Daidzein modulates cocaine-reinforcing effects and cue-induced cocaine reinstatement in CD-1 male mice

Abstract

Rationale: Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities.

Objectives: Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration.

Results: Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities.

Conclusions: Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.

Keywords: cocaine; daidzein; daidzin; dopamine receptors; genistein; isoflavones; reinforcing; reinstatement; self-administration.

Fig. 1:

Locomotor effects induced after acute isoflavone or disulfiram administration. Involvement of dopamine D2/3 and estrogen-receptor systems in the locomotor effects induced by daidzein. Total locomotor activity 60 min after acute administration (i.p.) of different doses of (a) daidzein (n = 8-10), (b) daidzin (n = 8-10), (c) genistein (n = 8-10), or (d) disulfiram (n = 8-10). Effects of acute administration (30 min before locomotion was evaluated) of different agonist or antagonist for the adrenergic, dopaminergic or estrogen receptor systems (n = 9-15 per group) in the locomotor activity induced by (e) acute vehicle (60 min before locomotion) or daidzein (200 mg/kg, 60 min before locomotion) administration. A total of 9-15 mice were included per experimental group. Results are expressed as average + SEM, ⋆ ⋆ p < 0.01, ⋆ p < 0.05 versus vehicle or versus daidzein-vehicle treated mice, post hoc pairwise comparisons

Fig. 2:

Chronic treatment with isoflavones decreases operant responding for cocaine. (a–d) Effects of the chronic treatment with vehicle (n = 12) and daidzein (100 mg/kg/day, i.p., n = 11) (a), daidzin (75 mg/kg/day, i.p., n = 10) (b), genistein (100 mg/kg/day, i.p., n = 10) (c) and disulfiram (75 mg/kg/day, i.p., n = 9) (d) on cocaine self-administration. (e–h) Area under the curve of the 5 days of chronic treatment with vehicle (n = 12) and daidzein (100 mg/kg/day, i.p., n = 11) (e), daidzin (75 mg/kg/day, i.p., n = 10) (f), genistein (100 mg/kg/day, i.p., n = 10) (g) and disulfiram (75 mg/kg/day, i.p., n = 9) (h) on cocaine self-administration. Animals received the injection of the vehicle, isoflavone or disulfiram for 5 consecutive days 1 h before the beginning of the operant training session. Data are represented as the mean number of nose-pokes in the active hole to obtain cocaine (0.5 mg/kg/infusion) during the preacquisition and acquisition-training, and following the chronic treatment for 5 days with vehicle, isoflavone or disulfiram. Data are expressed as mean + SEM. ⋆ ⋆ p < 0.01, ⋆ p < 0.05 versus vehicle treated mice post hoc pairwise comparisons

Fig. 3:

Involvement of the dopamine D2/3 receptor on daidzein-induced modulatory actions in cocaine self-administration paradigm. Effects of the exposure to vehicle, quinpirole (0.01 mg/kg, i.p.) or tamoxifen (1 mg/kg, i.p.) in the operant responding to obtain cocaine in mice previously treated with (a) vehicle (i.p., n = 7-10) or (b) daidzein (100 mg/kg/day, i.p., n = 8-9). Data are represented as the mean number of nose-pokes in the active hole to obtain cocaine (0.5 mg/kg/infusion) during the preacquisition and acquisition-training, and following the chronic treatment for 5 days with vehicle or daidzein (60 min before the beginning of the training session) and subsequent administration of vehicle, quinpirole, or tamoxifen (30 min before the beginning of the training session). Results are expressed as average + SEM. ⋆ p < 0.05 versus daidzein-vehicle treated animals on the same day, post hoc pairwise comparisons

Fig. 4:

Acute administration of daidzein, daidzin, and disulfiram, but not genistein, decreases cue-induced cocaine seeking and reinstatement behavior. Comparison of the effects of the administration of vehicle versus (a) vehicle (n = 9), (b) daidzein (100 mg/kg, i.p., n = 9), (c) daidzin (75 mg/kg, i.p., n = 9), (d) genistein (100 mg/kg, i.p., n = 9) or (e) disulfiram (75 mg/kg, i.p., n = 8) in the active nose-poke responding after exposure to cue-induced cocaine seeking behavior paradigm. All compounds were administered acutely 1 h before the beginning of each cue-induced reinstatement session. Data represents the active nose-poke responding the day of exposure to cue-induced reinstatement and also during the extinction period 3 days before and after. Results are expressed as average + SEM. ⋆ p < 0.05 versus vehicle-induced reinstatement, Student's t test

Fig. 5:

Involvement of the estrogen and dopamine type-II-receptor systems on daidzein-, but not daidzin-, effects in cue-induced cocaine seeking and reinstatement behavior. Comparison of the effects of an acute administration of vehicle or a subeffective dose of quinpirole (0.01 mg/kg, i.p.) or tamoxifen (1 mg/kg, i.p.) on cue-induced cocaine seeking behavior and reinstatement in mice acutely treated with (a) vehicle, (b) daidzein (100 mg/kg, i.p.) or (c) daidzin (75 mg/kg, i.p.). Animals were injected with vehicle, daidzein, or daidzin and 30 min later with tamoxifen, quinpirole, or vehicle. Thirty minutes after the last injection, animals were exposed to cue-induced cocaine seeking behavior paradigm. Results are expressed as average + SEM. ⋆ p < 0.05 versus daidzein-vehicle induced reinstatemnet, Dunnett's multiple comparison test