Cognitive impairment in spontaneously hypertensive rats: role of central nicotinic receptors. I.
Both human essential hypertension and genetically induced hypertension in rats have been associated with a range of impairments of cognitive ability. The spontaneous hypertensive rat (SHR) previously has been shown to exhibit a decrease in the expression of brain nicotinic acetylcholine receptors, a factor 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 help determine whether task impairment by SHR was related to the reduced expression of central nicotinic acetylcholine receptors. Twelve-week-old 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 exhibited significantly increased latencies to locate a hidden platform as compared with either WKY or Wistar rats. 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 again exhibited significantly impaired performance compared to the normotensive strains. 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 SHR by up to 25% in about half of the brain regions examined, with the deficits particularly apparent in cephalic regions. The binding of [125I]alpha-bungarotoxin to brain sections also was decreased in SHR; however, only certain brain areas exhibited significant interstrain differences. These alterations in the expression of putative nicotinic receptor subtypes in SHR were not due to changes in the density of cholinergic neurons since there were no interstrain differences in the binding densities for [3H]vesamicol, which labels the vesicular acetylcholine transporter. Moreover, the magnitude of nicotine-stimulated rubidium efflux from cortical and striatal synaptosomes in vitro was significantly reduced in samples derived from SHR as compared with those from normotensive rats. These results are consistent with the possibility that a reduction in the expression of cortical nicotinic receptors in SHR plays a role in this strain's impaired performance of both spatial and non-spatial learning and memory-related tasks.
Gattu
M
M
Department of Pharmacology and Toxicology / Alzheimer's Research Center, Medical College of Georgia, Augusta 30912-2300, USA.
Pauly
J R
JR
Boss
K L
KL
Summers
J B
JB
Buccafusco
J J
JJ
D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001362:Avoidance Learning / Q000502:physiology*; D001392:Azocines; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D002038:Bungarotoxins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000503:physiopathology*; D003342:Corpus Striatum / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007457:Iodine Radioisotopes; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D026901:Membrane Transport Proteins; D009928:Organ Specificity; D010880:Piperidines / Q000378:metabolism; D011807:Quinolizines; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000502:physiology*; D012413:Rubidium / Q000378:metabolism; D014316:Tritium; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D002038:Bungarotoxins; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D026901:Membrane Transport Proteins; D010880:Piperidines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D012413:Rubidium; D014316:Tritium; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; C493459:SLC18A3 protein, human; C493461:Slc18a3 protein, rat; C006189:vesamicol; C004712:cytisine; D000093843:Quinolizidine Alkaloids