EFFECTS OF THE SUBSTITUTED (S)-3-PHENYLPIPERIDINE(-)-OSU6162 ON PET MEASUREMENTS IN SUBHUMAN PRIMATES - EVIDENCE FOR TONE-DEPENDENT NORMALIZATION OF STRIATAL DOPAMINERGIC ACTIVITY

(-)-OSU6162 is a substituted (S)-3-phenylpiperidine derivative which e xhibits some affinity to the dopamine D-2 receptor family. In vivo, th e compound displays a unique normalizing profile on psychomotor activi ty by an intriguing mixture of stimulatory and inhibitory properties. In the present investigation, some of the effects of (-)-OSU6162 on ce ntral dopaminergic function were studied by positron emission tomograp hy (PET) and L-[C-11]DOPA in anaesthetized female rhesus monkeys. (-)- OSU6162 displayed a dopaminergic tone-dependent effect with a reductio n in the striatal L-[C-11]DOPA influx rate in monkeys with high baseli ne values and an increased striatal L-[C-11]DOPA influx rate in animal s with low baseline values. Infusion of (-)-OSU6162 for a whole day re sulted in a stable effect with no evidence of tolerance. (-)-OSU6162 a lso stabilized dopaminergic function by attenuating the upregulation o f the striatal L-[C-11]DOPA influx rate which has previously been show n to occur following 6R-BH4 or 6R-BH4 + L-tyrosine infusions. This ''P rotean'' effect of (-)-OSU6162 on the striatal dopaminergic function c orresponds to previous behavioral observations in intact animals and d emonstrates a true functional correlation to the measures obtained wit h L-[C-11]DOPA and PET. The normalizing and stabilizing profile of (-) -OSU6162 should be of value in treating a variety of disorders where a n underlying dysregulation or disruption of dopaminergic function can be assumed. (C) 1998 Wiley-Liss, Inc.