COMPARISON OF THE ACTION OF THE STEREOISOMERS OF THE PSYCHOSTIMULANT 4-METHYLAMINOREX (4-MAX) ON MIDBRAIN DOPAMINE CELLS IN THE RAT - AN EXTRACELLULAR SINGLE-UNIT STUDY

In this study, we examined and characterized the action of the stereoi somers of 2-amino-4-methyl-Delta(2)-5-phenyl-oxazoline (4-methylaminor ex, 4-MAX) on spontaneously active dopamine (DA) neurons in the substa ntia nigra pars compacta (SNC or A9) and ventral tegmental area (VTA o r A10) in anesthetized male rats. This was accomplished using the tech nique of extracellular single unit recording. The intravenous (i.v.) a dministration of the stereoisomers of 4-MAX (0.1-6.4 mg/kg) produced a dose-dependent suppression of the basal firing rate of A10 DA cells w ith the following rank order of potency: trans 4S,5S > cis 4R,5S appro ximate to cis 4S,5S much greater than trans 4S,5S 4-MAX. The rank orde r of potency of the isomers of 4-MAX to suppress the firing of A9 DA c ells was trans 4S,5S = cis 4R,5S = cis 4S,5R much greater than trans 4 R,5R. The trans 4S,5S isomer was Ei-fold more potent in suppressing DA cell firing in the A10 compared to the A9 area. The suppressant actio n of the isomers on A9 and A10 DA cells was reversed by the i.v. admin istration of haloperidol and the D-2/D-3 receptor antagonists (-)-sulp iride and (-)-eticlopride but not by the D-1 receptor antagonists SCH 23390 and SCH 39166. In addition, the suppressant action of the trans 4S,5S isomer on A10 DA cells was not antagonized or reversed by the i. v. administration of the receptor antagonists granisetron (5-HT3), rit anserin (5-HT2A,C), idazoxan (alpha(2)), phentolamine (peripheral alph a(1)), (+/-)-pindolol (5-HT(1A,B)beta) or prazosin (alpha(1)). The pre treatment of animals with either alpha-methyl-p-tyrosine (AMPT) or res erpine, but not p-chlorophenylalanine (PCPA), (+/-)-fluoxetine or tomo xetine, significantly attenuated the suppression of A10 DA cell firing produced by trans 4S,5S 4-MAX. Overall, our results suggest that the suppressant action of 4-MAX on midbrain DA cell firing may be mediated by the release of DA, which subsequently interacts with D-2/D-3 recep tors. (C) 1995 Wiley-Liss, Inc.