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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Neurosci Res. 2019 Jul 11;155:56–62. doi: 10.1016/j.neures.2019.07.003

Methylenedioxypyrovalerone (MDPV) impairs working memory and alters patterns of dopamine signaling in mesocorticolimbic substrates

David L Bernstein 1, Sunyl U Nayak 2, Chicora F Oliver 2, Scott M Rawls 2,3, Slava Rom 1,2
PMCID: PMC7110421  NIHMSID: NIHMS1571255  PMID: 31302200

Abstract

Knowledge remains limited about how chronic cathinone exposure impacts dopamine systems in brain reward circuits. In the present study, a binge-like MDPV exposure that impaired novel object recognition (NOR) dysregulated dopamine markers in mesocorticolimbic substrates of rats, with especially profound effects on D1 and D2 receptor’s and VMAT gene expression. Our data suggested that dopamine receptivity was reduced in the NAc but increased in the PFC and dopamine-producing VTA. The MDPV-induced impairment of NOR was prevented by a D1 receptor antagonist, suggesting that chronic MDPV exposure produces site-specific dysregulation of dopamine markers in the mesocorticolimbic circuit and memory deficits in the NOR test that are influenced by D1 receptors.

Keywords: Addiction, dopamine, methylenedioxypyrovalerone, neurotransmitters, cathinones

The first stimulant-like “new psychoactive substances” (NPS) to appear in the US were found in ‘bath salt’ products that flooded the recreational drug market in 2010 (Prosser and Nelson, 2012). Although different cathinones are found in ‘bath salt’ products (Shanks et al., 2012), MDPV (3,4-methylenedioxypyrovalerone) and its next-generation analogs are particularly prevalent in toxicology reports and appear more apt to cause life-threatening medical consequences than other cathinones (Froberg et al., 2015; Karch, 2015; Spiller et al., 2011). MDPV has also provided a template for the design of new generation synthetic compounds (e.g. α-PVP) that only differ in structure from MDPV by simple functional group substitutions. Synthetic cathinones are classified according to two broad cellular mechanisms of action on the monoamine transport system: 1) blockers such as MDPV that inhibit cellular monoamine reuptake and 2) substrates such as mephedrone (MEPH) that enter the presynaptic neuron and stimulate monoamine release. MDPV is mechanistically similar to cocaine (COC), a traditional monoamine reuptake blocker, with the main differences being that MDPV is 50-fold more potent at DAT, 10-fold more potent at NET, and 10-fold less potent at SERT than COC (Baumann et al., 2013; Simmler et al., 2013). Rodent studies indicate that the psychomotor and rewarding effects of MDPV reflect established psychostimulants (e.g., cocaine and methamphetamine) (Glennon and Young, 2016). Specifically, MDPV produces robust rewarding effects in conditioned place preference (CPP) assays (Gregg et al., 2016; Hicks et al., 2017; King et al., 2015) and maintains high rates of drug intravenous self-administration (SA) behavior (Aarde et al., 2013; Gannon et al., 2017; Hicks et al., 2018; Simmons et al., 2018; Watterson et al., 2014). Despite being placed into Schedule I classification of the U.S. Controlled Substances Act in 2011, MDPV is still available on the “dark web” and remains attractive to drug users due to its acute euphoric effects and ability to increase energy and sexual arousal (Marinetti and Antonides, 2013). However, reports of tachycardia, hypertension, and paranoia following repeated use have been documented and thought to contribute to fatalities (Valsalan et al., 2017).

Despite over a decade of anecdotal reports regarding synthetic cathinones, and a body of emerging literature on behavioral effects of cathinones in preclinical models, it remains largely unclear how monamine systems are impacted by chronic cathinone exposure, and whether such effects change over time. Another enduring gap in current research is the extent of dysfunction in the different regions of brain reward circuits. Thus, a more thorough understanding of the effects of MDPV on the expression of dopamine receptors and transporters, particularly within brain regions important for reward processing, is critical. Here, we address this critical gap in the existing pool of research by measuring the impact of binge-pattern consumption of MDPV on the expression of dopamine receptors and transporters, and for comparative purposes, also analyzed multiple targets in the glutamate and GABA systems. Since repeated MDPV exposure has been shown to induce neurocognitive dysfunction (Sewalia et al., 2018), we also investigated a role for dopamine D1 and D2 receptors in MDPV-induced deficits in novel object recognition (NOR).

