Elsevier

Biochemical Pharmacology

Volume 163, May 2019, Pages 84-93
Biochemical Pharmacology

7,8-Dihydroxyflavone blocks the development of behavioral sensitization to MDPV, but not to cocaine: Differential role of the BDNF-TrkB pathway

https://doi.org/10.1016/j.bcp.2019.02.004Get rights and content

Abstract

3,4-Methylenedioxypyrovalerone (MDPV) acts as a dopamine transporter blocker and exerts powerful psychostimulant effects. In this study we aimed to investigate the bidirectional cross-sensitization between MDPV and cocaine, as well as to evaluate the role of the BDNF-TrkB signaling pathway in the development of locomotor sensitization to both drugs.

Mice were treated with MDPV (1.5 mg/kg) or cocaine (10 or 15 mg/kg) once daily for 5 days. After withdrawal (10 days), animals were challenged with cocaine (8 mg/kg) or MDPV (1 mg/kg). For biochemical determinations, MDPV (1.5 mg/kg) or cocaine (15 mg/kg) were administered acutely or repeatedly, and BDNF, D3R and G9a transcription levels as well as pro- and mature BDNF protein levels were determined.

Our results demonstrate that repeated administration of MDPV or cocaine sensitizes to cocaine and MDPV locomotor effects. After an acute or a repeated exposure to MDPV, cortical mRNA BDNF levels were increased, while a decrease in mBDNF protein levels in the nucleus accumbens 2 h after repeated exposure was evidenced. Interestingly, such decline was involved in the development of locomotor sensitization, thus the pretreatment with 7,8-dihydroxyflavone (10 mg/kg), a TrkB agonist, blocked the development of sensitization to MDPV but not to cocaine, for which no changes in the BDNF-TrkB signaling pathway were observed at early withdrawal.

In conclusion, a bidirectional cross-sensitization between MDPV and cocaine was evidenced. Our findings suggest that decreased BDNF-TrkB signaling has an important role in the behavioral sensitization to MDPV, pointing TrkB modulation as a target to prevent MDPV sensitization.

Introduction

During the last decade the illicit drug market has changed considerably due to the emergence of New Psychoactive Substances which include synthetic cathinones. The popularity of cathinones as recreational drugs has been increasing since they broke into the drug market, so that they are used as substitutes for other classical psychostimulants such as cocaine or ecstasy.

3,4-Methylenedioxipyrovalerone (MDPV) is one of the most popular synthetic cathinones and one of the main ingredients of the so-called “bath salts” [1], [2]. As many psychostimulants, MDPV produces some of its neurochemical effects by interacting with the transporters of monoamine neurotransmitters. In the same way as cocaine, MDPV increases dopamine (DA) levels in the synaptic cleft by inhibiting its uptake. Animal studies indicate that MDPV is 10–50-fold more potent as a dopamine transporter (DAT) blocker than cocaine [3], [4]. Moreover, it has also been demonstrated that MDPV exerts powerful psychostimulant, rewarding and reinforcing effects related to cocaine at one tenth-doses [5], pointing to a high abuse liability and thus a presumable upward consumption of this substance in the next years, probably favored by its affordable cost. Therefore, new findings about MDPV and its relationship with addiction are of special interest. The research on this topic becomes important considering the potential health and social consequences associated with newly emerging molecular variants of this drug.

Behavioral sensitization to psychostimulants is the process whereby repeated intermittent exposure to drugs results in a progressive and enduring increase in the motor stimulant response to the drug [6], [7], [8], [9], [10]. Furthermore, behavioral sensitization is a long-lasting phenomenon, shown to persist for at least one year after cessation of drug administration [11]. Hence, repeated drug exposure may induce dynamic changes in neural processes, which may influence susceptibility to drug abuse and relapse by increasing the reinforcing value of acute drug administration [9], [12]. It is also known that the ventral tegmental area (VTA) is essential for the development of behavioral sensitization, whereas the nucleus accumbens (NAcc) seems to be necessary for its expression [13], [14].

There is convincing evidence that the brain-derived neurotrophic factor (BDNF) along with its specific receptor, tropomyosin receptor kinase B (TrkB), have a key role in the behavioral abnormalities observed in rodents after psychostimulant administration [15], [16], [17]. BDNF present in NAcc and dorsal striatum ischiefly, but not exclusively, supplied by anterograde axonal transport from cortical pyramidal neurons in frontal cortex [18], [19], [20], [21].

