Elsevier

Neuroscience

Volume 129, Issue 1, 2004, Pages 101-107
Neuroscience

Phosphodiesterase inhibitors: A novel mechanism for receptor-independent antipsychotic medications

https://doi.org/10.1016/j.neuroscience.2004.07.038Get rights and content

Abstract

OverviewAll current antipsychotic medications work by binding to Gi-coupled dopamine (DA) D2 receptors. Such medications are thought to affect cellular function primarily by decreasing DA-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP).However, several studies indicate that cAMP signal transduction abnormalities in schizophrenia may not be limited to D2-containing cells. The current study examines the potential of using non-receptor-based agents that modify intracellular signal transduction as potential antipsychotic medications.

MethodsThe indirect DA agonist amphetamine has been used to model the auditory sensory processing deficits in schizophrenia. Such pharmacologically induced abnormalities are reversed by current antipsychotic treatments. This study examines the ability of the phosphodiesterase-4 inhibitor, rolipram, to reverse amphetamine-induced abnormalities in auditory-evoked potentials that are characteristic of schizophrenia.

ResultsRolipram reverses amphetamine-induced reductions in auditory-evoked potentials.

ConclusionThis finding could lead to novel approaches to receptor-independent treatments for schizophrenia.

Section snippets

Animals

C57BL/6J mice (n=63) were obtained at 8 weeks of age from Jackson Laboratories (Bar Harbor, ME, USA). All testing was conducted between 9 and 10 weeks of age. All protocols were conducted in accordance with University Laboratory Animal Resources guidelines and were approved by the Institutional Animal Care and Use Committee.All experiments conformed to international guidelines on the ethical use of animals and all attempts were made to minimize the number of animals used and their suffering.

Results

There were no differences between groups on any component prior to drug exposure (Table 1). Both the rolipram dose response analysis and the reversal analysis yielded main effects of drug, stimulus condition and stimulus condition by drug interaction for each component (Table 1). Additionally, the haloperidol analysis revealed a drug by stimulus condition interaction on the P20N40 complex (Table 1). Rolipram alone dose dependently enhances the amplitude of the first stimulus on the P20, N40 and

Discussion

The current study demonstrates that the PDE4 inhibitor, rolipram, reverses amphetamine-induced decrement in P20, N40 and P20N40 AEP components in mice. Such reductions in the amplitude of evoked potentials, primarily in the response to the first stimulus, are similar to abnormalities seen in untreated schizophrenia (Freedman et al., 1983; Adler et al., 1986; Jin et al., 1997). More recent studies have focused on the pattern of AEP abnormalities in treated schizophrenia patients. These studies

Acknowledgments

This work was supported by P50 MH 6404501 (S.J.S., S.J.K., and T.A.) and The Stanley Medical Research Institute (S.J.S.). No authors have any involvement, financial or otherwise, that might potentially bias the work contained in this manuscript.

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