Several disorders may be linked by deficient """"""""gating"""""""" or suppression of intrusive thoughts and behaviors, and by dysfunction in neural circuitry linking the limbic system and basal ganglia. This proposal will use an animal model to define the brain substrates of deficient sensorimotor gating, focusing on interactions between the striatum and pallidum in rats and in patients with suspected striatal dysfunction. The overall aim of this proposal is to study the mechanisms that might contribute to deficient sensorimotor gating in Schizophrenia, Obsessive Compulsive Disorder (OCD) and Huntington's Disease (HD). Sensorimotor gating will be defined as the amount that a startle response to a loud noise is inhibited by a weak prestimulus. """"""""Prepulse inhibition"""""""" (PPI) is studied in rats and humans with similar parameters and dependent measures. Schizophrenic patients exhibit less PPI of eyeblink startle than do normal controls. In rats, PPI of whole body startle is decreased by drugs that stimulate dopamine (DA) receptors in the nucleus accumbens (NAC) and anteromedial striatum. Preliminary work suggests that the substrates for these deficits include interactions between the hippocampus, striatum and pallidum. First, I propose to study the pharmacology and anatomy of the striatal DAergic control of PPI in rats. In these studies, systemic and intra-striatal injections of selective D1 and D2 agonists and antagonists will be administered to study the role of these DA receptor subtypes in the control of PPI, and 6-hydroxydopamine lesions of presynaptic DA neurons will be used to assess the role of presynaptic DA autoreceptors in the reduction of PPI after intra-striatal DA infusion. Next. I propose to measure PPI in rats after cell-specific ibotenic acid lesions of the NAC, the anterior striatum or the posterior striatum. I will study the role of the pallidum in any striatal lesion-induced loss of PPI, using infusions of muscimol, picrotoxin and GABA into the ventral pallidum or the ventromedial or dorsolateral globus pallidus. To test the validity of this model and its relevance to gating substrates in humans, PPI will be measured in patients with HD, whose degenerative loss of the striato- pallidal GABAergic projection lay lead to deficient motor gating. Finally, PPI will be measured in patients with OCD, to assess whether impaired gating of intrusive thoughts and obsessions is accompanied by deficient PPI, and if so, whether PPI deficits in these patients suggest dysfunction in basal ganglia circuitry. This strategy may identify substrates in limbic system and basal ganglia circuitry where pharmacologic intervention will facilitate the suppression of intrusive thoughts and behaviors in several disorders.
