FIXED-RATIO DISCRIMINATION-TRAINING AS REPLACEMENT THERAPY IN PARKINSONS-DISEASE - STUDIES IN A 6-HYDROXYDOPAMINE-TREATED RAT MODEL

Severe B-hydroxydopamine (6-OHDA)-induced neostriatal dopamine (DA) de pletion is generally held to be irreversible. Adult rats administered 6-OHDA soon after weaning, or neonatally, respectively model Parkinson 's disease (PD) and Lesch-Nyhan syndrome (LNS). Prior studies in our l aboratory indicate that prolonged training on incrementally more diffi cult fixed-ratio (FR) discriminations can reverse 'irreversible' 6-OHD A-induced neostriatal DA depletion in adult LNS rats. The present stud y evaluated the effects of such training on neostriatal DA depletion a nd its functional consequences in adult PD and control (vehicle-inject ed) rats. After recovery from 6-OHDA-induced hypophagia, rats were sac rificed to assess neostriatal DA depletion magnitude, or were food-dep rived and either subjected to food-maintained operant FR discriminatio n training or allowed to remain in their home cages. 6-OHDA treatment antagonized amphetamine (AMP)-induced increases in brief rearing behav ior and locomotor activity in S-month-old PD rats prior to training, a nd reduced operant response rates throughout training without affectin g learning rates. One week after training, AMP-increased locomotor and brief-rearing frequencies were augmented in all groups except trained controls, and the prior inhibitory effect of 6-OHDA treatment on AMP- increased behavioral frequencies was essentially eliminated. Cumulativ e apomorphine (APO) dose-effect curve (0.1-3.2 mg/kg) construction 3 w eeks post-training revealed that 6-OHDA treatment abolished APO-induce d intense licking behavior. However, training eliminated the hyperresp onsiveness of 6-OHDA-treated rats to the locomotor-and brief-rearing s timulant effects of APO but did not affect the depletion of neostriata l DA. Nevertheless, 6-OHDA-induced increases in neostriatal DOPAC/DA a nd HVA/DA ratios were normalized by age/food-deprivation while that of 3MT/DA was not. These findings suggest that training reduces the func tional responsiveness of at least some central DA receptors, ER discri mination training could be a useful adjunct to PD replacement therapy and that the neostriatal DA-repleting action of training in 6-OHDA-tre ated rats depend on the age at which 6-OHDA is administered. (C) 1998 Elsevier Science B.V.