Deficits in spatial learning and nicotinic-acetylcholine receptors in older, spontaneously hypertensive rats.
Spontaneously hypertensive rats are often used as models of attention deficit hyperactivity disorder and to investigate the effects of hypertension on cognitive function. Along with the wide variety of cardiovascular anomalies, these animals as young adults also exhibit deficits in memory and attention and central nicotinic-acetylcholine receptor sites. These findings may have particular significance since nicotinic receptors appear to be involved in the regulation of cerebral circulation and mnemonic function. Furthermore, a lack of high affinity nicotinic receptors (in knockout mice) has also been shown to accelerate both the structural and cognitive degeneration associated with age, findings that may be especially relevant to age-related memory disorders such as Alzheimer's Disease where large deficits in nicotinic receptors are observed. Since spontaneously hypertensive rats appear to be both memory-impaired and deficient in nicotinic receptors at a young age (compared to the non-hypertensive phenotype, Wistar-Kyoto rats), we were interested to learn if these conditions were exacerbated in older animals with particular interest in specific nicotinic receptor subtypes in memory areas of the brain. Spatial learning was assessed in 15-month-old subjects of each phenotype (i.e. hypertensive and non-hypertensive) using a two-phase water maze paradigm, and nicotinic receptors were measured via autoradiography with [125I]-alpha-bungarotoxin and [3H]-epibatidine. In the water maze, both groups learned to locate a hidden platform as indicated by progressively shorter latencies across training days, however, Wistar-Kyoto rats were more efficient in both phases. While the number of both bungarotoxin and epibatidine binding sites was lower in the hypertensive rats across several brain regions, in the case of epibatidine binding, the magnitude of the difference and the number of areas affected was generally greater and included areas important for spatial learning (e.g. frontal and entorhinal cortex). In a direct comparison between 3-month-old and 15-month-old rats of each phenotype, epibatidine sites were markedly reduced by age (i.e. by greater than 50% in some cases) across multiple brain regions in both groups, although Wistar-Kyoto rats appeared to be more substantially affected by age. These data further support the use of the spontaneously hypertensive rat as model for studying learning-impairment and reduced central nicotinic receptors and also indicate that these characteristics persist and (in the case of high affinity nicotinic receptor cites) worsen with age.
Terry
A V
AV
University of Georgia College of Pharmacy, Medical College of Georgia, Augusta, GA 30912, USA. aterry@mail.mcg.edu
Hernandez
C M
CM
Buccafusco
J J
JJ
Gattu
M
M
D000109:Acetylcholine / Q000378:metabolism*; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002038:Bungarotoxins / Q000494:pharmacology; D006339:Heart Rate / Q000502:physiology; D007457:Iodine Radioisotopes; D007859:Learning Disabilities / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D010641:Phenotype; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay / Q000706:statistics & numerical data; D051381:Rats; D011918:Rats, Inbred SHR / Q000033:anatomy & histology / Q000378:metabolism*; D011921:Rats, Inbred WKY / Q000033:anatomy & histology / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013028:Space Perception / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D014316:Tritium
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D007457:Iodine Radioisotopes; D011725:Pyridines; D011978:Receptors, Nicotinic; D014316:Tritium; C082748:epibatidine; D000109:Acetylcholine