This is a proposal to study the neural circuit basis for heritable differences in the regulation of sensorimotor gating by dopamine (DA) activity in rats. Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating that is impaired in schizophrenia patients and their unaffected first-degree relatives. The inheritance of this phenotype in schizophrenia families must reflect inherited changes in brain circuitry that regulates PPI. PPI is also impaired in rats by DA agonists - e.g. apomorphine (APO) and amphetamine (AMPH) - and sensitivity to these effects appears to be genetically determined in rats, with robust and reliable innate differences seen across strains and substrains. Strain differences in the PPI-disruptive effects of DA agonists have large effect sizes - even across common outbred strains - and reflect differences in CNS effects, rather than differences in drug metabolism or distribution. Because the neurobiology of PPI is well understood in rats, it is possible to determine the neural basis for these inherited differences in the DA-regulation of PPI, and thereby to identify targets of inherited determinants of deficient PPI in schizophrenia families. Studies will use albino Sprague Dawley (SDH) and hooded Long Evans (LEH) rats, building on existing findings of strain differences in sensitivity to the PPI-disruptive effects of DA agonists.
Aim 1 will compare PPI across strains after manipulations of""""""""presynaptic"""""""" DA function, via stimulation of mesolimbic and nigrostriatal DA release. Strain differences in presynaptic DA substrates will also be assessed, including regional differences in DA, tyrosinase and tyrosine hydroxylase.
Aim 2 will assess PPI in these rats after manipulations of""""""""post-synaptic"""""""" DA function, via direct infusion of a D2 receptor agonist into mesolimbic and nigrostriatal terminal regions. Strain differences in DA receptor density and affinity will also be assessed.
Aim 3 will determine strain differences in """"""""post-receptor"""""""" immediate-early gene activating effects of DA receptor stimulation.
Aim 4 will compare PPI in these strains after manipulations """"""""downstream"""""""" from DA receptors, via GABA receptor blockade in the ventral pallidum. The heritability of strain differences in Aims 1-4 will be tested in an SDH x LEH cross. These studies will provide a clear understanding of the brain changes responsible for the expression of a heritable model of an important schizophrenia endophenotype. This new information will be a foundation for innovative models of the pathophysiology of schizophrenia and other inherited neuropsychiatric disorders, and for prospective strategies for novel drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068366-03
Application #
6892087
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Vicentic, Aleksandra
Project Start
2003-07-15
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$205,200
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Swerdlow, Neal R; Shilling, Paul D; Breier, Michelle et al. (2012) Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats. Psychopharmacology (Berl) 224:349-62
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
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
Chang, Wei-Li; Geyer, Mark A; Buell, Mahalah R et al. (2010) The effects of pramipexole on prepulse inhibition and locomotor activity in C57BL/6J mice. Behav Pharmacol 21:135-43
Weber, Martin; Chang, Wei-Li; Breier, Michelle R et al. (2010) The effects of the dopamine D2 agonist sumanirole on prepulse inhibition in rats. Eur Neuropsychopharmacol 20:421-5
Breier, Michelle R; Lewis, Brittanni; Shoemaker, Jody M et al. (2010) Sensory and sensorimotor gating-disruptive effects of apomorphine in Sprague Dawley and Long Evans rats. Behav Brain Res 208:560-5
Chang, Wei-li; Swerdlow, Neal R; Breier, Michelle R et al. (2010) Parametric approaches towards understanding the effects of the preferential D3 receptor agonist pramipexole on prepulse inhibition in rats. Pharmacol Biochem Behav 95:473-8
Weber, Martin; Chang, Wei-Li; Durbin, John P et al. (2009) Using prepulse inhibition to detect functional D3 receptor antagonism: effects of WC10 and WC44. Pharmacol Biochem Behav 93:141-7
Qu, Ying; Saint Marie, Richard L; Breier, Michelle R et al. (2009) Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats. Psychopharmacology (Berl) 207:271-80

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