Project Title: 16. Nuclear Medicine Technology and other Health Applications Treatment and Biochemical Dissection of Parkinsonism and Allied Conditions Technical Progress in FY 1973: (Cont'd.) RX-01-03-(a) tracer into brain after 4 hours and 20% after 30 days; 6) the animals' reactivity to levodopa tended to follow the manganese concentrations, These findings show that young animals are exceedingly susceptible to Mn poisoning early in life since they accumulate excesses of metal spontaneously; have almost no blood-brain barrier against it; and their homeostatic mechanisms are insufficient to deal with these excesses. “ peyoe . ’ ' Pharmacological parkinsonism induced in psychotic patients by reserpine became a biochemical model in treating idiopathic parkinsonism. Conversely, the induction of pharmacological psychoses while treating parkinsonism with levodopa might constitute biochemical models for spontaneously occurring mental aberrations, Since apomorphine (which can stimulate both dopaminergic and cholinergic receptors) had not induced such psychoses, it appeared desirable to determine whether a cholinergic agent given together with levodopa could prevent psychoses without jeopardizing the control of parkinsonism. Physostigmine was the first cholinergic agent to be used for this purpose, since it has aggravated parkinsonism only when given without levodopa. A preliminary study of four parkinsonians with levodopa-induced mental aberrations showed that injected physostigmine (0.5 - 1,75 mg s.c.) diminished garrulity, hallucinations and delusions, Adverse effects on parkinsonism were Limited to bursts of tremor and occasionally salivation, both of which were mild. On the basis of these observations the FDA has been petitioned for permission to use physostigmine orally on a chronic ‘ basis. Acting as an acetylcholinesterase inhibitor, physostigmine is an indirect stimulator of cholinergic receptors as opposed to oxotremorine, a potent direct stimulator of muscarinic receptors. The oral LDsg of oxotremorine (2.59 ug/g in Swiss albino mice) was increased fivefold by pretreatment with 1 - 1.5 ug/day oxotremorine (once a day for 4 days) and sixfold by pretreatment with probanthine. Decreased lethality was also achieved by adding oxotremorine to drinking water (2.5 or 12.5 wg/ml) for one week prior to testing the LDsg. The cerebral signs generated from the test injections were similar in both pre-and non-treated animals, suggesting that one can again diminish toxicity without diminishing cerebral effects, as with D,L-dopa, levodopa, and apomorphine. en oxotremorine was given i.p. (0.1 or 0.2 ug/g) into unilaterally g@mized mice it caused marked turning opposite from the lesion and Pretreatment with levodopa “dm that direction For several hours. (0.3 and 0.4 mg/g i.p.) blocked these effects. When both drugs were given, the animals became immobile but showed no postural changes. These results indicated that one can control the activities of both the dopaminergic —~ and cholinergic systems. (See Continuation Sheet) pb y9r9g4 RX-41