Effect of denervation of the locus coeruleus projections by DSP-4 treatment on [ 3H]-raclopride binding to dopamine D 2 receptors and D 2 receptor–G protein interaction in the rat striatum

Abstract

Changes in the control of dopaminergic neurotransmission by noradrenergic locus coeruleus (LC) projections has been implicated in such disorders as depression, drug addiction, and Parkinson’s disease. In the present study, the effect of DSP-4, a neurotoxin highly selective for LC projections, on D 2 receptor abundance as assessed by [ 3H]-raclopride binding in the striatum was studied in rats after administration in doses of 10 and 50 mg/kg either 3 days or 1 month before decapitation. Three days after DSP-4 the levels of noradrenaline in the frontal cortex were dose-dependently reduced; after 1 month, noradrenaline levels were lowered only by the higher dose. DOPAC levels were dose-dependently reduced in the frontal cortex and striatum 3 days but not 1 month after DSP-4 treatment. Cortical 5-HIAA levels were reduced 3 days but not 1 month after DSP-4. The apparent number of D 2 receptor binding sites in the striatum was higher 1 month after either dose of DSP-4. DSP-4 treatment had no effect on [ 3H]-raclopride binding affinity, the ability of dopamine (DA) to compete with [ 3H]-raclopride binding and to activate [ 35S]GTPγS binding or on the binding affinities of GDP and [ 35S]GTPγS for corresponding G proteins 1 month after administration of the neurotoxin. These data suggest that after administration of DSP-4, short-term reduction in DA and 5-HT metabolism occurs. Subsequently, an upregulation of D 2 receptor binding sites develops in the striatum even after a minor denervation of the LC projections. Thus, alterations in the LC projection systems elicit lasting adaptive changes in DA-ergic neurotransmission that can serve as a substrate for psychiatric disorders.