cAMP Response Element Binding Protein Phosphorylation in Nucleus Accumbens Underlies Sustained Recovery of Sensorimotor Gating Following Repeated D2-Like Receptor Agonist Treatment in Rats

Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA.
Biological psychiatry (Impact Factor: 10.26). 10/2010; 69(3):288-94. DOI: 10.1016/j.biopsych.2010.08.032
Source: PubMed


Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits are observed in humans and rats upon acute treatment with dopamine D₂-like receptor agonists and in patients with schizophrenia. Repeated treatment with a D₂-like agonist, however, reverses PPI deficits and increases cyclic adenosine monophosphate (cAMP) signaling in the nucleus accumbens (NAc). This study examined the short- and long-term effects on PPI of treatment with quinpirole and ropinirole, dopamine D₂/D₃ receptor agonists, and the molecular mechanism by which they occur.
PPI was assessed in adult male Sprague-Dawley rats following acute and chronic treatment with quinpirole or ropinirole and 1, 2, 3, and 4 weeks after termination of repeated ropinirole treatment. Finally, the effect of dominant negative mutant cAMP response element binding protein (CREB) overexpression in the NAc on PPI following chronic quinpirole treatment was assessed.
Acute quinpirole produced dose-dependent PPI deficits, whereas ropinirole caused consistent PPI reduction at all but the highest dose. Repeated ropinirole treatment significantly increased PPI compared with acute treatment, and increased CREB phosphorylation in NAc neurons. Subsequent ropinirole challenge had no effect as long as 28 days later, at which time NAc CREB phosphorylation had normalized. Overexpression of dominant negative mutant CREB prevented PPI recovery induced by chronic quinpirole treatment.
Chronic quinpirole or ropinirole treatment produces sustained PPI recovery; CREB activity in the NAc is required to induce PPI recovery but not to maintain it. The results suggest that transcriptional regulation by CREB mediates long-lasting changes occurring within NAc circuits to promote recovery of sensorimotor gating.

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    • "The CREB-GFP fusion protein has been shown to function similar to wildtype CREB in reporter mice (Wallace et al., 2009). Expression of the AAV viruses is chronic and persistent, with peak transgene expression occurring by 7-10 days post-infusion and elevated expression levels last for at least 1-2 months (Wallace et al., 2009; Sun et al., 2010; Berger et al., 2011). A bicistronic herpes simplex viral vector (HSV) was used to construct the HSV-GFP, HSV-CREB, and HSV-mCREB viruses as previously described (Neve et al., 1997). "
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