Animals and chemicals

Male Sprague–Dawley rats (250–275 g) obtained from Harlan Laboratories (Indianapolis, IN) were used. Rats were pair-housed in a humidity- and temperature-controlled vivarium on a 12 h light/dark cycle. Rats were provided with food and water ad libitum, except during behavioral testing. Experimental procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals and Temple University’s Guidelines for the Care of Animals. MDPV was synthesized according to published methods by colleagues at Fox Chase Chemical Diversity Center (Doylestown, PA, USA)(Gregg et al., 2016). Drugs were dissolved in 0.9% saline and administered in a volume of 1 ml/kg. MDPV was injected intraperitoneally (IP), either one time for one day, or over three injections a day for a period of 10 days. Rats from both treatment groups were pretreated with a D1 antagonist (SCH 23390) (0.3 mg/kg, dissolved in saline), D2 antagonist (eticlopride) (0.1 mg/kg, dissolved in saline), both purchased from Sigma-Aldridge (St. Louis MO, USA) or saline 30 min before the first daily injections of MDPV.

Novel Object Recognition (NOR) test

The NOR test was performed 1 hr after last injection. NOR evaluates an animal’s ability to remember if it has previously faced an object or not. It is built on the idea that a rat will spend more time investigating and surveying a new object, which it has never seen, than a familiar object. NOR was performed as described before (Christakis et al., 2012). In short, rats were habituated to the box a day before the test. On the test day, rats were placed in the box for the acquisition period with two identical objects, and were allowed to explore and familiarize themselves with the objects for 5 minutes. The rats were given a one hour inter trial interval (ITI) and where then placed back in the test box. Everything was the same as during the acquisition period except that one of the two identical objects was replaced with a new, novel object. During the testing period, rats were allowed to explore both of the objects for 5 minutes. This trial was recorded with a video camera, and scored by a trained and blinded experimenter to define the time the animal spent inspecting each object. Interaction was considered when the rat’s nose touched the object or was pointed towards the object within a 1cm radius. The discrimination ratio was calculated using the following formula: [(Time Spent on the Novel Object – Time Spent on the Familiar Object)/Total Time)].

Gene expression (quantitative RT-PCR)

Rats were injected with MDPV (as described above). Brains were extracted 120 min following the last MDPV injection, and NAc, VTA and PFC tissue was extracted for quantification of gene expression. RNA was extracted using the mirVana miRNA extraction kit (#AM1560) (Thermo Fisher Scientific, Waltham, MA). mRNA was converted into cDNA utilizing RT2 First Strand Kit (#330404) (Qiagen Inc. Valencia, CA) per the manufacturer’s protocol as described previously (Rom et al., 2015). TaqMan PCR primer/probe sets to detect gene expression of DRD1, DRD2, VMAT2, DAT1, GRIA2, GABRR2, GRM2, GRM5 and GAPDH genes were purchased from Thermo Fisher. Quantitative real-time RT-PCR (qRT-PCR) was performed using 25 ng of template using the QuantSudio 3 real-time PCR system (Thermo Fisher) for each treatment group. Amplification was analyzed using the ΔΔCt method, using a web-based data analysis tool (SABiosciences, Qiagen Inc.), by normalization to the corresponding values of housekeeping gene (GAPDH) and fold-change calculated from the difference between experimental condition and untreated control.

Statistical analysis

Gene expression data and NOR data was tested for normality using the Shapiro-Wilk test, and then was analyzed by Student t-test. Statistical analyses were performed utilizing Prism v8.0.2 software (GraphPad Software Inc., San Diego, CA). Statistical significance was p < 0.05 in all cases.

