Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. Part II.
The adult spontaneously hypertensive rat (SHR) has been shown to exhibit a decrease in the expression and nicotine-stimulated function of brain nicotinic acetylcholine receptors, factors that could play a role in the impaired ability of this strain in the performance of learning and memory-related tasks. The purpose of this study was to determine whether either or both the impaired task performance and the loss of nicotinic receptors is directly related to the presence of the hypertensive state. To address this issue, two experimental approaches were taken. In the first series, 4-week-old pre-hypertensive SHR were tested in two phases of a water maze (spatial memory) task, and their performance was compared with that of two age-matched normotensive strains, Wistar Kyoto (WKY) and Wistar rats. During phase 1, SHR and WKY rats were not different in their ability to learn the task. In contrast, during phase 2 (subsequent series of trials after a 4 day inter-phase period), where rats were required to find a new platform location, SHR exhibited significantly impaired performance compared to both WKY and Wistar normotensive controls. In a single trial passive avoidance paradigm, SHR again displayed significantly reduced avoidance behavior as compared with both WKY and Wistar rats. In consecutive coronal sections the density of [3H]cytisine binding sites was decreased in pre-hypertensive SHR by up to 18% in about 40% of the brain regions examined, with the deficits particularly apparent in frontal cortex (layers 4-6), posterior subiculum, several thalamic regions, and the interpeduncular nucleus. In the second series, age-matched SHR and WKY were treated with the antihypertensive agent hydralazine administered in the drinking water beginning at 4 weeks of age. Hydralazine prevented the development of hypertension in adult SHR, but did not forestall the reduced expression of brain nicotinic receptors, nor the impairment in learning- and memory-related tasks normally observed in untreated adults with established hypertension. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from hydralazine-treated SHR as compared with those from hydralazine-treated, or untreated WKY. These results support the contention that the hypertensive state does not directly contribute to the reduced expression of nicotinic receptors in SHR. Therefore, the SHR may provide an important genetic model for the study of the role of central nicotinic receptors in cognitive and learning abnormalities.
Gattu
M
M
Department of Pharmacology and Toxicology / Alzheimer's Research Center, Medical College of Georgia, Veterans Affairs Medical Center, Augusta 30912-2300, USA.
Terry
A V
AV
Pauly
J R
JR
Buccafusco
J J
JJ
D000375:Aging; D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning; D001392:Azocines; D001665:Binding Sites; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology* / Q000523:psychology*; D008297:Male; D018782:Maze Learning; D011807:Quinolizines; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism; D012414:Rubidium Radioisotopes; D013997:Time Factors; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012413:Rubidium; D012414:Rubidium Radioisotopes; C004712:cytisine; D000093843:Quinolizidine Alkaloids