title: Modulation of nerve growth factor and choline acetyltransferase expression in rat hippocampus after chronic exposure to haloperidol, risperidone, and olanzapine.
abstract: BACKGROUND
  Recently, we reported that compared to haloperidol, chronic exposure to either the risperidone (RISP) or olanzapine (OLZ) resulted in superior effects on spatial learning performance as well as the cholinergic neurons, although the mechanism for these effects was not addressed.
  
  
  OBJECTIVE
  The objective of this study was to investigate one plausible mechanism whereby RISP and OLZ exert superior effects on cholinergic neurons, i.e. positive effects on nerve growth factor (NGF), which is known to regulate the brain cholinergic activity as well as cognitive function. Therefore, the effects of chronic exposure to HAL, RISP, or OLZ on the expression of NGF and choline acetyltransferase (ChAT) in the hippocampus (i.e. a brain area well known to be involved in cognitive function and known to receive major cholinergic projections from the medial septum) were compared.
  
  
  METHODS
  Rats were treated with HAL (1 or 2 mg/kg per day), RISP (1.25 or 2.5 mg/kg per day), or OLZ (5 or 10 mg/kg per day) for 45 days in drinking water. NGF and ChAT were measured by immunohistochemistry and NGF protein was also measured by an enzyme-linked ImmunoSorbent assay.
  
  
  RESULTS
  Compared to controls, HAL exposure resulted in a marked reduction in NGF immunoreactivity in the hippocampal dentate gyrus (DG), CA1 and CA3 areas. In contrast, RISP did not alter, while OLZ significantly increased levels of NGF. These changes in NGF levels corresponded well with changes in ChAT immunoreactivity in the hippocampus and the medial septum.
  
  
  CONCLUSIONS
  These preclinical data, combined with previously published behavioral results, support the premise that OLZ and RISP, in contrast to HAL, preserve cholinergic pathways and cognitive function via superior effects on NGF expression and are thus therapeutically superior for extended use.
authors.affiliation: Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, Ga., USA.
authors.forename: Vinay
authors.initials: V
authors.lastname: Parikh
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Khan
authors.forename: Sahebarao P
authors.initials: SP
authors.lastname: Mahadik
mesh_terms: D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006220:Haloperidol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D000077152:Olanzapine; D051381:Rats; D017208:Rats, Wistar; D018967:Risperidone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D020665:Septum of Brain / Q000201:enzymology / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D006220:Haloperidol; D018967:Risperidone; D000077152:Olanzapine