Prolonged activation of mesolimbic dopaminergic neurons by morphine withdrawal following clonidine: Participation ofimidazoline and norepinephrine receptors

Abstract

The α2 adrenoceptor (α2R) agonist clonidine is used as a treatment for heroin addiction. Substantial evidence indicates that dopaminergic and noradrenergic systems have key roles in opiate dependence and withdrawalbut the possible interactions between these two pathways remain unclear. The objective of this study was to establish the effects of clonidine pretreatment on ventraltegmentalarea dopaminergic (VTA DA) neuronal activity during morphine withdrawal. Responses of VTA DA neurons to withdrawal precipitated by naltrexone were characterized in anesthetized rats using extra cellular recordings. As expected, withdrawal produced amarked inhibition of VTA DA neuronalactivity. However, pretreatment with clonidine prevented this inhibition induced by withdrawal, and instead produced a long-lasting activation of firing rate (+50%) and burst firing (+19%). In contrast, pretreatment with a moreselective α2R agonist, UK14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether thehigh affinity of clonidine for imidazoline-I receptors (lIRs) was responsible for the difference between these two α2R agonists. Inmorphine-dependent rats pretreated with rilmenidine (mixed α2R/IIR agonist), precipitation of withdrawalelicited a 22% increase of VTA DA impulse activity. The action of clonidine on lIRs was studied by coadministering clonidine with RX821002, a specific α2Rantagonist. Pretreatment with RX821002 plus clonidine prevented the inhibition of VTA DA activity during withdrawalbut failed toproduce excitation. These results indicate that the pharmacologicaleffects of clonidine on VTA DA neurons during morphine withdrawalis related to actions on lIRs as wellas α2Rs. © 2003 Nature Publishing Group.