COGNITIVE IMPAIRMENT IN SPONTANEOUSLY HYPERTENSIVE RATS - ROLE OF CENTRAL NICOTINIC RECEPTORS .2.

The adult spontaneously hypertensive rat (SHR) has been shown to exhib it a decrease in the expression and nicotine-stimulated function of br ain 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 w hether either or both the impaired task performance and the loss of ni cotinic receptors is directly related to the presence of the hypertens ive state. To address this issue, two experimental approaches were tak en. In the first series, 4-week-old pre-hypertensive SHR were tested i n two phases of a water maze (spatial memory) task, and their performa nce was compared with that of two age-matched normotensive strains, Wi star Kyoto (WKY) and Wistar rats. During phase 1, SHR and WKY rats wer e not different in their ability to learn the task. In contrast, durin g phase 2 (subsequent series of trials after a 4 day inter-phase perio d), where rats were required to find a new platform location, SHR exhi bited significantly impaired performance compared to both WKY and Wist ar normotensive controls. In a single trial passive avoidance paradigm , SHR again displayed significantly reduced avoidance behavior as comp ared with both WKY and Wistar rats. In consecutive coronal sections th e density of [H-3]cytisine binding sires was decreased in pre-hyperten sive SHR by up to 18% in about 40% of the brain regions examined, with the deficits particularly apparent in frontal cortex (layers 4-6), po sterior subiculum, several thalamic regions, and the interpeduncular n ucleus. In the second series, age-matched SHR and WKY were treated wit h the antihypertensive agent hydralazine administered in the drinking water beginning at 4 weeks of age. Hydralazine prevented the developme nt of hypertension in adult SHR, but did not forestall the reduced exp ression of brain nicotinic receptors, nor the impairment in learning-a nd memory-related tasks normally observed in untreated adults with est ablished hypertension. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was s ignificantly reduced in samples derived from hydralazine-treated SHR a s compared with those from hydralazine-treated, or untreated WKY. Thes e results support the contention that the hypertensive state does not directly contribute to the reduced expression of nicotinic receptors i n SHR. Therefore, the SHR may provide an important genetic model for t he study of the role of central nicotinic receptors in cognitive and t eaming abnormalities. (C) 1997 Elsevier Science B.V.