Abuse of MDPV has been demonstrated to have significant effects on the dopaminergic signaling with particularly nuanced effects on the presynaptic elements of the pathway (Gannon et al., 2018; Shekar et al., 2017). We assessed such impacts by measuring the expression of the cellular structures involved in the production, transport, and responses to dopamine. We measured mRNA expression after a period of either 1 or 10 days of MDPV exposure.

At the single injection paradigm test, dopamine receptor expression had already begun to shift, particularly in the nucleus accumbens (NAc). We determined that the expression of excitatory D1 receptor (DRD1) expression was decreased nearly two-fold within the NAc (0.49 ±0.08, p<0.01) and VTA (0.58 ±0.06, p<0.05), but unchanged within PFC (Figure 1a). Inhibitory D2 (DRD2) expression was similarly diminished within NAc (0.41 ±0.11, p<0.005), but statistically unchanged within PFC and VTA. (Figure 1b). Presynaptic dopaminergic protein expression was similarly altered, with dopamine transporter (DAT) expression reduced significantly within NAc (0.64 ±0.07, p< 0.05), while unchanged within PFC and VTA. Finally, the expression of vesicular monoamine transporter (VMAT), the enzyme most responsible for packaging of dopamine into synaptic vesicles, was profoundly reduced within NAc (0.45 ±0.14, p<0.05) and PFC (0.21 ±0.04, p<0.01), while unchanged within VTA (Figure 1d). t = 24 for all groups.

Figure 1. Single injection of MDPV affects dopamine-related gene expression in the NAc, VTA and PFC regions of rat’s brain.

Figure 1.

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qRT-PCR quantification of the mRNA levels for DRD1 (A), DRD2 (B), DAT1 (C) and VMAT2 (D), genes in brain tissue obtained from rats treated with single injection of MDPV (1 mg/kg) (brains extracted 120 min after last MDPV injection). Gene expression level in control group was set as 1. Data are presented as fold-change in gene expression normalized to GAPDH, represented as ±SEM. N=4–6. *p < 0.05 or **p < 0.01 versus saline control (MDPV 0 mg/kg).

At the 10-day binge paradigm, we determined that the expression of excitatory DRD1 expression was decreased by two-fold within the NAc (0.45 ±0.12, p < 0.05), while increased within PFC (1.58 ±0.32, p<0.01), and VTA (1.60 ±0.06, p<0.005) (Figure 2a). Interestingly, the expression of inhibitory DRD2 expression was also reduced in the NAc (0.33 ±0.05, p < 0.005), as well as the VTA (0.36 ±0.06, p<0.005), but increased within the PFC (1.86 ±0.21; p= 0.01) (Figure 2b). While the direction of effect was the same for excitatory and inhibitory receptor expression within the NAc and the PFC (downstream targets of the VTA), expression in the VTA was uniquely altered. In the region where dopamine is produced and sent to the NAc and PFC, excitatory receptor expression was upregulated while inhibitory expression was downregulated, suggesting a heightened level of excitability of dopamine-producing cells. This is further corroborated by the decrease in the presynaptic dopamine transporter (DAT) in the NAc (0.43 ±0.05; p<0.05), without statistically significant changes to DAT within PFC or VTA (though a positive trend was observed in both) (Figure 2c). Finally, there were no observed significant differences in vesicular monoamine transporter (VMAT), in any region (Figure 2d). t = 28 for all groups.

Figure 2. Repeated MDPV exposure affects dopamine-related gene expression in the NAc, VTA and PFC regions of rat’s brain.

Figure 2.

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qRT-PCR quantification of the mRNA levels for DRD1 (A), DRD2 (B), DAT1 (C) and VMAT2 (D) genes in brain tissue obtained from rats treated with MDPV (1 mg/kg) 3 times/day for 10 consecutive days (brains extracted 120 min after last MDPV injection). Gene expression level in control group was set as 1. Data are presented as fold-change in gene expression normalized to GAPDH, represented as ±SEM. N=4–6. *p < 0.05 or **p < 0.01 versus saline control (MDPV 0 mg/kg).

