DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice

Susan L. Lautar, Camilo Rojas, Barbara S. Slusher, Krystyna M. Wozniak, Ying Wu, Ajit G. Thomas, Daniel Waldon, William Li, Dana Ferraris, Sergei Belyakov

Research output: Contribution to journalArticle

Abstract

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-Amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2- carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalBrain research
Volume1048
Issue number1-2
DOIs
StatePublished - Jun 28 2005
Externally publishedYes

Keywords

  • Amphetamine-induced hyperactivity
  • CD26
  • DPP IV
  • Enzyme inhibition
  • Mescaline-induced scratching
  • NPY
  • Peptide
  • Psychosis
  • Schizophrenia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Fingerprint Dive into the research topics of 'DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice'. Together they form a unique fingerprint.

  • Cite this

    Lautar, S. L., Rojas, C., Slusher, B. S., Wozniak, K. M., Wu, Y., Thomas, A. G., Waldon, D., Li, W., Ferraris, D., & Belyakov, S. (2005). DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice. Brain research, 1048(1-2), 177-184. https://doi.org/10.1016/j.brainres.2005.04.069