RATIONALE: Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease (AD). In addition to memory dysfunction, attentional functions are also impaired in AD. OBJECTIVE: We investigated the extent to which the cholinesterase inhibitor donepezil reversed the attentional performance deficit in nucleus basalis magnocellularis (NBM) lesioned rats. We also examined the effects of a selective and potent 5-HT(1A) receptor antagonist, WAY 100635, on the attentional deficit of NBM lesioned rats. METHODS: We injected alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the NBM to selectively destroy cholinergic neurons projecting to the neocortex. Attentional functions were examined using the 5-CSRT task, in which hungry rats were required to locate brief visual targets presented randomly in one of five locations in a specially designed chamber. RESULTS. AMPA lesions of the NBM caused marked reductions in choline acetyltransferase activity (ChAT) ranging from 30 to 46% in medial areas of the cortex (medial-frontal and cingulate) and from 58 to 72% in more lateral areas (anterior-dorso-lateral and parietal). AMPA lesioned rats made fewer correct responses (choice accuracy), longer latency to correct response and an increase in the number of premature and perseverative responses. These impairments showed some recovery over the next 12 weeks. Reducing the duration of the visual stimulus reinstated the impairments in choice accuracy. The anticholinesterase inhibitor donepezil at 1.0 mg/kg but not 0.5 mg/kg reversed the impairments in choice accuracy and correct response latency. The premature and perseverative over-responding of AMPA lesioned rats remained unchanged. A dose of 0.1 mg/kg WAY 100635 to AMPA-lesioned rats improved their choice accuracy but did not shorten correct response latencies. The number of premature responses was reduced by WAY 100635 but perseverative over-responding was not affected. CONCLUSIONS: The attentional impairments induced due to cortical cholinergic dysfunction may be ameliorated by cholinergic treatments such as cholinesterase inhibitors. In addition, 5-HT(1A) receptors and the cortical cholinergic system exert balanced opposition in regulating attentional performance in the rat. Blockade of 5-HT(1A) receptors may be useful to treat some aspects of attentional dysfunction in AD.
RATIONALE: Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease (AD). In addition to memory dysfunction, attentional functions are also impaired in AD. OBJECTIVE: We investigated the extent to which the cholinesterase inhibitor donepezil reversed the attentional performance deficit in nucleus basalis magnocellularis (NBM) lesioned rats. We also examined the effects of a selective and potent 5-HT(1A) receptor antagonist, WAY 100635, on the attentional deficit of NBM lesioned rats. METHODS: We injected alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) into the NBM to selectively destroy cholinergic neurons projecting to the neocortex. Attentional functions were examined using the 5-CSRT task, in which hungry rats were required to locate brief visual targets presented randomly in one of five locations in a specially designed chamber. RESULTS. AMPA lesions of the NBM caused marked reductions in choline acetyltransferase activity (ChAT) ranging from 30 to 46% in medial areas of the cortex (medial-frontal and cingulate) and from 58 to 72% in more lateral areas (anterior-dorso-lateral and parietal). AMPA lesioned rats made fewer correct responses (choice accuracy), longer latency to correct response and an increase in the number of premature and perseverative responses. These impairments showed some recovery over the next 12 weeks. Reducing the duration of the visual stimulus reinstated the impairments in choice accuracy. The anticholinesterase inhibitor donepezil at 1.0 mg/kg but not 0.5 mg/kg reversed the impairments in choice accuracy and correct response latency. The premature and perseverative over-responding of AMPA lesioned rats remained unchanged. A dose of 0.1 mg/kg WAY 100635 to AMPA-lesioned rats improved their choice accuracy but did not shorten correct response latencies. The number of premature responses was reduced by WAY 100635 but perseverative over-responding was not affected. CONCLUSIONS: The attentional impairments induced due to cortical cholinergic dysfunction may be ameliorated by cholinergic treatments such as cholinesterase inhibitors. In addition, 5-HT(1A) receptors and the cortical cholinergic system exert balanced opposition in regulating attentional performance in the rat. Blockade of 5-HT(1A) receptors may be useful to treat some aspects of attentional dysfunction in AD.
Authors: Jared W Young; Susan B Powell; Victoria Risbrough; Hugh M Marston; Mark A Geyer Journal: Pharmacol Ther Date: 2009-03-06 Impact factor: 12.310