COCAINE NEUROTOXICITY AND ALTERED NEUROPEPTIDE-Y IMMUNOREACTIVITY IN THE RAT HIPPOCAMPUS - A SILVER DEGENERATION AND IMMUNOCYTOCHEMICAL STUDY

Neuroanatomical methods were used to determine if cocaine irreversibly injures neurons. Despite acute and chronic high-dose treatments for m onths that produced stereotYPed behavior and seizures, and the use of a sensitive silver impregnation method, we were unable to find any evi dence of neuronal damage anywhere in the brain. Since expression of th e inducible 72 kDa heat shock protein (HSP72) is a sensitive indicator of potentially toxic neuronal stress, we next determined if cocaine e voked HSP72 expression. Even high doses of cocaine that evoked seizure s did not induce HSP72 immunoreactivity anywhere within the brain, whe reas kainic acid produced widespread HSP72 immunoreactivity and irreve rsible injury. Having failed to find indications of frank neurotoxicit y, we examined peptide and protein cell marker immunoreactivities in s earch of cocaine-induced changes. Although cocaine treatment had no ob vious effects on the patterns of hippocampal calbindin-D28K, somatosta tin-, tyrosine hydroxylase- and parvalbumin immunoreactivities, cocain e reliably altered neuropeptide Y-like immunoreactivity (NPY-LI). Most notably, NPY-LI was expressed in hippocampal dentate granule cells an d pyriform cortical neurons, which do not normally express it. Convers ely, we noted decreased NPY-LI in dentate hilar neurons that normally do express it. Since both changes in NPY-LI were seen only in cocaine- treated rats that exhibited seizures, the role of seizure activity per se in producing the NPY changes was addressed in normal rats by elect rical stimulation of the perforant path. Like cocaine, perforant path stimulation for as little as 15min evoked NPY-LI in granule cells but did not replicate the cocaine-induced decrease in hilar cell NPY-LI. T hese results suggest that cocaine does not irreversibly injure neurons in the rat, even at doses that induce seizures. However, cocaine prod uces long-lasting changes in NPY expression that are of unknown functi onal significance. Our inability to demonstrate cocaine-induced neuron al damage in rats should in no way be taken as evidence of its safety in humans.