Behavioral and neurochemical effects of intra-caudate nucleus MPTP in the cat

S140 BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF INTRA-CAUDATE NUCLEUS MPTP IN THE CAT TAKEO SUZUKI ~, HISAMASA IMAI, FUMIO MIYAKAWA * and HIROTARO NARABAYASHI, Dept. of Neurology, School of Medicine, Juntendo Univ., 1-1, Hongo 2, Bunkyo-ku, Tokyo 113, Japan Short t e r m r e p e a t e d a d m i n i s t r a t i o n of l - m e t h y l - 4 - p h e n y l - l , 2 , 3 , 6 - t e t r a h y d r o p y r i d i n e (MPTP) in humans and monkeys induces s y m p t o m s and pathology c h a r a c t e r i s t i c of Parkinsonism. In c o n t r a s t , it has been r e p o r t e d t h a t MPTP is much less e f f e c t i v e in o t h e r animal s p e c i e s including r a t s and mice. Markham and c o l l e a g u e s (1985} have r e p o r t e d t h a t MPTP s y s t e m i c a l l y a d m i n i s t e r e d to c a t s can produce a P a rki ns oni a n syndrome with many s i m i l a r i t i e s to t h a t observed in p r i m a t e s . But, so far, t h e r e seem to be no more r epor ts on MPTP n e u r o t o x i c i t y in cats. We have a d m i n i s t e r e d MPTP into the u n i l a t e r a l c a u d a t e nucleus of c a t s and have i n v e s t i g a t e d its n e u r o t o x i c e f f e c t b e h a v i o r a l l y and n e u r o c h e m i c a l l y . C a t s were a n e s t h e t i s e d with k e t a m i n e and placed in a s t e r e o t a × i c i n s t r u m e n t . A s t a i n l e s s s t e e l cannula was i m p l a n t e d in the head of the u n i l a t e r a l c a u d a t e nucleus and was c o n n e c t e d to an A l z e t 200 ul o s m o t i c minipump that had been filled with 0.4 mg or 4 mg of MPTP in physiological saline. The minipumps w e r e designed to d e l i v e r solution at a c o n s t a n t r a t e for 14 days. No drooling was observed, and no a p p a r e n t m otor s y m p t o m s such as hypokinesia, dystonia or t r e m o r w e re r e c o g n i z e d through the six w e e ks ' observation period. The cats, however, showed a m a r k e d response to oral L-dopa a d m i n i s t r a t i o n (L-dopa 100 mg with c a r b i d o p a 10 mg tablet), t h a t is, e o n t r a l a t e r a l circ l i ng, the s a me d i r e c t i o n as L-dopa induced c i r c l i n g of r a t s with u n i l a t e r a l 6-hydroxydopamine lesions of the n i g r o s t r i a t a l dopa mi ne pathway. L-Dopa induced c i r c l i n g by a single dose r e a c h e d a peak in I to 2.5 hours and l a s t e d for 4 to 5 hours. The number of c i r c l i n g s / m i n a f t e r the minipump i m p l a n t a t i o n was i n v e s t i g a t e d once or t w i c e a week and it was found that the c i r c l i n g r e a c h e d a peak at around 2 weeks l a t e r when the MPTP was t o t a l l y r e l e a s e d from the minipump and then d e c r e a s e d gradually to near zero in 3 to 4 weeks. 4 c a t s out of e i g h t with MPTP 0.4 mg showed no c i r c l i n g at all. For n e u r o c h e m i c a l analysis some c a t s w e re s a c r i f i c e d at two or six weeks a f t e r the minipump i m p l a n t a t i o n . The brains w e r e re gi ona l l y d i s s e c t e d and the dopa mi ne (DA) and nor adren aline (NA) were q u a n t i f i e d by an HPLC procedure. At 2 weeks, the c a t s w i t h MPTP 0.4 rng had 36 % s t r i a t a l and 3 1 % nigral DA depletions, and the c a t s with MPTP 4 mg had 76 % s t r i a t a l and 4 1 % nigral DA depletions. In c o n t r a s t , s t r i a t a l and nigral NA had no d e c r e a s e . At 6 weeks, the s t r i a t a l and nigral DA of the c a t s with MPTP 4 mg r e t u r n e d to th e normal range. F u r t h e r r e s e a r c h is n e c e s s a r y to a s c e r t a i n w h e t h e r MPTP produces a p e r m a n e n t r e t r o g r a d e d e g e n e r a t i o n of the n i g r o s t r i a t a l dopamine neurons and a p e r s i s t e n t syndrome which m i m i c s P a r k i n s o n ' s d i s e a s e in the c a t .

CHANGES OF MONOAMINE METABOLITES AFTER RESERPINE ADMINISTRATION

IN CISTERNAL CSF IN CONSCIOUS AND FREELY MOVING RATS

YUTAKA SAWA, RITSUKO OHKUBO, YOSHONORI SUZUKI, SHINJI OKUYAMA and TSUNEYUKI NAKAZAWA, DEPARTMENT OF NEURO-PSYCHIATRY, SCHOOL OF MEDICINE, FUJITA-GAKUEN HEALTH UNIV, NAGOYA DOPAC, HVA and 5-HIAA ( unconjugated and conjugated form ) in the cisternal CSF from conscious and freely moving rats were measured every hour for 6 hrs after the administration of reserpine ( 2mg/kg;i.p. ). Percent changes of unconjugated DOPAC after reserpinization were significantly higher than in vehicle ( 7% propyleneglycol ) administered rats from 1 hr to 5 hr, but there was no significant difference at 6 hr. Total DOPAC ( unconjugated and conjugated which was obtained after acid hydrolysis following Sarna's method ) was significantly higher in reserpinized rats for 6 hr. Uuconjugated and total HVA were significantly higher in reserpinized rats from 2 to 6 hr but not at i hr. 5-HIAA ( measured only in the unconjugated form ) was significantly higher in reserpinized rats from 1 to 6 hr. As unconjugated DOPAC was not higher in the unconjugated form but in total at 6 hr, the total value was more sensitive than the unconjugated value. As unconjugated/total values were not changed in the time course in all three metabolites, reserpine was not thought to have the effect on phenolsulphotransferase activity.