Blockade of Dopamine D4 Receptors Attenuates Reinstatement of Extinguished Nicotine-Seeking Behavior in Rats

Abstract

Since cloning of the dopamine receptor D4 (DRD4), its role in the brain has remained unclear. It has been reported that polymorphism of the DRD4 gene in humans is associated with reactivity to cues related to tobacco smoking. However, the role of DRD4 in animal models of nicotine addiction has seldom been explored. In our study, male Long-Evans rats learned to intravenously self-administer nicotine under a fixed-ratio (FR) schedule of reinforcement. Effects of the selective DRD4 antagonist L-745,870 were evaluated on nicotine self-administration behavior and on reinstatement of extinguished nicotine-seeking behavior induced by nicotine-associated cues or by priming injections of nicotine. L-745,870 was also tested on reinstatement of extinguished food-seeking behavior as a control. In addition, the selective DRD4 agonist PD 168,077 was tested for its ability to reinstate extinguished nicotine-seeking behavior. Finally, L-745,870 was tested in Sprague Dawley rats trained to discriminate administration of 0.4 mg/kg nicotine from vehicle under an FR schedule of food delivery. L-745,870 significantly attenuated reinstatement of nicotine-seeking induced by both nicotine-associated cues and nicotine priming. In contrast, L-745,870 did not affect established nicotine self-administration behavior or reinstatement of food-seeking behavior induced by food cues or food priming. L-745,870 did not produce nicotine-like discriminative-stimulus effects and did not alter discriminative-stimulus effects of nicotine. PD 168,077 did not reinstate extinguished nicotine-seeking behavior. As DRD4 blockade by L-745,870 selectively attenuated both cue- and nicotine-induced reinstatement of nicotine-seeking behavior, without affecting cue- or food-induced reinstatement of food-seeking behavior, DRD4 antagonists are potential therapeutic agents against tobacco smoking relapse.

Dopamine D3 Receptors in the Basolateral Amygdala and the Lateral Habenula Modulate Cue-Induced Reinstatement of Nicotine Seeking

“…This is consistent with the previous finding that eticlopride decreased cue-induced reinstatement of nicotine seeking (Liu et al, 2010). Eticlopride has traditionally been classed as a D 2 antagonist, but it targets all types of D 2 receptors, including the D 3 and D 4 subtypes, the latter has recently been shown to control nicotine seeking (Yan et al, 2012). Thus, it has been difficult to determine which receptor subtype was mediating the effects of D 2 ligands.…”

“…In the present study, the selective D 2 antagonist, L741626, was used and was able to block cueinduced reinstatement of nicotine seeking suggesting that D 2 is involved in mediating nicotine-seeking behavior. Together with our earlier reports that systemic administration of selective D 3 (Khaled et al, 2010) and D 4 antagonist (Yan et al, 2012) blocked cue-induced reinstatement of nicotine seeking, this suggests that all D 2 subtypes mediate nicotine seeking. Further demonstration of the specific involvements of the selective receptor subtypes could be provided by using transgenic mice lacking the D 3 receptor, as already reported by some investigators (Song et al, 2012).…”

Therapeutic doses of buspirone block D3 receptors in the living primate brain

“…Since there is in vivo evidence that D 4 R antagonists are effective (Feldpausch et al, 1998;Yan et al, 2012) in animal models of SUD, this highlights a potential role of D 4 R antagonism in the anti-addictive properties of buspirone. Moreover, given that the affinity of 6′-hydroxybuspirone, a metabolite with a total plasma exposure ∼40-fold higher than buspirone following oral administration (Dockens et al, 2006) approximates that of the parent drug at D 4 R , it is likely that D 4 R occupancy would be similar or higher than at D 3 R.…”

Electrical Stimulation of the Insular Region Attenuates Nicotine-Taking and Nicotine-Seeking Behaviors

“…Initial training procedures and surgical techniques for nicotine SA were similar to those reported previously (Forget et al, 2010a, b;Gamaleddin et al, 2012;Le Foll et al, 2011;Yan et al, 2012). Animals were initially trained on a schedule in which each lever press resulted in the delivery of a 45-mg food pellet (continuous reinforcement, no cues associated with food delivery).…”