Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications.
BACKGROUND
All 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.


METHODS
The 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.


RESULTS
Rolipram reverses amphetamine-induced reductions in auditory-evoked potentials.


CONCLUSIONS
This finding could lead to novel approaches to receptor-independent treatments for schizophrenia.
Stanley Center for Experimental Therapeutics in Psychiatry, Division of Neuropsychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA.
C R
CR
Maxwell
S J
SJ
Kanes
T
T
Abel
S J
SJ
Siegel
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*; D012559:Schizophrenia / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects*
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D010726:Phosphodiesterase Inhibitors; D000661:Amphetamine; D020889:Rolipram; D004298:Dopamine