The Huntington disease (HD) phenotype is associated with expansion of a trinucleotide repeat in the ITIS gene, which is predicted to encode a 348-kDa protein named huntingtin. We used polyclonal and monoclonal anti-fusion protein antibodies to identify native huntingtin in rat, monkey, and human. Western blots revealed a protein with the expected molecular weight which is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cell lines from control cases. In lymphoblastoid cell lines from juvenile-onset heterozygote HD cases, both normal and mutant huntingtin are expressed, and increasing repeat expansion leads to lower levels of the mutant protein. Immunocytochemistry indicates that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons. In the human striatum, huntingtin is enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD. Subcellular localization of huntingtin is consistent with a cytosolic protein primarily found in somatodendritic regions. Huntingtin appears to particularly associate with microtubules, although some is also associated with synaptic vesicles. On the basis of the localization of huntingtin in association with microtubules, we speculate that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules.Huntington disease (HD) is an inherited neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive disturbances. The neuropathology of HD includes selective loss of neurons that is most severe in the caudate and putamen but also affects other brain regions. It has been hypothesized that neuronal death in HD is due to a metabolic defect that leads to excitotoxicity (1, 2). The genetic mutation, however, has not yet been directly linked to neuronal metabolism.HD has been associated with the abnormal expansion of a polymorphic trinucleotide (CAG) repeat sequence occurring in the coding region of a gene (IT1S) located on chromosome 4 (3). In HD, the length of this repeat is substantially increased, ranging from 40 to over 100 copies (3-5). Juvenile-onset HD cases are associated with the highest numbers of repeats (3, 6). The IT1S gene encodes a large unknown protein (-343 kDa) that has been termed "huntingtin" (3). Its mRNA is normally distributed in diverse tissues in human and rat (3, 7) and is expressed predominantly in neurons in brain (7,8). In HD heterozygotes, both normal and mutant mRNA are present, suggesting that the trinucleotide expansion does not prevent transcription (9). Thus, the pathophysiology of HD likely depends on the effect of the mutant allele at the protein level. Understanding huntingtin is therefore crucial for determining how the genetic mutation could be linked to the pathophysiology of HD and for developing treatments based on the molecular defect. We have developed polyclonal and monoclonal antibodies specific to huntingtin to enable its identifica...

Exposure of rats to a series of inescapable shocks produced in sequence both an early naltrexone-insensitive and a late naltrexone-reversible analgesic reaction. Activation of the opiate system was necessary and sufficient to produce an analgesic reaction 24 hours later on exposure to a small amount of shock. The amount of inescapable shock which induced naltrexone-reversible analgesia also produced hyperreactivity to morphine 24 hours later.

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Five experiments examined the influence ot opiate antagonists on both the short-term analgesic reaction resulting 30 min after exposure to inescapable shock and the long-term analgesic reaction resulting after reexposure to shock 24 hr after inescapable shock exposure. Experiment 1 showed that the longterm analgesic reaction could be reduced by administration of naltrexone prior to exposure to inescapable tail shock. Experiment 2 showed that the reduction in the long-term analgesic reaction produced by naltrexone was dosedependent. Experiment 3 showed that the long-term analgesic reaction could also be reduced by administration of naltrexone prior to reexposure to shock. Experiment 4 showed that the long-term analgesic reaction could be reduced by administration of a large dose of naloxone prior to reexposure to shock. Experiment 5 showed that the short-term analgesic reaction was reduced by naltrexone administered prior to inescapable shock. Some implications of these results for the biochemical substrates of both learned helplessness and stress-induced analgesia are discussed.Exposure to inescapable and unavoidable aversive events has widespread behavioral and physiological consequences (see Maier & Seligman, 1976, for a review). Under some conditions, organisms exposed to inescapable and unavoidable electric shocks later show poor learning to escape shock in a different situation in which escape is possible (the so-called "learned helplessness effect"; cf. Overmier & Seligman, 1967), reduced activity in the presence of shock