Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements in subhuman primates: evidence for tone-dependent normalization of striatal dopaminergic activity

Synapse. 1998 Apr;28(4):280-7. doi: 10.1002/(SICI)1098-2396(199804)28:4<280::AID-SYN3>3.0.CO;2-5.

Abstract

(-)-OSU6162 is a substituted (S)-3-phenylpiperidine derivative which exhibits some affinity to the dopamine D2 receptor family. In vivo, the compound displays a unique normalizing profile on psychomotor activity by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (-)-OSU6162 on central dopaminergic function were studied by positron emission tomography (PET) and L-[11C]DOPA in anaesthetized female rhesus monkeys. (-)-OSU6162 displayed a dopaminergic tone-dependent effect with a reduction in the striatal L-[11C]DOPA influx rate in monkeys with high baseline values and an increased striatal L-[11C]DOPA influx rate in animals with low baseline values. Infusion of (-)-OSU6162 for a whole day resulted in a stable effect with no evidence of tolerance. (-)-OSU6162 also stabilized dopaminergic function by attenuating the upregulation of the striatal L-[11C]DOPA influx rate which has previously been shown to occur following 6R-BH4 or 6R-BH4 + L-tyrosine infusions. This "Protean" effect of (-)-OSU6162 on the striatal dopaminergic function corresponds to previous behavioral observations in intact animals and demonstrates a true functional correlation to the measures obtained with L-[11C]DOPA and PET. The normalizing and stabilizing profile of (-)-OSU6162 should be of value in treating a variety of disorders where an underlying dysregulation or disruption of dopaminergic function can be assumed.

MeSH terms

  • Animals
  • Biopterin / analogs & derivatives
  • Biopterin / pharmacology
  • Corpus Striatum / diagnostic imaging
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism*
  • Dopamine / metabolism*
  • Dopamine Agents / metabolism
  • Dopamine Antagonists / pharmacology*
  • Female
  • Levodopa / metabolism
  • Macaca mulatta
  • Piperidines / pharmacology*
  • Reference Values
  • Tomography, Emission-Computed*
  • Tyrosine / pharmacology

Substances

  • Dopamine Agents
  • Dopamine Antagonists
  • Piperidines
  • OSU 6162
  • Biopterin
  • Tyrosine
  • Levodopa
  • sapropterin
  • Dopamine