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.
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