Research has connected synthetic cathinone usage with significant alterations to working memory (Motbey et al., 2012). Hence, we sought to verify the effects of MDPV on memory by pairing the single or repeated MDPV consumption paradigm with the NOR test (Figure 3). We determined that repeated-exposure to MDPV produced strong impairment of object discrimination between familiar and unfamiliar objects. MDPV-exposed rats demonstrated a 87% lower discrimination index vs nontreated controls (t(28)=4.170, p = 0.0009) (Figure 3b), while single administration didn’t reach significant effect on NOR. Since dopamine receptors expression was affected by MDPV, we decided to check whether administration of D1 or D2 antagonists would have any effect on NOR. Indeed, D1 antagonist was able to reverse MDPV influence on NOR (p<0.05) (Figure 3b), however D2 did not produce similar effects.

Figure 3. Repeated MDPV exposure produces deficit in NOR that is prevented by a D1 receptor antagonist.

Figure 3.

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(A) Rats were treated with MDPV (1 mg/kg) or saline 3x/day for 10 days. Rats from both treatment groups were pretreated with a D1 antagonist (SCH 23390) (0.3 mg/kg), D2 antagonist (eticlopride) (0.1 mg/kg), or saline 30 min before the first daily injections of MDPV. Data are presented as discrimination index + S.E.M., N=8 rats/group. **p < 0.05 versus SAL + MDPV group. (Insert) Rats injected once with MDPV (1 mg/kg) or saline were tested for NOR. N=4–6 rats/group.

Binge dosage of MDPV also produced significant effects on the neurotransmitter receptors responsible for modulating the general excitability of the brain. After 10 days of exposure, we found that expression of GABA receptor 2 (GABRR2), the most common inhibitory receptor in the CNS (Gassmann and Bettler, 2012), was highly augmented in NAc (2.35 ±1.1; p>0.05)), while significantly increased within the PFC (1.45 ±0.12; p<0.05), and unchanged within the VTA (Supplemental Figure 1b). Fast glutamatergic transmission was impacted in a different fashion, MDPV significantly amplified the expression of AMPA receptor subunit 3 (GRIA3) within NAc (3.25 ±0.22; p<0.001), and VTA (1.53 ±0.06; p<0.01), but did not change expression within the PFC (Supplemental Figure 1a). Slow, metabotropic glutamatergic transmission was altered only in the NAc, with particularly nuanced effects. Expression of metabotropic receptor 2 (GRM2) was decreased by more than 2-fold (0.43 ±0.09; p<0.01), while expression of metabotropic glutamate receptor 5 (GRM5) was substantially increased by roughly the same degree (2.12 ±0.16; p<0.01). No significant differences were observed in VTA or PFC (Supplemental Figure 1c–d). t = 28 for all groups.

For this study, we characterized the neurochemical impacts of single-dose or binge consumption of MDPV on neurotransmitter expression and working memory. We focused our assessment on brain regions which are particularly important for reward and reinforcement behavior, such as the NAc, PFC, and VTA, for two reasons. First, these regions play a critical role in developing and maintaining addictive behaviors (Carlezon and Thomas, 2009), and contain a high density of the neurocellular targets which are most immediately impacted by MDPV, such as the D1 and D2 dopamine receptors. Second, the mesocorticolimbic circuit (VTA, NAc, PFC) is a critical regulator of body homeostasis, and impacts on this circuit can strongly affect an individual’s overall state (Fortin and Roitman, 2018), and lead to compensatory or correlative changes in many other regions of the CNS, and even regions beyond (Segarra et al., 2013; Zbrozyna and Westwood, 1991). Hence, it is likely that some of the addictive potential and physical harm resulting from MDPV can be attributed to its unique pattern of long-term psychological and pharmacological effects. Studies which can elucidate such impacts will be critical for understanding patterns of abuse and developing effective pharmacotherapeutics to combat them.

The results lead to some interesting conclusions about the nature of mesolimbic dopamine signaling. First, effects on dopaminergic expression within NAc generally present within a day, and maintain the same direction and intensity of effect even after 10 days of repeated exposure (one exception is VMAT, which drops initially and returns to baseline by day 10). It is also important to note that of all genes assessed, the majority were significantly altered within NAc, a finding which was not observed as strongly in other brain regions. Within the PFC, the effects on the dopamine circuitry generally took longer to develop, and in the case of VMAT, actually reversed direction. In VTA the effects were more mixed, with a general flipping in the expression of D1 and D2 receptors between 1 and 10 days.

