Cellular basis of amphetamine-induced hallucinations

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DESCRIPTION (provided by applicant): Hallucinations are perceptions of stimuli that are not really there. In humans, high doses of amphetamine can trigger hallucinations, as well as paranoid psychotic episodes that are virtually indistinguishable from those of schizophrenia. While the pharmacology of how amphetamine acts in the brain is known in some detail, the electrophysiological mechanisms underlying its psychotogenic effects are not yet understood. This laboratory recently found that single, high doses of amphetamine elicit apparent hallucinations in an invertebrate model system, the marine mollusk Tritonia Diomedea. In isolated brain preparations, amphetamine caused repeated, spontaneous eruptions of the animal's high-threshold escape swim motor program. This effect was traced to spontaneous bursts of action potentials in the centrally-located afferent neurons that normally trigger the swim. Because these neurons are disconnected from the skin in this preparation, the animal's brain is generating a complex response to a perceived skin stimulus that isn't really there -- i.e., it is experiencing a somatic hallucination. The project has three specific aims. The first aim will focus on the biophysical mechanism by which amphetamine induces plateau potential properties in the afferent neurons, rendering them bistable and thus prone to erupt into spontaneous bursts of activity. The second aim will determine whether the explosive spread of firing observed among the members of the afferent neuron population in the presence of amphetamine is due to enhanced chemical or electrical synaptic connections. The third aim will explore whether repeated amphetamine leads to sensitization of its effects over time. Our results should facilitate the development of improved pharmacotherapy for treating amphetamine overdose and addiction. They may also have relevance for the treatment of hallucinations caused by other drugs of abuse as well as by diseases such as schizophrenia.