REVERSAL OF VISUAL ATTENTIONAL DYSFUNCTION FOLLOWING LESIONS OF THE CHOLINERGIC BASAL FOREBRAIN BY PHYSOSTIGMINE AND NICOTINE BUT NOT BY THE 5-HT3 RECEPTOR ANTAGONIST, ONDANSETRON

To investigate further the cholinergic specificity of the effects of b asal forebrain lesion-induced disruption of attentional performance, t he present study examined the efficacy of various pharmacological agen ts in improving performance of a five-choice serial reaction time task in rats that had received lesions of the cholinergic basal forebrain. Specifically, the effects of the novel 5-HT3 receptor antagonist, ond ansetron (0.3, 1, 10 ng/kg), and of nicotine (0.03, 0.06, 0.1, 0.3 mg/ kg) and the anticholinesterase, physostigmine (0.05, 0.1 mg/kg), on at tentional function were examined in animals which had received AMPA-in duced lesions of the nucleus basalis magnocellularis (nbM). The behavi oural impairments observed immediately following the lesion were a red uction were choice accuracy and an increase in correct response latenc y. Although these impairments showed recovery over the course of the f ollowing weeks, the deficit in choice accuracy could be reinstated by reducing the duration of the visual stimulus and thus increasing the a ttentional load placed on the animals. This reduction in choice accura cy could be dose dependently improved by systemic administration of ei ther physostigmine or nicotine, suggesting that this impairment in att entional function may be attributed to disruption of cholinergic funct ion. The pharmacological specificity of these improvements was support ed by the inability of d-amphetamine to improve task performance (0.2, 0.3, 0.8 mg/kg). Ondansetron was also unable to improve accuracy of p erformance in lesioned animals, but was effective in reducing the anti cipatory or premature responding observed in both control and lesioned animals, even when elevated (in the case of controls) by treatment wi th systemic d-amphetamine. The results of the present study therefore suggest that cholinergic dysfunction can lead to attentional impairmen ts which can be ameliorated by cholinergic treatments such as physosti gmine and nicotine, but that ondansetron, despite its proposed ability to release cortical acetylcholine, was unable to restore choice accur acy at the doses employed. The results further suggest a double dissoc iation of effects on accuracy and the disinhibition of responding.