olanzapine was administered subcutaneously for 21 days, water-maze (spatial learning) impairments were observed (Didriksen et al, 2006). In previous rat studies in our laboratory, in which longer periods of treatment were evaluated (i.e., 90-180 days in drinking water), water-maze spatial-learning deficits were associated with haloperidol, chlorpromazine, risperidone, olanzapine, and ziprasidone (see reviews, Terry and Mahadik, 2007;Terry et al, 2006Terry et al, , 2007aTerry et al, ,b, 2008. The purpose of the study described here was to compare the effects of long-term treatment with the FGA haloperidol and the SGA risperidone on both the acquisition and performance of tasks designed to assess spatial working or short-term memory and sustained attention in rats.…”