Cells in midline thalamus, central amygdala, and nucleus accumbens responding specifically to antipsychotic drugs.
BACKGROUND
Determining brain regions in which neuroleptic drugs of different types produce similar effects, especially where these effects are not shared with drugs lacking antipsychotic efficacy, provides evidence as to how and where the clinical effects of neuroleptic drugs are mediated.


OBJECTIVE
For this study, the pattern of expression of the protein Fos, a marker of cellular activation, was compared after administration of the typical neuroleptic haloperidol, the antipsychotic drug clozapine, and the atypical neuroleptic olanzapine, as well as the sedative drug diphenhydramine and the anxiolytic lorazepam.


METHODS
Animals (Sprague-Dawley rats, three per cohort) received intraperitoneal injections of haloperidol (1 mg/kg), clozapine (20 mg/kg), olanzapine (5 mg/kg), diphenhydramine hydrochloride (1 mg/kg), lorazepam (5 mg/kg) or vehicle (2% lactic acid, 1 ml/kg). Two hours after drug administration, animals were killed. Patterns of activated cells were observed by immunohistochemistry for Fos-like antibodies in regions previously suggested as responding to all antipsychotic drugs, including nucleus accumbens, central amygdala, and central medial thalamus. Cells staining for Fos were counted by semi-automated methods. RESULTS. A very similar pattern and number of Fos positive cells in nucleus accumbens, central amygdala, and central medial thalamus followed administration of each antipsychotic drug. The numbers of apparently activated cells were much greater following antipsychotic drug administration than after vehicle, with differences between each drug and vehicle being highly statistically significant in each region. Lorazepam produced apparent activation of cells of the central amygdala similar in degree and location but not identical in distribution to that of antipsychotic drugs. Diphenhydramine produced no apparent activation of cells in any of the sites tested.


CONCLUSIONS
Typical and atypical antipsychotic drugs shared a distinctive pattern of robust activation of cells in nucleus accumbens, central medial thalamus, and central amygdala. Antipsychotic drug-induced activation of amygdala was shared by lorazepam, but activation of thalamus and nucleus accumbens was much greater following antipsychotic drugs than following lorazepam. The pattern of activated cells may be relevant to the therapeutic actions of antipsychotic drugs.
Cohen
Bruce M
BM
Molecular Pharmacology Laboratory, McLean Hospital, Department of Psychiatry, Harvard Medical School, 115 Mill Street, Belmont, MA 02478-9106, USA. cohenb@mclean.harvard.edu
Cherkerzian
Sara
S
Ma
Jianyi
J
Ye
Nancy
N
Wager
Carrie
C
Lange
Nicholas
N
D000679:Amygdala / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D003024:Clozapine / Q000494:pharmacology; D004155:Diphenhydramine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008140:Lorazepam / Q000494:pharmacology; D008297:Male; D020644:Midline Thalamic Nuclei / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D014150:Antipsychotic Agents; D016760:Proto-Oncogene Proteins c-fos; D001569:Benzodiazepines; D010890:Pirenzepine; D004155:Diphenhydramine; D003024:Clozapine; D006220:Haloperidol; D000077152:Olanzapine; D008140:Lorazepam