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.