Excitotoxin injection

Application of kainic acid, and the more specific quinolinic acid, into the striatum is followed by Huntington-like structural and biochemical changes excitotoxin injection into the striatum produces locomotor hyperactivity and deficits in learning tests (DiFiglia, 1990). 

Two different methods have been used to determine the structure-activity relations of the neurotoxic action of the excitatory amino acids. With the first, the amino acids are administered by peripheral injection, which produces neuronal damage in areas of the brain to which the excitotoxins gain access. The second approach involves direct intracranial injection with analysis of the affected area to determine the scope and specificity of the lesion. While the latter method allows for more precise definition of toxic potencies and avoids variables such as metabolism and penetration of the blood-brain barrier, the systemic administration of these compounds was exploited first and continues to be used. 

Because of its extreme potency and commercial availability, kainic acid has been the excitotoxin most widely used for producing localized lesions in the mammalian central nervous system. While most studies indicate that in situ injection of kainic acid is an effective means of selectively destroying most neuronal perikarya in the vicinity of the injection site, it has become increasingly apparent that the effects of this agent are complex, variable, and often indirect. In order to appreciate the specificity, selectivity, and variability of neuronal vulnerability to locally injected kainic acid, the effects of this agent in two well-characterized brain regions will be reviewed. 

While most studies have focused on the acute and subacute neurotoxic effects of kainic acid within the straitum, one must also consider the longterm consequences of the excitotoxin lesion. Neurochemical and histologic analysis of the striatum nine months after in situ kainate injection has revealed a profound atrophy of the region congruent with the loss of the... 

After kainic acid, ibotenic acid has been the most extensively characterized of the excitotoxins effective with local injection. On a molar basis, ibotenic acid has approximately 20-fold lower potency than kainic acid... 

Typically, the excitotoxins are dissolved immediately prior to injection in buffered isotonic saline or artificial CSF. The long-term stability of... 

The maturity of brain plays an important role in neuronal vulnerability to excitotoxins. The CVO regions and neural retina of immature rats and mice (less than 10 days of age) are much more sensitive to peripherally administered excitotoxins than the adult. In contrast, the striatum of the neonatal rat is remarkably resistant to doses of kainic acid that produce extensive lesions in the adult but full vulnerability is attained by three weeks after birth (Campochiaro and Coyle, 1978). Similarly, Honnegar and Richelson (1977) have found that reaggregating brain cultures exhibit increasing sensitivity to the neurotoxic effects of kainic acid with differentiation. At the other extreme, neuronal sensitivity of the striatum to directly injected kainate appears to increase with advancing age (Gaddy et aL, 1979). An age dependence for the neurotoxic action of ibotenic acid and other directly injected excitotoxins has not yet been described. 

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