The goal of this proposal is to evaluate a potential new target for the treatment of schizophrenia and other psychiatric disorders that involve aberrant nucleus accumbens (Acb) function: the Acb-localized AMY1 receptor. This receptor binds members of the calcitonin family of peptides, including amylin, salmon calcitonin, and calcitonin gene-related peptide (CGRP). Despite the fact that the Acb possesses among the densest concentrations of this receptor in the brain, the evidence that the Acb-localized amylin receptor represents a unique receptor subtype, and the finding that amylin in the Acb produces potent behavioral effects reminiscent of functional dopamine antagonism, there has been no research exploring the effects of Acb amylin receptor manipulations on schizophrenia-like information-processing deficits. This is a surprising omission given that that hyperdopaminergia within Acb is widely thought to contribute to the symptomatology of schizophrenia, but antipsychotic drugs that can selectively influence dopamine transmission in Acb without concomitantly altering DA signaling in other sites and/or causing potent side-effects are not available. The Acb-localized AMY1 receptor represents an attractive target with which to enact such an anatomically specific pharmacotherapy for schizophrenia. The present proposal seeks to explore this hypothesis by evaluating in animal models of deficient prepulse inhibition (PPI) the effects of stimulating and antagonizing the Acb AMY1 receptor in rats. PPI is the normal diminution of the startle response that occurs when a weak prestimulus immediately precedes the startling stimulus, and is an operational measure of core information-filtering deficits that are seen in schizophrenia, Tourette's Syndrome, Obsessive-compulsive disorder, and certain other mental illnesses. PPI is among the most well-validated preclinical paradigms with which to assess antipsychotic efficacy, as drugs that normalize PPI deficits in animals successfully treat clinical PPI deficits. The present studies will determine if stimulation of Acb AMY1 receptors improves baseline or deficient PPI (induced by psychotomimetic drugs such as amphetamine or phencyclidine), and/or if agonists for this receptor augment the efficacy of clinically prescribed antipsychotic medications in the PPI paradigm. Finally, we will explore whether the family of amylin-related genes is regulated by isolation rearing, a developmental manipulation in rats that is known to produce schizophrenia-like PPI deficits in adulthood. In the course of this last study, we will also determine whether amylin-related genes themselves are developmentally regulated.

Public Health Relevance

The direct translational implication of the proposed work would be the identification of a novel target for antipsychotic drug development, to use in the treatment of schizophrenia, which affects 1% of the population worldwide. Schizophrenia is a devastating chronic illness characterized by hallucinations, delusions, affective dysregulation, and thought disorder. Current treatments, albeit helpful, are not completely effective and produce serious side effects including weight gain, insulin resistance, and diabetes. By virtue of its selective localization in one of the brain regions most likely to underlie many schizophrenic symptoms the AMY1 receptor represents a powerful new putative candidate for producing antipsychotic effects. Moreover, because stimulation of AMY receptors promotes weight loss, this drug target has the potential be free of or even reverse one of the most problematic side-effects of current antipsychotics (weight gain, insulin resistance and diabetes).

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Winsky, Lois M
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University of Wisconsin Madison
Schools of Medicine
United States
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Baisley, Sarah K; Baldo, Brian A (2014) Amylin receptor signaling in the nucleus accumbens negatively modulates ?-opioid-driven feeding. Neuropsychopharmacology 39:3009-17
Baldo, Brian A; Pratt, Wayne E; Will, Matthew J et al. (2013) Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior. Neurosci Biobehav Rev 37:1985-98