Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington's disease.

1. The present study compared the effects of acute intrastriatal administration of quinolinic acid (QA) and 3-nitropropionic acid (3-NP), two neurotoxins used in animal models of Huntington's disease (HD), on the following behavioral and histological measures: (1) open field activity levels; (2) performance on balance beam and grip strength tasks; (3) acquisition of a radial-arm-water-maze (RAWM) task; (4) size of striatum and lateral ventricles; (5) amount of cytochrome oxidase (CYO) labeling; and (6) counts of Nissl-stained neurons and NADPH-diaphorase-labeled neurons in the striatum. 2. Rats were given bilateral intrastriatal injections of either 200 nmol QA, 750 nmol 3-NP, or phosphate buffered saline (PBS) two weeks prior to behavioral testing and four weeks prior to histological processing. 3. The behavioral results indicated that both QA and 3-NP injections caused an increase in activity levels at two weeks postlesion, but only the QA rats showed hyperactivity at four weeks postlesion. Both QA and 3-NP rats showed significant impairment in the balance beam task, but only 3-NP rats differed significantly on the grip-strength task. Both toxins caused learning impairments in the RAWM task, with 3-NP rats being more severely impaired. 4. The neuroanatomical results indicated that both QA and 3-NP produced significant striatal atrophy and ventricular dilation, as well as a reduction in CYO staining and loss of Nissl-stained neurons, but only the 3-NP lesions created necrotic cavities in the striatum. However, the QA treatments resulted in significant loss of NADPH-diaphorase neurons in regions peripheral to the site of injection. 5. In general, these results suggest that QA treatments produce milder behavioral and neuroanatomical effects that mimic some of the earlier symptoms of HD, while 3-NP produced more severe effects which mimic both the later symptoms and the juvenile onset of HD.

Small drug sample fabrication of controlled release polymers using the microextrusion method.

Ethylene vinylacetate polymer (EVA) has been used for many years to fabricate controlled-release polymeric implant devices with which drugs of high or low molecular weight compounds could be delivered with zero-order kinetics. However, because the known fabrication methods such as solvent evaporation, casting and possible shrinkage are not sufficiently controllable we have now developed the microextrusion method with which even small amount of clinically important and expensive drugs can be incorporated into EVA with high reproducibility. We show here that devices produced by the microextrusion method allows for a controlled delivery of several neurotoxic and neurotherapeutic compounds such as alpha-methyl-p-tyrosine, diazepam, quinolinic acid, and phencyclidine. Each substance is slowly released from the polymer, as evidenced by spectrophotometric data, for up to 120 days at daily rates varying from 18.4 microg of phencyclidine to 97.6 microg/day of diazepam. Thus, microextrusion is a valuable method for fabricating controlled-release polymers in which small amounts of scarce drugs can be incorporated. Another advantage of the current procedure is that polymers can be fabricated with very little amount of solvent.

Chronic administration of quinolinic acid in the rat striatum causes spatial learning deficits in a radial arm water maze task.

Chronic intrastriatal administration of quinolinic acid (QA) in the rat produces a pattern of neurodegeneration similar to that seen in Huntington's disease (HD). Although these changes have been related to transient motor abnormalities, the effects of chronic QA administration on cognitive abilities have not been assessed. The present study investigated whether the striatal deterioration observed during chronic QA administration produces cognitive impairments in this animal model of HD by testing the effects of chronic administration of QA on spatial learning ability of rats in a radial arm water maze (RAWM) task. Rats were given bilateral implantation of a chronic dialysis probe apparatus which delivered either vehicle or QA (20 mM) into the striatum. Beginning 1 day after implantation, the rats were tested daily for 3 weeks in the RAWM. Nocturnal activity levels were also assessed at 1-, 3-, 5-, 7-, 14-, and 21-days following probe implantation. Results of behavioral testing indicated that chronic exposure to QA causes spatial learning deficits in the RAWM task with only a transient increase in activity levels. Collectively, these results suggest that chronic striatal exposure to QA mimics some aspects of the cognitive deficits observed in HD.