Continuous or pulsatile chronic D 2 dopamine receptor agonist (U91356A) treatment of drug-naive 4-phenyl-1,2,3,6-tetrahydropyridine monkeys differentially regulates brain D 1 and D 2 receptor expression: in situ hybridization histochemical analysis

Abstract

The effect of a chronic D 2 dopamine receptor agonist (U91356A) treatment on dopamine receptor gene expression in the brain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys was investigated using quantitative in situ hybridization histochemistry. U91356A was administered to MPTP-monkeys for 27 days in a pulsatile ( n=3) or continuous ( n=3) schedule. Animals treated in a pulsatile mode showed progressive sensitization and developed dyskinesia; whereas with the continuous mode behavioural tolerance was observed but no dyskinesia developed. Untreated MPTP as well as naive control animals were also studied. The efficacy and uniformity of the MPTP effect was assessed by measures of dopamine concentrations by high performance liquid chromatography with electrochemical detection in the relevant brain areas. D 1 and D 2 receptor messenger RNAs levels were examined by in situ hybridization histochemistry using human complementary RNA probes. Intense specific labelling for D 1 and D 2 receptor messenger RNAs was measured in the caudate and putamen with a rostrocaudal gradient for D 2 receptors and a lower density in the cortex for D 1 receptors messenger RNA. D 1 receptor mRNA levels in rostral striatum and cortex decreased whereas D 2 receptor messenger RNA in caudal striatum increased in MPTP-monkeys compared to control animals. Continuous administration of U91356A reversed the MPTP-induced increase of D 2 receptor messenger RNA, whereas the pulsatile administration did not significantly correct these messenger RNA changes. U91356A treatment whether continuous or pulsatile partially corrected the D 1 receptor messenger RNA lesion-induced decrease in the striatum, whereas no correction was observed in the cortex. All MPTP-monkeys were extensively and similarly denervated suggesting that the D 1 and D 2 receptor expression changes following U91356A administration were treatment related. Our data show a lesion-induced imbalance of D 1 (decrease) and D 2 (increase) receptor messenger RNAs in the striatum of MPTP-monkeys. The response of these receptors to D 2 agonist treatment showed receptor selectivity and was influenced by the time-course of drug delivery. Hence chronic continuous but not pulsatile administration of U91356A reversed the striatal D 2 receptor messenger RNA increase.