Modulation of MK-801-elicited mouse popping behavior by galantamine is complex and dose-dependent.
The ability of phencyclidine (PCP), a noncompetitive antagonist of NMDA receptor-mediated neurotransmission, to precipitate a schizophreniform psychosis in susceptible individuals is consistent with the hypothesized pathologic occurrence of NMDA receptor hypofunction in this disorder. Because the psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, investigators have sought to characterize animal models of NMDA receptor hypofunction. MK-801 (dizocilpine) binds to the same hydrophobic channel domain in the NMDA receptor-associated ionophore as PCP, and has been shown to elicit intense irregular episodes of jumping behavior in mice, termed "popping." MK-801-elicited mouse popping is an animal model of NMDA receptor hypofunction that has been used to screen novel candidate compounds for the treatment of schizophrenia. Recently, a selective abnormality in the transduction of the acetylcholine signal at the level of the alpha 7 nicotinic receptor has been described in schizophrenia. The existence of a nicotinic cholinergic abnormality in schizophrenia has stimulated interest in a potential therapeutic role for positive allosteric modulation of nicotinic receptors. Galantamine is a compound that possesses two interesting properties: inhibition of acetylcholinesterase and positive allosteric modulation of nicotinic neurotransmission. Theoretically, galantamine would be expected to increase the efficiency or likelihood that acetylcholine will promote channel opening and ionic conductance at nicotinic receptors. As expected, in the current investigation statistically significant popping behavior was elicited by MK-801 in mice (T(22) = 2.16, P < 0.05). This MK-801-elicited popping was significantly attenuated by 100 mg/kg of galantamine (T(22) = 2.24, P < 0.05). The data show that nicotinic interventions can influence NMDA receptor-mediated neurotransmission in the intact mouse.
Deutsch
Stephen I
SI
Mental Health Service Line, Veterans Integrated Service Network (VISN) 5, 849 International Drive, Suite 275, Linthicum, MD 21090, USA. Stephen.Deutsch@med.va.gov
Rosse
Richard B
RB
Billingslea
Eddie N
EN
Bellack
Alan S
AS
Mastropaolo
John
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004336:Drug Antagonism; D005702:Galantamine / Q000008:administration & dosage / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000008:administration & dosage / Q000494:pharmacology*; D012559:Schizophrenia
D018696:Neuroprotective Agents; D010277:Parasympathomimetics; D005702:Galantamine; D016291:Dizocilpine Maleate