Poor evidence for depolarization block but uncoupling of nigral from striatal dopamine metabolism after chronic haloperidol treatment in the rat.
Chronic haloperidol treatment induces depolarization block in midbrain dopamine neuronal systems. We studied the effect of this treatment on nigrostriatal dopamine catabolism using microwave fixation in situ of the brain to prevent post-mortem changes. Male Sprague-Dawley rats were given haloperidol (0.4 mg/kg/day, i.p.) or vehicle for 21 days. On day 22, some rats in each group received a haloperidol challenge (0.4 mg/kg, i.p.), and the remaining rats were given the vehicle. Dopamine metabolite levels 60 min after the challenge were assayed by combined gas chromatography-mass fragmentography. Haloperidol pretreatment significantly modified haloperidol challenge effect on regional dopamine metabolite contents. The challenge elevated all striatal metabolites studied similarly in the chronic vehicle- or chronic haloperidol-pretreated rats. In contrast, it did not significantly affect nigral dopamine metabolites except it elevated 3,4-dihydroxyphenylacetic acid in the haloperidol-pretreated rats. A linear correlation between the nigral and striatal contents of 3-methoxytyramine (R = 0.72, p = 0.03), and a trend for correlation (R = 0.65, p = 0.06) between the respective 3,4-dihydroxyphenylacetic acid contents were found after the haloperidol challenge in the vehicle-pretreated rats only. These results suggest that chronic haloperidol treatment uncouples somatodendritic dopamine turnover and release from those in the axon terminals of nigrostriatal dopamine neurons.
Chrapusta
S J
SJ
Department of Experimental Pharmacology, Polish Academy of Sciences Medical Research Center, Warsaw, Poland. chrapuss@medres.cmdik.pan.pl
Egan
M F
MF
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D018492:Dopamine Antagonists; D015102:3,4-Dihydroxyphenylacetic Acid; D006220:Haloperidol; D004298:Dopamine