Spatial learning and memory deficits induced by dopamine administration with decreased glutathione.
Administration of buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) biosynthesis and induces a GSH deficiency. Decreased GSH levels in the brain may result in less oxidative stress (OS) protection, because GSH contributes substantially to intracellular antioxidant defense. Under these conditions, administration of the pro-oxidant, dopamine (DA), which rapidly oxidizes to form reactive oxygen species, may increase OS. To test the cognitive behavioral consequences of decreased GSH, BSO (3.2 mg in 30 microliters, intracerebroventricularly) was administered to male Fischer 344 rats every other day for 4 days. In addition, DA (15 microliters of 500 microM) was administered every day [either 1 h after BSO (BSO + DA group) or 1 h before BSO (DA + BSO group), when given on the same day as BSO] and spatial learning and memory assessed (Morris water maze, six trials/day). BSO + DA rats, but not DA + BSO rats, demonstrated cognitive impairment compared to a vehicle group, as evidenced by increased latencies to find the hidden platform, particularly on the first trial each day. Also, the BSO + DA group utilized non-spatial strategies during the probe trials (swim with no platform): i.e., less time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent around the edge of the pool rather than in the platform zone. Therefore, the cognitive behavioral consequences of decreasing GSH brain levels with BSO in conjunction with DA administration depends on the order of administration. These findings are similar to those seen previously on rod and plank walking performance, as well as to those seen in aged rats, suggesting that the oxidation of DA coupled with a reduced capacity to respond to oxidative stress may be responsible for the induction of age-related cognitive deficits.
Shukitt-Hale
B
B
USDA-ARS, Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA. hale_ne@hnrc.tufts.edu
Erat
S A
SA
Joseph
J A
JA
D000375:Aging / Q000378:metabolism / Q000523:psychology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004298:Dopamine / Q000008:administration & dosage*; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency* / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology*; D008568:Memory / Q000187:drug effects* / Q000502:physiology*; D016877:Oxidants / Q000008:administration & dosage; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
D005609:Free Radicals; D016877:Oxidants; D019328:Buthionine Sulfoximine; D005978:Glutathione; D004298:Dopamine