Idazoxan blocks the nicotine-induced reversal of the memory impairment caused by the NMDA glutamate receptor antagonist dizocilpine.
BACKGROUND
Alpha2-adrenoreceptor (alpha(2)-AR) antagonists have been shown to improve, while alpha(2)-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) alpha(2)-AR agonists attenuate the cognitive impairments. The effect with alpha(2)-AR antagonists remains unclear.


OBJECTIVE
We investigated the effects of the alpha(2)-AR antagonist idazoxan on memory function in rats treated/not treated with NMDAR antagonist dizocilpine or a combination of dizocilpine and nicotine to clarify noradrenergic/cholinergic regulation of memory function.


METHODS
Female Sprague-Dawley rats (n=12) were trained for food reward on the radial maze. Working and reference memory errors and response latency were assessed after injections of idazoxan (0.5, 1.0 mg/kg), dizocilpine (0.05 mg/kg), nicotine (0.2, 0.4 mg/kg) or vehicle, alone or in combination.


RESULTS
Dizocilpine potently impaired memory. Nicotine (0.4 mg/kg) reversed this impairment. Idazoxan at the doses tested did not affect performance when given alone or with dizocilpine, but it did block the nicotine reversal of the dizocilpine-induced memory impairment. Three rats after 10-12 drug treatments developed limbic seizures. Our findings suggest that combination of drugs which block alpha(2)-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.
Timofeeva
Olga A
OA
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA. timofeev@duke.edu
Levin
Edward D
ED
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D019329:Idazoxan / Q000494:pharmacology*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology*; D008570:Memory, Short-Term / Q000187:drug effects; D009538:Nicotine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009638:Norepinephrine / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000523:psychology; D009435:Synaptic Transmission / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D009538:Nicotine; D009638:Norepinephrine; D019329:Idazoxan