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

The alpha2 adrenoceptor (alpha2R) 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 withdrawal but the possible interactions between these two pathways remain unclear. The objective of this study was to establish the effects of clonicine pretreatment on ventral tegmental area dopaminergic (VTA DA) neuronal activity during morphine withdrawal. Responses of VTA DA neurons to withdrawal precipitated by naltrexone were characterized in anesthetized rats using extracellular recordings. As expected, withdrawal produced a marked inhibition of VTA DA neuronal activity. However, pretreatment with clonicine 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 more selective a2R agonist, UK 14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether the high affinity of clonidine for imidazoline-I receptors (IIRs) was responsible for the difference between these two alpha2R agonists. In morphine-dependent rats pretreated with rilmenidine (mixed alpha2R/IIR agonist), precipitation of withdrawal elicited a 22% increase of VTA DA impulse activity. The action of clonidine on IIRs was studied by coadministering clonidine with RX821002, a specific alpha2R antagonist. Pretreatment with RX821002 plus clonicine prevented the inhibition of VTA DA activity during withdrawal but failed to produce excitation. These results indicate that the pharmacological effects of clonidine on VTA DA neurons during morphine withdrawal is related to actions on IIRs as well as alpha2Rs.