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

Miriam Gutiérrez-Martos,Roberto Cabrera,Klaus Langohr,Rafael Maldonado,Miquel Martin,Magi Farre,Rafael De La Torre

doi:10.1007/s00213-021-05820-z

Abstract

ABSTRACTRationaleCocaine 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.ObjectivesBased 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.ResultsChronic 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.ConclusionsOur 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.

Highlights

Cocaine addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use
Further research in rodents demonstrated an important role of daidzin in these responses, reducing alcohol consumption by selectively inhibiting the activity of the aldehyde dehydrogenases (ALDH), a family of enzymes involved in dopamine (DA) and ethanol metabolism (Keung et al 1997)
Daidzein and genistein were administered at the doses of 100, 200, and 400 mg/kg, i.p.; whereas daidzin and disulfiram at the doses of 75, 150, and 300 mg/kg, i.p

Summary

Introduction

Cocaine addiction is a chronic relapsing disorder characterized by compulsive drug seeking and use. Cocaine inhibits the monoamine transporters producing an increase in the concentration of dopamine (DA) and other monoamines in the synaptic cleft in different brain areas, including the mesocorticolimbic pathway, a brain circuit crucially involved in drugs reinforcing effects (Camí and Farré 2003). Studies performed in the lasts decades have described important effects of these isoflavones regulating a variety of neurophysiological responses, including the activity of the mesocorticolimbic dopaminergic system In this regard, Kudzu root extracts have been used in traditional Chinese medicine for centuries to treat alcoholism (Keung and Vallee 1994). Changes in ALDH activities and in DA neurotransmission in the mesocorticolimbic system were considered the main neurobiological mechanism involved in the responses observed after CVT-10216 administration (Arolfo et al 2009; Lange and Diamond 2009; Yao et al 2010; Bocarsly et al 2014)

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