FR discrimination training reverses 6-hydroxydopamine-induced striatal dopamine depletion in a rat model of Lesch-Nyhan syndrome.

Five-day-old rats received 6-hydroxydopamine (6-HD; 100 micrograms base) or vehicle intracisternally. Striatal and cortical dopamine (DA) and metabolite levels were then determined when animals were three or 8.5 months of age and the latter rats had been weight-reduced for 5.5 months. In the latter animals these determinations were made 1 month following 4.5 months of home-cage confinement (untrained animals) or of food-maintained fixed-ratio (FR) discrimination training involving either a single discrimination (performance animals) or incrementally more difficult discriminations. Striatal DA levels in 3-month-old and 8.5-month-old (untrained) 6-HD-treated rats were, respectively, only 3% and 11% of those in untrained vehicle-treated animals (controls). Despite such large depletions, striatal DA levels in 6-HD-treated performance rats were 3-fold higher than those in untrained age-matched 6-HD-treated rats (i.e., were 32% of values in controls) while those in incrementally trained 6-HD-treated animals were even higher (i.e., were 60% of control values). Related changes occurred in levels of most metabolites. However, in incrementally trained rats, striatal 3-methoxytyramine concentrations were 154% of control values. Cortical DA and metabolite levels were little affected by 6-HD treatment. The present results confirm and extend our earlier observations suggesting that reversal of 'irreversible' neonatal 6-HD-induced striatal dopamine and metabolic depletion can be accomplished by environmental (training) manipulations in adult rats.