Disruption of nicotine conditioning by dopamine D3 receptor ligands

Abstract

Tobacco smoking is the first cause of preventable death in modern countries. Nicotine replacement therapy or sustained release bupropion helps smoking cessation, but relapse rates are still very high. Nicotine, like other drugs of abuse, activates the dopamine mesolimbic system, which originates in the ventral tegmental area and projects notably to the nucleus accumbens. Situations or environmental stimuli previously associated with cigarette smoking, for example, smell of cigarette smoke, can elicit craving in abstinent smokers and promote relapse. Reducing the effects of nicotineassociated cues might therefore have potential therapeutic utility for smoking cessation. Such an approach has been validated for cocaine in animals, by using the dopamine D 3 receptor-selective partial agonist BP 897, which inhibits cocaine cue-induced drug-seeking behavior. Here we show that rats repeatedly injected with nicotine in a particular environment develop nicotineconditioned locomotor responses, accompanied by an increase in D 3 receptor expression in the nucleus accumbens. This conditioned behavior was inhibited by BP 897 or a selective D 3 receptor antagonist, suggesting that antagonizing dopamine selectively at the D 3 receptor disrupts nicotine-conditioned effects and might represent a novel therapeutic approach for smoking cessation.

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

“…A recent series of experiments has also shown that termination of a cocaine self-administration regimen increases DA D 3 binding over time in the NAc core and ventral caudate-putamen, an adaptive change that may occur through regulatory responses to an increase in phasic DA levels associated with cocaine-taking and -seeking behavior [212]. In addition, nicotineinduced conditioned locomotion [169] and nicotine behavioral sensitization [170] are both associated with significant increases in D 3 receptor binding and mRNA levels in the NAc shell without altering D 1 or D 2 receptor mRNA in the NAc shell or core subregions. Furthermore, twice daily morphine administration over 8 consecutive days with an escalating dosing regimen starting at 10 mg/kg was shown to produce a significant increase in D 3 receptor mRNA in the caudate-putamen and ventral midbrain, including the substantia nigra and VTA.…”

“…BP-897 (0.3, 1, or 3 mg/kg ip) reduces cocaine cue-induced hyperlocomotion in SwissWebster mice [168] as well as nicotine-induced conditioned locomotion [169] and nicotineinduced behavioral sensitization in rats [170]. Aujla et al [12] also showed that BP-897 (1 mg/kg) blocked the expression of conditioned locomotor activity to amphetamine (2 mg/kg) in male Wistar rats without altering the acquisition of conditioning or the locomotor activating effect of amphetamine.…”

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

“…Indeed, systemic administration of the selective D 3 antagonist, SB-277011-A, attenuated cue-induced reinstatement of nicotine seeking (Khaled et al, 2010). In addition, repeated systemic administration of nicotine to animals produced an elevation in D 3 binding sites (Le Foll et al, 2003a) and D 3 antagonism reduced the response to a conditioned stimulus (Le Foll et al, 2003b;Le Foll et al, 2005). Furthermore, recent imaging studies revealed elevations in dopamine binding to D 3 receptors in the brains of smokers after smoking a single cigarette (Le Foll et al, 2014).…”

Behavioral and neuropharmacological characterization of nicotine as a conditional stimulus

“…When eticlopride, a dopamine D 2 / D 3 receptor antagonist (Hall et al, 1985, Köhler et al, 1986and Tang et al, 1994, is infused into the ventral tegmental area, nicotine-induced increases in dopamine in the nucleus accumbens are partially inhibited (Sziráki et al, 2002). Dopamine D 3 receptor antagonists have been shown to block expression of nicotine-conditioned place preference (Le Foll et al, 2005) and nicotine-conditioned hyperactivity (Le Foll et al, 2003). Although the effects of the dopamine D 3 receptor antagonist nafadotride have not been explicitly studied with nicotine, its specifi city in vivo makes it a useful tool for studying potential dopamine D 3 -mediated behaviors (Audinot et al, 1998 andLevant andVansell, 1997).…”