Research done over the last two decades, has reported BDNF to be involved in the long-term neuronal adaptations leading to functional modifications in the synapses associated with cocaine abuse and related behaviors [17], [22], [23]. Moreover, it is also involved in the behavioral abnormalities and neurotoxicity induced by methamphetamine consumption [24]. Hence, the BDNF-TrkB signaling may be a potential therapeutic target for treating drug addiction.

Transcription of the BDNF gene is under control of not only transcriptional factors but also of epigenetic mechanisms including chromatin remodeling and DNA methylation [25]. G9a is a histone 3 lysine 9 (H3K9me2)-specific dimethyltransferase that acts as a negative regulator of BDNF signaling through TrkB [26]. It is also known that repeated exposure to cocaine induces long-lasting epigenetic changes in the brain, modifying the chromatin structure of DNA via histone acetylation, phosphorylation, and/or methylation [27], [28]. For instance, Maze et al. [29] demonstrated that H3K9me2 is substantially reduced in the NAcc after chronic cocaine exposure due to decreased levels of G9a. In this sense, it has been identified an essential role for H3K9m3 and G9a in cocaine-induced structural and behavioral plasticity [29].

At the same time BDNF, synthesized in either VTA neurons or neurons originating from the cortex, controls dopamine 3 receptor (D3R) expression [30]. Interestingly, hyperresponsiveness to drug-associated cues and context-dependent behavioral sensitization might be related to hypersensitive postsynaptic dopaminergic receptors. Among them, D3R seems to be a key target since it is highly expressed in the shell of NAcc, in which DA release is mainly triggered by drugs [31]. Furthermore, D3R expression controls behavioral sensitization and BDNF [30], [32], which at the same time controls D3R expression and enhances the conditioned reward and locomotor activity induced by cocaine [33].

Drug-induced locomotor sensitization has been described for both cocaine and MDPV [34], [35], [36], [37]. The fact that different addictive drugs produce the same effect implies that they may exert some of their effects through the same neural mechanisms. Furthermore, cross-sensitization between other addictive drugs has also been described [38], [39]. For this reason, the present study aims to investigate for the first time the bidirectional cross-sensitization between MDPV and cocaine, as well as to determine and compare the changes induced by either acute or chronic exposure to MDPV or cocaine on the transcription of plasticity genes in early abstinence. Thus, this work is mainly focused on the role of BDNF-TrkB signaling pathway in the development of behavioral sensitization to MDPV and cocaine, and also its target gene, d3r, and the regulator histone methyltransferase G9a.

Section snippets

Animals

Male adolescent (PND 41-44) Swiss CD-1 mice (Charles River, Spain) were used for all experiments due to its optimal sensitivity to the reinforcing and psychostimulant effects of cocaine. Animals were randomly assigned to an experimental group and housed six per cage in temperature-controlled conditions (22 ± 1 °C) under a 12 h light/dark cycle and had ad libitum access to standard food and water. During the behavioral manipulations, researchers were not aware of the treatment that each animal

Cross-sensitization between MDPV and cocaine

To evaluate the ability of cocaine to sensitize to the motor stimulant effects of MDPV and vice versa, a bidirectional cross-sensitization experiment was performed following the administration regime displayed in Fig. 1, in which two different doses of cocaine were tested (10 mg/kg and 15 mg/kg, i.p.).

During the treatment phase, HLA was measured daily and immediately after each saline or drug injection. MDPV induced an acute hyperlocomotion that, unlike cocaine, significantly increased with

Discussion

In a previous work, we reported that exposure of adolescent mice to MDPV sensitizes to cocaine effects and induces a higher vulnerability to cocaine abuse in adulthood [48]. Cocaine abuse represents a heavy burden of disease in many countries, becoming a global problem. Any factor that increases the vulnerability to cocaine abuse must be carefully evaluated. In this sense, the present study examines more closely the common pathways involved in the effects of MDPV and cocaine, using the same

Acknowledgements

This study was supported by Ministerio de Economia y Competitividad (grant number SAF2016-75347-R), and Plan Nacional sobre Drogas (#2016I004). LDC received FPU grants from the Ministerio de Economía y Competitividad (15/02492). R. López-Arnau position was funded by an institutional program of the Universitat de Barcelona in collaboration with Obra Social de la Fundació Bancària La Caixa. JC, DP and EE belong to 2017SGR979 from the Generalitat de Catalunya.

Author contributions

E.E. conceived and designed the research study. LDC performed the main part of research study and acquired data. SV conducted parts of experiments. RLA and DP contributed to analysis and interpretation of data. JC and DP were involved in revising the manuscript critically for important intellectual content. LDC and EE wrote the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

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