Antipsychotic compounds differentially modulate high-frequency oscillations in the rat nucleus accumbens: a comparison of first- and second-generation drugs

Int J Neuropsychopharmacol. 2013 Jun;16(5):1009-20. doi: 10.1017/S1461145712001034. Epub 2012 Nov 21.

Abstract

Improved understanding of the actions of antipsychotic compounds is critical for a better treatment of schizophrenia. Abnormal oscillatory activity has been found in schizophrenia and in rat models of the disease. N-Methyl-D-aspartic acid receptor (NMDAR) antagonists, used to model certain features of schizophrenia, increase the frequency and power of high-frequency oscillations (HFO, 130-180 Hz) in the rat nucleus accumbens, a brain region implicated in schizophrenia pathology. Antipsychotics can be classified as first- and second-generation drugs, the latter often reported to have wider benefit in humans and experimental models. This prompted the authors to examine the pre- and post-treatment effects of clozapine, risperidone (second-generation drugs) and sulpiride and haloperidol (first-generation drugs) on ketamine and MK801-enhanced accumbal HFO. Both NMDAR antagonists increased HFO frequency. In contrast, clozapine and risperidone markedly and dose-dependently reduced the frequency of spontaneous and NMDAR-antagonist-enhanced HFO, whilst a moderate effect was found for sulpiride and a much weaker effect for haloperidol. Unexpectedly, we found reductions in HFO frequency were associated with an increase in its power. These findings indicate that modulation of accumbal HFO frequency may be a fundamental effect produced by antipsychotic compounds. Of the drugs investigated, first- and second-generation compounds could be dissociated by their potency on this measure. This effect may partially explain the differences in the clinical profile of these drugs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Biological Clocks / drug effects*
  • Disease Models, Animal
  • Dizocilpine Maleate / therapeutic use
  • Dose-Response Relationship, Drug
  • Electric Stimulation / adverse effects
  • Electroencephalography
  • Excitatory Amino Acid Antagonists / toxicity
  • Ketamine / toxicity
  • Locomotion / drug effects
  • Male
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology*
  • Rats
  • Rats, Wistar
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy*
  • Schizophrenia / physiopathology*
  • Time Factors

Substances

  • Antipsychotic Agents
  • Excitatory Amino Acid Antagonists
  • Ketamine
  • Dizocilpine Maleate