Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation.
BACKGROUND
Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists--including atypical antipsychotics that are prescribed for the treatment of schizophrenia--in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition.


RESULTS
Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10(-10)-10(-6) M) that display nM affinities for D2 and/or D4 receptors (clozapine, haloperidol, (+/-)-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+)-butaclamol and L-741,742). These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (-)-raclopride and remoxipride, two drugs that preferentially bind D2 over D4 receptors were ineffective, as well as the selective D3 receptor antagonist U 99194. Interestingly, (-)-raclopride (10(-6) M) was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10(-6) M).


CONCLUSIONS
Taken together, these data suggest that D2-like receptors, particularly the D4 subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.
Bastianetto
Stéphane
S
Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal, Québec, H4H 1R3, Canada. basste@douglas.mcgill.ca
Danik
Marc
M
Mennicken
Françoise
F
Williams
Sylvain
S
Quirion
Rémi
R
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D002069:Butaclamol / Q000494:pharmacology; D061945:Caspase Inhibitors; D016923:Cell Death; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D002746:Chlorpromazine / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020441:Ginkgo biloba; D006220:Haloperidol / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000196:embryology; D007189:Indans / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017330:Remoxipride / Q000494:pharmacology; D018967:Risperidone / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D000096983:Ginkgo Extract
D000840:Anisoles; D014150:Antipsychotic Agents; D001552:Benzazepines; D002069:Butaclamol; D061945:Caspase Inhibitors; D002746:Chlorpromazine; D003024:Clozapine; D004294:Domperidone; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D006220:Haloperidol; D007189:Indans; D007555:Isoxazoles; D018696:Neuroprotective Agents; D010455:Peptides; D010880:Piperidines; D010936:Plant Extracts; D011437:Propylamines; D020891:Raclopride; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D017330:Remoxipride; D018967:Risperidone; D013469:Sulpiride; C475574:Ac-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Leu-Glu-His-Asp-Cho; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; C099631:L 741742; C063170:Ginkgo biloba extract; D000096983:Ginkgo Extract