This application seeks renewed support for MH59803, "Dopaminergic substrates of startle gating across species". For 20 years, systematic studies in rodents have identified specific neural substrates regulating prepulse inhibition (PPI) of startle. These limbic cortico-striatal-pallido-pontine (CSPP) substrates regulating PPI are relevant to several neuropsychiatric disorders, and are implicated in the reinforcing properties of drugs of abuse. One major challenge is to develop the capacity to probe and understand this PPI-regulatory circuitry in humans, and to identify genes that regulate its function and dysfunction. If neural circuit and genetic information, derived from animal studies, could be translated across species, PPI could become an important, new tool for understanding this biology in normal and neuropsychiatric disordered populations. MH59803 has identified areas of convergence and divergence in the effects of dopamine (DA) and glutamate manipulations on PPI and related measures in rats vs. normal human subjects. These studies also identified both rat and human phenotypes associated with distinct PPI-altering effects of several drugs, including the DA releaser, amphetamine (AMPH). The present proposal extends this translational approach to assess genes associated with PPI-reducing vs. increasing effects of AMPH in inbred rats and normal humans. The expression and its functional consequences of 5 specific genes in three brain regions that regulate PPI -- the nucleus accumbens, medial prefrontal cortex and ventral hippocampus -- will be assessed in inbred rat strains that exhibit PPI-reducing effects of AMPH ("PreA") vs. PPI-increasing effects of AMPH ("PieA"). Analyses will focus on 5 genes based on their association with both PreA vs. PieA phenotypes in outbred rats and PPI phenotypes in 2 separate schizophrenia cohorts;their expression in these 3 brain regions will facilitate a functional circuit-based analyses of gene effects. Specific genes associated with PPI AMPH- sensitivity in rats, together with others associated with human phenotypes that moderate PPI AMPH sensitivity, will be interrogated as predictors of PPI AMPH effects in normal human subjects, based on their response to placebo vs. 20 mg p.o. AMPH in a double-blind, cross-over design. In total, these studies will leverage new information generated in the past funding period, to discover genetic and neurobiological substrates regulating sensorimotor gating across species. Strong inference would then link these substrates to causative factors in the loss of sensorimotor gating in schizophrenia and other disorders, and to therapeutic interventions to remedy these deficits and their associated functional consequences.

Public Health Relevance

The ability of the human brain to filter or "gate" irrelevant sensory information is regulated by several neurotransmitters, including dopamine and glutamate, and is impaired in specific inherited brain disorders, including schizophrenia. This application will identify genes in humans and laboratory animals that control the sensitivity to sensorimotor gating changes in response to the dopamine releaser, amphetamine. The findings will inform studies searching for the genes associated with dopamine-linked disorders of impaired sensorimotor gating in humans.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Brady, Linda S
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Swerdlow, Neal R; Gur, Raquel E; Braff, David L (2015) Consortium on the Genetics of Schizophrenia (COGS) assessment of endophenotypes for schizophrenia: an introduction to this Special Issue of Schizophrenia Research. Schizophr Res 163:16-Sep
Chou, Hsun-Hua; Talledo, Jo A; Lamb, Sarah N et al. (2013) Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults. Psychopharmacology (Berl) 227:165-76
Swerdlow, Neal R; Hines, Samantha R; Herrera, Sebastian D et al. (2013) Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains. Pharmacol Biochem Behav 106:128-31
Swerdlow, Neal R; Light, Gregory A; Trim, Ryan S et al. (2013) Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats. Behav Brain Res 257:118-28
Swerdlow, Neal R; Powell, Susan B; Breier, Michelle R et al. (2013) Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats. Neuropharmacology 75:38-46
Swerdlow, Neal R (2012) Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia. Neuropsychopharmacology 37:310-1
Chang, Wei-Li; Weber, Martin; Breier, Michelle R et al. (2012) Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats. Brain Res 1437:69-76
Chang, Wei-li; Breier, Michelle R; Yang, Alex et al. (2011) Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague-Dawley rats. Pharmacol Biochem Behav 99:634-8
Sutherland Owens, Ashley N; Miguel, Euripedes C; Swerdlow, Neal R (2011) Sensory gating scales and premonitory urges in Tourette syndrome. ScientificWorldJournal 11:736-41
Swerdlow, Neal R; Breier, Michelle R; Saint Marie, Richard L (2011) Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats. Psychopharmacology (Berl) 216:401-10

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