Several major psychiatric disorders, including schizophrenia, involve deficits in sensorimotor gating, a form of pre-attentional information-processing. Sensorimotor gating refers to the inhibitory mechanism by which an organism is able to filter out information from the internal and external environment. Prepulse inhibition (PP-) is an operational measure of sensorimotor gating and refers to the ability of a weak prestimulus to inhibit the magnitude of the startle response to a subsequent intense stimulus. Previous studies examining the neural systems regulating PPI have focused on dopamine, serotonin, and glutamate systems, but have largely ignored the norepinephrine (NE) system. This is surprising given the proposed role of NE in attention and cognition, as well as evidence indicating dysfunction of the NE system in diseases involving deficient sensorimotor gating such as schizophrenia, attention deficit disorder, and post-traumatic stress disorder. Thus, the goal of this project is to systematically test the hypothesis that increasing central NE transmission disrupts PPI.
Specific Aim 1 will examine whether pharmacological stimulation of the locus-coeruleus (LC), the primary source of NE to the forebrain, disrupts PPI. The hypothesis of Aim 1 is that stimulation of the LC dose-dependently and selectively disrupts PPI. Using microdialysis, Specific Aim 2 will determine if LC stimulation-induced deficits in PPI are associated with an increase in NE levels within a forebrain LC terminal region, the medial prefrontal cortex (mPFC). The hypothesis of Aim 2 is that increases in NE in the mPFC will correlate with deficits in PPI and that antagonism of NE receptors in the mPFC will attenuate LC stimulation-induced deficits in PPI.
Specific Aim 3 will examine the role of the LC in mediating the effects of stress on PPI. The hypothesis of Aim 3 is that antagonizing corticotrophin-releasing factor (CRF) receptors n the LC will block deficits in PPI induced by predator stress. These studies will thus systematically investigate the involvement of a novel mechanism underlying a core information-processing deficit that is seen in several psychiatric illnesses including schizophrenia. Results from this work could have broad implications for the development of novel antipsychotic treatments that target the LC-NE system in a number of psychiatric-disorders^ attention deficit disorder, post-traumatic stress disorder). Given the high incidence of these illnesses in the US population, the present preclinical studies could have far-reaching clinical applications. ? ? ?
| Alsene, Karen M; Bakshi, Vaishali P (2011) Pharmacological stimulation of locus coeruleus reveals a new antipsychotic-responsive pathway for deficient sensorimotor gating. Neuropsychopharmacology 36:1656-67 |
| Alsene, Karen M; Rajbhandari, Abha K; Ramaker, Marcia J et al. (2011) Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating. Neuropsychopharmacology 36:1003-14 |
| Alsene, Karen M; Fallace, Katie; Bakshi, Vaishali P (2010) Ventral striatal noradrenergic mechanisms contribute to sensorimotor gating deficits induced by amphetamine. Neuropsychopharmacology 35:2346-56 |