Such impacts upon excitatory and inhibitory neurotransmission are associated with likewise alterations to motivated behavior, including NOR. Disruptions to D1R (Snigdha et al., 2011), D2R (Watson et al., 2012), Gabbr2 (Jacobson et al., 2007), GRM2 and 5 (Horiguchi et al., 2011; Marszalek-Grabska et al., 2018), and GRIA3/AMPA (Wong et al., 2019) have all been shown to profoundly alter NOR. The links to DAT and VMAT are even more extensive, as both are critical for the motor and cognitive functions which are altered under the influence of MDPV (Duart-Castells et al., 2019).

Some of the observed neurochemical impacts are consistent with what has been postulated to occur following long-term psychostimulant exposure. Within the VTA, which supplies dopamine to the PFC and NAc, MDPV induced a higher expression density of most excitatory receptors, including DRD1, as well as raising the level of VMAT (the enzyme responsible for sending dopamine into the synapse). Simultaneously, MDPV also induced a significant decrease in inhibitory receptors, such as GABBR2 and DRD2, as well as in the DAT, the protein responsible for removing dopamine from the synapse. This suggests that MDPV is capable of creating a strong excitatory impact on dopaminergic signaling, by increasing dopamine concentration within the synapse, promoting its excitatory impacts, while diminishing its inhibitory ones. Such impacts are likely to produce major alterations to the physiology of the mesocorticolimbic system. GABBR2 and DRD2 activation are associated with reduced firing rate of dopaminergic cells (Kalivas, 1993), while glutamate and DRD1 lead to enhanced dopaminergic cell excitability (Adell and Artigas, 2004). We have determined that MDPV both excites and disinhibits dopaminergic cells, a phenomenon which has been observed during withdrawal of other psychostimulants (Tang et al., 2004), and can lead to severe neurotoxicity and even death of monoaminergic cells (Valente et al., 2017).

Given this significant augmentation to dopamine release and likely to dopamine cell firing, one would expect a compensatory reduction to the expression of dopamine receptors in efferent regions. However, such a decrease is only observed in the NAc, while such receptors significantly increase within the PFC. While the precise mechanism for this is currently unknown, there are several possibilities. First, MDPV may preferentially drive dopaminergic transmission towards the mesolimbic route (VTA-NAc), and somewhat away from the mesocortical route (VTA-PFC). In this scenario, drug tolerance (controlled by the NAc) would strongly increase, while feelings of psychological cravings (driven by the PFC) would also increase, leading to a profound state of addiction. This is a plausible scenario, as dopamine signaling within the NAc tends to closely follow DA signaling within the PFC (St Onge et al., 2012; Stefani and Moghaddam, 2006), but this connection is readily disrupted by psychostimulants of abuse, such as cocaine and amphetamine (Pignatelli and Bonci, 2015).

Impacts on DAT expression were predictably smaller in VTA, where overall gene expression is exponentially lower, compared with PFC and NAc (Nirenberg et al., 1997). The vast majority of dopamine-producing cells within the VTA are projection neurons with extremely long ( > 2mm) axons, which synapse onto efferent targets in the NAc, PFC, and other discrete cortical and sub-cortical regions. There is a very limited number of DA-DA connections within the VTA, because the vast majority of intra-VTA communication occurs via changes to local field potentials (LFPs) (Kim et al., 2012) and through GABAergic interneurons(Beier et al., 2015).

