Modulation of the D3R-nAChR Heteromeric Complex Attenuates Nicotine Self-Administration

Background: Tobacco dependence remains one of the largest preventable causes of disease and death worldwide. Unfortunately, currently available therapeutics are only modestly effective in assisting individuals to achieve long-term abstinence. Thus, there is a critical need to identify novel targets for therapeutic intervention. It has been recently shown that nicotinic acetylcholine receptors (nAChRs) and dopamine D3 receptors (D3Rs) form heteromeric complexes on dopaminergic neurons, and a novel compound, HyNDA-1, can enhance the interaction between the nACHR-D3R complex. Thus, in these studies, we sought to examine whether HyNDA-1 modulation of the nAChR-D3R complex could serve as a novel target for therapeutic intervention to promote nicotine cessation. Methods: In the first study, male mice (n = 12) were examined for the effects of HyNDA-1 on nicotine intake with the intravenous nicotine self-administration protocol. Subjects were tested across a range of HyNDA-1 doses (0-30 mg/kg) in a within-subject Latins-quare manner. Based on these findings, we next examined whether HyNDA-1 would alter general operant responding for food reward in a separate cohort (n = 5). Finally, a third cohort of mice (n = 6) were examined in the conditioned place preference protocol (CPP) to determine if HyNDA-1 infers rewarding or aversive properties at the effective dose for nicotine self-administration. Nicotine and food self-administration data were analyzed by a mixed-effects model analysis with correction for multiple comparisons, followed by a Tukey post-hoc test as appropriate. The CPP data were analyzed by a paired t-test. Results: We found that pre-administration of HyNDA-1 attenuated nicotine self-administration in a dose-dependent manner. Specifically, HyNDA-1 at the 30 mg/kg dose led to a statistically significant decrease in the number of nicotine infusions earned compared to the vehicle (p < 0.01) and lower doses (p < 0.05). Interestingly, the effective dose of HyNDA-1 was ineffective in altering food self-administration (p > 0.05) and did not induce a chamber preference in the CPP test (p > 0.05). Conclusions: These data demonstrate that modulation of the D3R-nAChR complex by HyNDA-1 decreases nicotine self-administration. Importantly, these effects were specific for nicotine, as HyNDA-1 treatment did not alter food self-administration. Moreover, the HyNDA-1 compound does not appear to infer any rewarding or aversive properties by itself, as no differences were found with CPP. Taken together, these findings reveal that modulation of the D3R-nAChR complex has the potential to be an effective novel target for smoking cessation. Supported by the National Institute on Drug Abuse (NIH DA039658 to CDF) and Tobacco-Related Disease Research Program (TRDRP T30FT0967 to VL). Keywords: Nicotine/Substance Use Disorder, Dopamine D3 Receptors, Nicotinic Acetylcholine Receptors, Intravenous Drug Self-Administration, Conditioned Place Preference Disclosure: Nothing to disclose.