Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats

Kerry E. Culm, Natasha Lugo-Escobar, Bruce T. Hope, Ronald P. Hammer

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 μM), or SKF 82958- (10 μM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP-dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia.

Original languageEnglish (US)
Pages (from-to)1823-1830
Number of pages8
JournalNeuropsychopharmacology
Volume29
Issue number10
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

Keywords

  • D-like receptors
  • Nucleus accumbens
  • PKA
  • Phospho-CREB
  • Prepulse inhibition
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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