Idazoxan blocks the nicotine-induced reversal of the memory impairment caused by the NMDA glutamate receptor antagonist dizocilpine

Abstract

Rationale Alpha2-adrenoreceptor (α 2-AR) antagonists have been shown to improve, while α 2-AR agonists impair cognitive function in subjects with functioning NMDA receptors (NMDAR). In subjects with inhibited NMDAR (a model of schizophrenia) α 2-AR agonists attenuate the cognitive impairments. The effect with α 2-AR antagonists remains unclear. Objectives We investigated the effects of the α 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 α 2-AR with nicotinic agonists in schizophrenia may prevent therapeutic effect of nicotinic agonists and increase risk for convulsive activity with repeated administration.