Counteractive effects of a partial (sabcomeline) and a full (RS86) muscarinic receptor agonist on deficits in radial maze performance induced by S-AMPA lesions of the basal forebrain and medial septal area.
After S-AMPA (8.0 mM) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting and relatively stable impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Treatment with four doses of the partial agonist at the M1 cholinergic muscarinic receptor, sabcomeline (formerly known as SB 202026: 0.01-0.156 mg/kg), substantially reduced working and reference memory errors in both tasks in lesioned rats, in a mainly dose-related manner. These effects were more consistent than those found with the direct muscarinic agonist RS86 (0.05-0.781 mg/kg). The performance of non-lesioned controls was largely unaffected by either treatment. These findings are consistent with previous evidence for cholinergic participation in the radial maze deficits induced by excitotoxic lesions to the forebrain cholinergic projection system. They show that with a relatively selective lesion, which respectively, reduced choline acetyltransferase activity to 36.5 and 22.5% of control level in frontal and dorsolateral cortex, and to 61.8 and 69.2% of control level in dorsal and ventral hippocampus, lesioned rats were responsive to pharmacological treatments aimed to enhance cholinergic function by full or partial agonist activity at M1 receptors. Findings that nicotine (0.1 mg/kg) also reduced radial maze errors in the lesioned animals supports the suggestion that lesion-induced deficits in radial maze performance were amenable to improvement by cholinergic receptor manipulation. However, given the potential adverse side effects of full receptor agonists, which nonselectively target cholinergic receptors throughout the organism, the functional efficacy of sabcomeline, which shows regional selectivity for the central M1 receptor subtypes, suggests that deleterious effects of cholinergic depletion on cognition can be counteracted without incurring the risk of unwanted side effects.
Hodges
H
H
Department of Psychology, Institute of Psychiatry, Denmark Hill, London, UK.
Peters
S
S
Gray
J A
JA
Hunter
A J
AJ
D000818:Animals; D001479:Basal Ganglia / Q000201:enzymology / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005731:Ganglionic Stimulants / Q000494:pharmacology; D007097:Imines / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D016548:Prosencephalon / Q000201:enzymology / Q000502:physiology*; D011812:Quinuclidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012686:Septal Nuclei / Q000201:enzymology / Q000502:physiology*; D013388:Succinimides / Q000494:pharmacology*; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
D018690:Excitatory Amino Acid Agonists; D005731:Ganglionic Stimulants; D007097:Imines; D018721:Muscarinic Agonists; D018722:Nicotinic Agonists; D011812:Quinuclidines; D013388:Succinimides; C001886:2-ethyl-8-methyl-2,8-diazaspiro(4,5)decane-1,3-dione; D009538:Nicotine; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002795:Choline O-Acetyltransferase; C109640:sabcomeline