Ketamine increases striatal dopamine release and hyperlocomotion in adult rats after postnatal functional blockade of the prefrontal cortex

Behav Brain Res. 2013 Nov 1;256:229-37. doi: 10.1016/j.bbr.2013.08.017. Epub 2013 Aug 16.

Abstract

Schizophrenia is a complex psychiatric disorder that may result from defective connectivity, of neurodevelopmental origin, between several integrative brain regions. Different anomalies consistent with brain development failures have been observed in patients' left prefrontal cortex (PFC). A striatal dopaminergic functional disturbance is also commonly acknowledged in schizophrenia and could be related to a dysfunctioning of dopamine-glutamate interactions. Non-competitive NMDA antagonists, such as ketamine, can induce psychotic symptoms in healthy individuals and worsen these symptoms in patients with schizophrenia. Our study set out to investigate the consequences of neonatal functional blockade of the PFC for dopaminergic and behavioral reactivity to ketamine in adult rats. Following tetrodotoxin (TTX) inactivation of the left PFC at postnatal day 8, dopaminergic responses induced by ketamine (5 mg/kg, 10 mg/kg, 20 mg/kg sc) were monitored using in vivo voltammetry in the left part of the dorsal striatum in freely moving adult rats. Dopaminergic responses and locomotor activity were followed in parallel. Compared to PBS animals, in rats microinjected with TTX, ketamine challenge induced a greater release of dopamine in the dorsal striatum for the highest dose (20 mg/kg sc) and the intermediate dose (10mg/kg sc). A higher increase in locomotor activity in TTX animals was observed only for the highest dose of ketamine (20 mg/kg sc). These data suggest transient inactivation of the PFC during early development results in greater behavioral and striatal dopaminergic reactivity to ketamine in adulthood. Our study provides an anatomo-functional framework that may contribute toward a better understanding of the involvement of NMDA glutamatergic receptors in schizophrenia.

Keywords: Dopamine; Dorsal striatum; In vivo voltammetry; Ketamine; Neonatal functional blockade; Prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Corpus Striatum / drug effects*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Ketamine / pharmacology*
  • Male
  • Motor Activity / drug effects*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / growth & development
  • Prefrontal Cortex / physiopathology*
  • Rats, Sprague-Dawley
  • Schizophrenia / physiopathology
  • Tetrodotoxin / toxicity
  • Time Factors

Substances

  • Excitatory Amino Acid Antagonists
  • Tetrodotoxin
  • Ketamine
  • Dopamine