PRE-084, a sigma selective PCP derivative, attenuates MK-801-induced impairment of learning in mice.
We investigated the effect of the sigma selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that sigma sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at sigma sites, reverses the amnesia induced by a drug acting at the PCP site.
Maurice
T
T
INSERM U. 336, Ecole Nationale Supérieure de Chimie, Montpellier, France.
Su
T P
TP
Parish
D W
DW
Nabeshima
T
T
Privat
A
A
D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D018678:Cholinergic Agents; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007858:Learning / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D010622:Phencyclidine / Q000031:analogs & derivatives*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors
D014151:Anti-Anxiety Agents; D018678:Cholinergic Agents; D009025:Morpholines; D011743:Pyrimidines; D017480:Receptors, sigma; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; D016291:Dizocilpine Maleate; D010622:Phencyclidine; D006220:Haloperidol