Brain extracellular levels of the putative antipsychotic CI-1007 and its effects on striatal and nucleus accumbens dopamine overflow in the awake rat

The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl- 1 [(3-phenyl-3-cyc lohexen- 1-yl)methyl]pyridine maleate) has been identified as a partial dop amine agonist and putative antipsychotic in in-vitro and in-vivo neurochemi cal, neurophysiological and behavioural tests. By use of microdialysis in conjunction with high-performance liquid chromat ography (HPLC) with electrochemical detection, the effects of the drug on b rain dopamine release, previously observed in anaesthetized animals, were s hown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug's ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem ma ss spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40mgkg (-1)) significantly inhibits dopamine release in the nucleus accumbens, a r egion associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function. The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extra pyramidal side effects are lower than those of typical antipsychotics.