Amphetamine-haloperidol interactions on striatal and mesolimbic tyrosine hydroxylase activity and dopamine metabolism.
Rat striatal and mesolimbic dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid levels and the activity of tyrosine hydroxylase (TOH) were determined as a function of dose of amphetamine (AMPH) or haloperidol (HAL). AMPH increases DA levels with an ED50 of 0.6 mg/kg and decreases DOPAC and homovanillic acid levels with an ED50 of 1.5 mg/kg, suggesting two sites of action for the drug. HAL increases DOPAC and homovanillic acid levels and activates TOH all with an ED50 near 0.05 mg/kg and maximal activation at 0.2 mg/kg. AMPH administered subsequent to 0.2 mg/kg of HAL has no effect on mesolimbic TOH activity or DA metabolism. In contrast AMPH after HAL still increases striatal DA levels and, in addition, partially reverses the HAL-induced increases in both DOPAC levels and TOH activity, all with an ED50 near 0.6 mg/kg. The maximal reversal by AMPH is near 25% of the HAL-induced increases with doses of AMPH to 10 mg/kg. The ED50 for AMPH reversal and the extent of reversal are independent of HAL dose. The equivalent reversal by AMPH of HAL-induced increases in striatal TOH activity and DOPAC levels suggest a neuronally mediated phenomenon involving a noncompetitive interaction between the two drugs on the nigrostriatal pathway. The data are discussed in terms of sites of action for AMPH in both the striatum and the substantia nigra.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D006220:Haloperidol / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000032:analysis; D008032:Limbic System / Q000378:metabolism; D008297:Male; D051381:Rats; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D014793:Visual Cortex / Q000378:metabolism
D015102:3,4-Dihydroxyphenylacetic Acid; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D004298:Dopamine; D006719:Homovanillic Acid