Our behavioral experiments revealed that MDPV, when administered in a binge-type paradigm, impaired NOR, thus suggesting that chronic MDPV exposure produces neurocognitive dysfunction in rats. The present results are consistent with recently published work showing deficits in NOR following repeated binge-like self-administration of MDPV (Sewalia et al., 2018). Furthermore, in a broader context, literature suggests that, as a drug class, synthetic cathinones can induce neurocognitive dysfunction in both rodents and humans (Simmons et al., 2018). For example, rodents exposed to mephedrone or methylone show deficits in object recognition and discrimination, as well as working memory, that are accompanied by dysregulation of striatal proteins that facilitate dopaminergic and serotonergic transmission (Motbey et al., 2012; den Hollander et al., 2013; Shortall et al., 2013; Lopez-Arnau et al., 2015; Angoa-Perez et al., 2017). In our hands, the binge-like MDPV exposure paradigm produced both dysregulation of dopamine transporter and receptor gene expression in mesocorticolimbic substrates and impairment of NOR that was reduced by dopamine D1 receptor antagonism but not D2 antagonism. It is important to note that administration of dopamine receptor antagonists (SCH 23390 and eticlopride) was during chronic MDPV exposure rather than after cessation of MDPV exposure. Thus, based on our dosing paradigm, the data suggest that MDPV reduces the ability of rats to acquire NOR through mechanisms related to active D1 receptors. An involvement of D1 receptors in the development of MDPV-induced neurocognitive dysfunction is not surprising, as MDPV, is an indirect dopamine agonist that inhibits cellular dopamine reuptake but with 50-fold greater potency than cocaine (Simmler et al., 2013), and produces related behavioral effects, such as acquisition of place preference and self-administration, that are dependent on active dopamine receptors (Atehortua-Martinez et al., 2019; Simmons et al., 2018; Hicks et al., 2018). Thus, in the present case in which D1 receptors are blocked throughout MDPV exposure, the deficits in NOR are unable to develop and manifest. A limitation of our study is that we only tested effects of dopamine receptor antagonism during MDPV exposure. It will be important in future studies to assess how D1 agonists and antagonists, injected after cessation of chronic MDPV exposure, affect later phases of NOR, since D1 receptor activity in the PFC is important for both the consolidation and retrieval of long term recognition memory (Hotte et al., 2006; Nagai et al., 2007, Rossato et al., 2013). Future studies will also quantify protein levels of dopamine markers, along with mRNA levels, to better correlate MDPV-induced impairment of neurocognitive function with underlying dysregulation at cellular and circuit levels. It should also be noted that impairment in NOR was only detected following chronic MDPV exposure as significant deficits were not detected following a single injection, although widespread deficits in cortical and subcortical functional connectivity are detected following acute MDPV exposure (Colon-Perez et al., 2016, 2018).

In summary, we have provided substantial evidence for the long-term impacts of heavy MDPV use, particularly on the reward circuitry of the brain. While further studies will be needed to better characterize the full nature of its effects, we have demonstrated the nuanced and powerful effects on different elements of dopamine signaling, which distinguish MDPV from other drugs such as cocaine or methamphetamine. MDPV contains a unique neurochemical profile, and highly specialized forms of treatment will be needed to combat the rapidly increasing number of cathinone-associated overdoses and emergency room visits. This research is an important step in this direction, and it lays the groundwork for further studies to better elucidate the types of harm produced by MDPV, and the best ways to reduce them.

Supplementary Material

Supplemental figure

Highlights.

  • MDPV increases dopamine- and glutamatergic- neurotransmission within VTA

  • MDPV promotes dopaminergic signaling within PFC; reduces such signaling within NAc

  • MDPV impairs novel object recognition

Acknowledgments

This work was supported in part by R01 DA039139, R01 DA045499, and P30 DA013429 NIH research grant.

Abbreviations

DAT

Dopamine Transporter

DRD1

Dopamine Receptor 1

DRD2

Dopamine Receptor 2

GABBR2

GABA (gamma amino butyric acid) Receptor 2

GRIA3

Glutamate Receptor, AMPA subunit 3

GRM2

Metabotropic Glutamate Receptor 2

GRM5

Metabotropic Glutamate Receptor 5

MDPV

3,4-methylenedioxypyrovalerone

NAc

Nucleus Accumbens

PFC

Prefrontal Cortex

VMAT

Vesicular Monoamine Transporter

VTA

Ventral Tegmental Area

Footnotes

Disclosure/Conflict of Interest

None

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