The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions

Abstract

Increasing evidence suggests that enhanced dopamine (DA) neurotransmission in the nucleus accumbens (NAc) may play a role in mediating the reward and reinforcement produced by addictive drugs and in the attentional processing of drug-associated environmental cues. The meso-accumbens DA system is selectively enriched with DA D3 receptors, a DA receptor subtype increasingly implicated in reward-related brain and behavioural processes. From a variety of evidence, it has been suggested that selective DA D3 receptor antagonism may be a useful pharmacotherapeutic approach for treating addiction. The present experiments tested the efficacy of SB-277011A, a selective DA D3 receptor antagonist, in rat models of nicotine-enhanced electrical brain-stimulation reward (BSR), nicotine-induced conditioned locomotor activity (LMA), and nicotine-induced conditioned place preference (CPP). Nicotine was given subcutaneously within the dose range of 0.25-0.6 mg/kg (nicotine-free base). SB-277011A, given intraperitoneally within the dose range of 1-12 mg/kg, dose-dependently reduced nicotine-enhanced BSR, nicotine-induced conditioned LMA, and nicotine-induced CPP. The results suggest that selective D3 receptor antagonism constitutes a new and promising pharmacotherapeutic approach to the treatment of nicotine dependence.

Figures

Figure 1

Effect of nicotine (0.25 mg/kg s.c.) and various doses of the DA D3 receptor antagonist SB-277011A (0, 3, 6, 12 mg/ kg i.p.) on electrical brain reward thresholds (θ0) in laboratory rats. Changes in brain reward threshold are plotted as percent enhancement or inhibition of brain reward ± s e m. Statistical significance levels for specific inter-treatment comparisons, wherein nicotine is compared to baseline by the paired Student’s t test (a) and other inter-treatment comparisons are made by post-ANOVA Newman–Keuls tests (b), are as shown directly on the figure.

Figure 2

Effect of nicotine (0.5 mg/kg s.c.) and various doses of the DA D3 receptor antagonist SB-277011A (0, 3, 6, 12 mg/kg i.p.) on electrical brain reward thresholds (θ0) in laboratory rats. Changes in brain reward threshold are plotted as percent enhancement or inhibition brain reward ± s e m. Statistical significance levels for specific inter-treatment comparisons, wherein nicotine is compared to baseline by the paired Student’s t test (a) and other inter-treatment comparisons are made by post-ANOVA Newman–Keuls tests (b), are as shown directly on the figure.

Figure 3

Nicotine (0.5 mg/kg s.c.) cue-conditioned locomotion in laboratory rats, shown as the area under the curve (AUC - see text) of horizontal activity counts for the first 20 min of locomotion in the four groups of animals treated with vehicle or with SB-277011A (10 mg/kg i.p.). Rats that received nicotine in the cue-specific test environment for 4 consecutive days (nicotine-paired) showed enhanced locomotor response compared to rats that received saline in the test environment (saline-paired), while there was no difference between the nicotine and the saline unpaired groups. SB-277011A produced an attenuation of nicotine-associated cue-induced locomotor activity and slightly reduced the nicotine unpaired response. * p < 0.05 vs. nicotine unpaired; †p <0.001 vs. vehicle saline paired; ‡p < 0.0001 vs. vehicle nicotine paired; §p = 0.04 vs. vehicle nicotine unpaired. Data are expressed as means ±s.e.m.

Figure 4

Effect of nicotine (0.6 mg/kg s.c.) and various doses of the DA D3 receptor antagonist SB-277011A (0, 1, 3, 10 mg/kg i.p.) on the expression of conditioned place preference in laboratory rats. Times spent in the nicotine-paired chamber on test day are shown as means ± s e m. Statistical significance levels for specific inter-group comparisons, as determined by Student’s t test for independent samples (a) and by post-ANOVA Newman–Keuls tests (b), are as shown directly on the figure (also see text).