Brain Research, 572 (1992) 281-285 © 1992 Elsevier Science Publishers B.V. All rights reserved. 0006-8993/92/$05.00

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Effects of nicotine on spatial memory deficits in rats with septal lesions Michael W. Decker, Mark J. Majchrzak and David J. Anderson Neuroscience Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064 (U.S.A.)

(Accepted 5 November 1991) Key words: Nicotine; Nicotinic cholinergic agonist; Medial septal area; Spatial memory; Rat

Impaired septohippocampal function has been implicated in the memory deficits associated with Alzheimer's disease (AD), and septal lesions have been used to model the cognitive deficits associated with AD. In this study, we assessed the effects of systemic administration of nicotine on lesion-induced deficits in the acquisition of a spatial discrimination version of the Morris water maze. Rats with radiofrequency lesions of the medial septum were required to learn which of two visible platforms in a pool of water provided a means of escape. On each of the first 4 days of training, the rats received an injection of (-)nicotine (0, 0.1 or 0.3 mg/kg, i.p.) before training. Nicotine markedly improved the performance of septal rats. This enhanced performance was maintained in rats subsequently tested 1 and 15 days later without additional drug treatment. Septal rats initially trained under nicotine were impaired, however, when the platform locations were reversed and training was conducted under saline. Our findings suggest that nicotinic receptor stimulation might be useful in the treatment of cognitive deficits. Cholinergic neurons in the nucleus basalis of Meynert (NBM) and the medial septum/diagonal band, which provide extensive cholinergic input to the cortex, amygdala and hippocampus, degenerate in Alzheimer's disease (AD)2; and experimental lesions of the rat homologues of these basal forebrain nuclei impair performance on a variety of m e m o r y tasks 3'8. These observations suggest that cholinergic dysfunction may underlie some of the cognitive deficits associated with A D . In part because muscarinic antagonists, such as scopolamine, also impair memory, much of the current research has emphasized the role of muscarinic cholinergic neurotransmission in learning and m e m o r y deficits associated with A D . Accordingly, preclinical exploration of treatment approaches has tended to focus on pharmacological enhancement of muscarinic tone. For example, several studies have investigated the effects of muscarinic agonists on the performance of NBM-lesioned rats 1°'16'22. However, evidence that the nicotinic receptor stimulation enhances 4'5'9'15'17 and nicotinic blockade impairs 12A4,IT'1s memory in experimental animals suggests that nicotinic cholinergic neurotransmission might also play an important role in learning and memory. Recent findings that nicotinic but not muscarinic receptors are decreased in the brains of A D victims also suggest that nicotinic cholinergic dysfunction might be particularly important in the m e m o r y deficits associated with AD 21'23. Thus, nicotinic receptor stimulation might be effective in attenuating some of the m e m o r y deficits as-

sociated with A D . Consistent with this suggestion are findings that nicotine appears to improve matching to sample performance in aged monkeys 1 and to enhance radial maze performance in rats with N B M lesions 22. Relatively little additional data regarding the effects of nicotine in animal models of A D is available. Therefore, in the current study, we assessed the effects of nicotine on spatial m e m o r y performance in a water maze in rats with lesions of the medial septum. Radiofrequency lesions of the medial septal nucleus were produced in male, L o n g - E v a n s rats under pentobarbital anesthesia using the coordinates: 0.5 m m anterior to bregma, 0.0 m m lateral to the midline, and 6.5 m m ventral to the skull surface. Radiofrequency current sufficient to maintain a temperature of 61°C at the electrode tip was passed for 25 s. Sham surgery consisted of lowering an electrode to a point 1.0 m m above the target location for the lesions, but passing no current. At the end of the behavioral experiments, lesions were evaluated by measuring choline acetyltransferase (CHAT) activity in the hippocampus using an adaptation of the procedure of Fonnum 6. Behavioral testing was conducted using a round pool (180 cm in diameter and 60 cm high) filled to a depth of 37 cm with water (26 + I°C) rendered opaque by the addition of powdered milk. Two weeks after surgery, rats were habituated to the water maze by training them to swim to a visible escape platform (13 cm in diameter). Four trials per day were conducted for two days.

Correspondence: M.W. Decker, Department 47W, AP-10, Abbott Laboratories, Abbott Park, IL 60064, U.S.A. Fax: (1) (708) 937-9195.

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Effects of nicotine on spatial memory deficits in rats with septal lesions.

Impaired septohippocampal function has been implicated in the memory deficits associated with Alzheimer's disease (AD), and septal lesions have been u...
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