Phosphodiesterase inhibitors: A novel mechanism for receptor-independent antipsychotic medications
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.
References (56)
- et al.
Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol
Biol Psychiatry
(1986) - et al.
P50 suppression among schizophrenia and normal comparison subjects: a methodological analysis
Biol Psychiatry
(1997) - et al.
GABA(B) receptor inhibition causes locomotor stimulation in mice
Eur J Pharmacol
(2001) - et al.
Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains
Brain Res
(2003) - et al.
Rolipram and its optical isomers, phosphodiesterase 4 inhibitors, attenuated the scopolamine-induced impairments of learning and memory in rats
Jpn J Pharmacol
(1997) - et al.
Schizophrenia and reduced cyclic AMP production: evidence for the role of receptor-linked events
Life Sci
(1982) - et al.
Ameliorating effects of rolipram on experimentally induced impairments of learning and memory in rodents
Eur J Pharmacol
(1997) - et al.
Effects of P50 temporal variability on sensory gating in schizophrenia
Psychiatry Res
(1997) - et al.
Amphetamine disrupts P50 suppression in normal subjects
Biol Psychiatry
(1999) - et al.
Neuroleptics block the positive reinforcing effects of amphetamine but not of morphine as measured by place conditioning
Pharmacol Biochem Behav
(1985)
Suppression of oro-facial movements by rolipram, a cAMP phosphodiesterase inhibitor, in rats chronically treated with haloperidol
Eur J Pharmacol
Effect of neuroleptics and tricyclic antidepressants upon d-amphetamine discrimination
Pharmacol Biochem Behav
Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile
Eur J Pharmacol
Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from schizophrenic patients
Neuropsychopharmacology
Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism
Neuropsychopharmacology
Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme
Neuropsychopharmacology
Schizophrenia, sensory gating, and nicotinic receptors
Schizophr Bull
Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs
Pharmacol Toxicol
Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway
Proc Natl Acad Sci USA
Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory
Proc Natl Acad Sci USA
A mouse model of Rubinstein-Taybi syndrome: defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4
Proc Natl Acad Sci USA
Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys
J Pharmacol Exp Ther
The current status of the dopamine hypothesis of schizophrenia
Neuropsychopharmacology
Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation
Science
Poor P50 suppression among schizophrenia patients and their first-degree biological relatives
Am J Psychiatry
The effects of ketamine vary among inbred mouse strains and mimic schizophrenia for the P80, but not P20 or N40 auditory ERP components
Neurochem Res
A meta-analysis of the efficacy of second-generation antipsychotics
Arch Gen Psychiatry
Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients
Biol Psychiatry
Cited by (101)
Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities
2021, Pharmacology and TherapeuticsThe role of striatum and prefrontal cortex in the prevention of amphetamine-induced schizophrenia-like effects mediated by nitric oxide compounds
2018, Progress in Neuro-Psychopharmacology and Biological PsychiatryEfficient synthesis of (−)-(R)- and (+)-(S)-rolipram
2017, Tetrahedron LettersPhosphodiesterase-4 inhibition restored hippocampal long term potentiation after primary blast
2017, Experimental NeurologyCitation Excerpt :Those results suggested that modulation of the cAMP pathway could have therapeutic potential in preventing memory deficits following primary bTBI. Intriguingly, increasing cAMP through phosphodiesterase-4 inhibition was effective in improving outcome in some experimental models of TBI and also reduced cognitive impairments associated with Alzhemer's disease, schizophrenia and aging (Gong et al., 2004; Maxwell et al., 2004; Smith et al., 2009; Titus et al., 2014; Wiescholleck and Manahan-Vaughan, 2012). Currently, there are no clinically-approved treatments for TBI (Silverberg et al., 2016).
PDE and cognitive processing: Beyond the memory domain
2015, Neurobiology of Learning and Memory