Symptoms of schizophrenia include sensory flooding and cognitive fragmentation which are thought to be the result of a deficiency in sensorimotor gating. Sensorimotor gating can be measured in humans and animals using a quantitative test that assesses reduction of the startle response to a pulse stimulus after presentation of a weaker prepulse stimuls. Prepulse inhibition (PPI) of the startle response is disrupted in patients with schizophrenia. An identical test has been used in animals to elucidate the mechanisms underlying PPI. Acute administration of dopamine agonists placed into the nucleus accumbens (NAc) disrupts PPI by stimulating dopamine D2-like receptors. This effect is blocked by antipsychotic pretreatment or by local D2-like receptor antagonist administration. Several other neurotransmitter systems are implicated, but the mesolimbic dopamine system remains an important substrate for these effects. The long-range goal of the project is to determine the specific cellular and molecular targets related to sensorimotor gating deficits in schizophrenia. An animal model of sensorimotor gating will be used to examine the neuroadaptive responses leading to recovery of PPI disruption following chronic drug treatment. In contrast to the disrupting effect of acute dopamine agonist treatment, we have shown that repeated treatment attenuates the behavioral disruption by desensitizing dopamine D2-like receptors.
The specific aims of the project are (1) to determine whether functional downregulation of dopamine D2-like receptors induced by chronic treatment with a D2-like receptor-selective agonist attenuates disruption of PPI in a time-and dose-dependent manner by actin in the NAc,(2) to ascertain whether reduction of inhibitory G proteins in the Nac is sufficient to attenuate disruption of PPI, and (3) to define and characterize the subset of NAc neurons whose function is altered following chronic D2-receptor agonist treatment using retrograde labeling and immunohistochemical detection of an immediate early gene marker. Together, these studies will produce novel data on the circuitry and signaling mechanisms underlying the recovery of PPI disruption in rodents. The results will advance our understanding of sensorimotor gating deficits win schizophrenia from the regional level to the cellular and molecular levels, and may provide novel therapeutic targets for future development.
| Berger, Alison K; Green, Thomas; Siegel, Steven J et al. (2011) cAMP response element binding protein phosphorylation in nucleus accumbens underlies sustained recovery of sensorimotor gating following repeated D?-like receptor agonist treatment in rats. Biol Psychiatry 69:288-94 |
| Culm, Kerry E; Lugo-Escobar, Natasha; Hope, Bruce T et al. (2004) Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats. Neuropsychopharmacology 29:1823-30 |
| Culm, Kerry E; Hammer Jr, Ronald P (2004) Recovery of sensorimotor gating without G protein adaptation after repeated D2-like dopamine receptor agonist treatment in rats. J Pharmacol Exp Ther 308:487-94 |
| Culm, Kerry E; Lim, Antonio M; Onton, Julie A et al. (2003) Reduced G(i) and G(o) protein function in the rat nucleus accumbens attenuates sensorimotor gating deficits. Brain Res 982:12-8 |
