Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

Abstract

The a2 adrenoceptor (a2R) 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 clonidine 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 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 more selective a2R agonist, UK14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether the high affinity of clonidine for imidazoline-1 receptors (I1Rs) was responsible for the difference between these two a2R agonists. In morphine-dependent rats pretreated with rilmenidine (mixed a2R/I1R agonist), precipitation of withdrawal elicited a 22% increase of VTA DA impulse activity. The action of clonidine on I1Rs was studied by coadministering clonidine with RX821002, a specific a2R antagonist. Pretreatment with RX821002 plus clonidine 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 I1Rs as well as a2Rs.

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

“…This reduction of activity was biphasic: (1) the first rapid inhibition was maximal 30 s after the injection and was followed by a return to baseline activity (Fig. 4 F, trace); and (2) a second inhibition started 3 min after the injection and persisted for several hours [as reported previously (Georges and Aston-Jones, 2003)] (Fig. 4 E).…”

α1-Noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access

“…However, clonidine is a mixed α 2 -noradrenergic and imidazoline-1 receptor agonist, whereas UK14304 is a selective α 2 receptor agonist (Andorn et al, 1988;Ernsberger et al, 1997;Georges et al, 2005;Georges and Aston-Jones, 2003). Therefore, the action of clonidine may be mediated by imidazoline receptors.…”

“…Likewise, we observed that 1 mg/kg of UK14304 produced a loss of muscle tone and sedation, indicating that behaviorally active doses were tested. Moreover, UK14304 (0.1 mg/ kg) decreased firing rates of rat locus coeruleus neurons immediately after an intraperitoneal injection in in vivo cell recordings, suggesting that the drug easily crossed the blood-brain barrier (Georges and Aston-Jones, 2003). UK14304 pretreatment (0.05 mg/kg, i.p.)…”

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

“…Furthermore it has been shown that the BNST sends monosynaptic projections to dopaminergic VTA neurons to modulate reward (Georges and Aston-Jones, 2002). During withdrawal from morphine there is an inhibition of the firing of these dopaminergic cells that can not only be reversed with the a 2 -AR agonist clonidine, but potentiated by its administration (Georges and Aston-Jones, 2003). It is an interesting notion that the NET KO animals lack a mechanism (a 1 -AR LTD) that may contribute to the inhibition of the dopaminergic cells in the withdrawal state while simultaneously demonstrating increased behavioral sensitization and reward mediated behaviors to drugs of abuse.…”