Project Title

Dopaminergic Effects of major Bath Salt Constituents 3, 4-methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone are Enhanced Following Co-exposure

Authors' Affiliations

Lily H. Tran, Bill Gatton College of Pharmacy, Department of Pharmaceutical Sciences, East Tennessee State University, Johnson City, Tennessee, USA Serena A. Allen, Bill Gatton College of Pharmacy, Department of Pharmaceutical Sciences, East Tennessee State University, Johnson City, Tennessee, USA Hannah V. Oakes, Bill Gatton College of Pharmacy, Department of Pharmaceutical Sciences, East Tennessee State University, Johnson City, Tennessee, USA Russell W. Brown, Quillen College of Medicine, Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee, USA Brooks B. Pond, Bill Gatton College of Pharmacy, Department of Pharmaceutical Sciences, East Tennessee State University, Johnson City, Tennessee, USA

Location

Clinch Mtn

Start Date

4-12-2019 9:00 AM

End Date

4-12-2019 2:30 PM

Poster Number

179

Faculty Sponsor’s Department

Pharmaceutical Sciences

Name of Project's Faculty Sponsor

Dr. Brooks Pond

Type

Poster: Competitive

Classification of First Author

Pharmacy Student

Project's Category

Physiological Controls and Systems, Xenobiotics, Other Diseases

Abstract Text

An unprecedented rise in the availability of new synthetic drugs of abuse has been observed in the recent years. One of the most noted cases is that of a popularized designer drug mixture known as ‘bath salts’. Commonly obtained from various shops and on the internet, “bath salts” often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in diverse combinations. Individually, the synthetic cathinones are known to have similar pharmacology to controlled psychostimulants such as cocaine and the amphetamines, increasing the levels of dopamine (DA) in the synaptic cleft. DA is an important neurotransmitter that regulates a variety of behaviors and functions; neurons within the mesolimbic DA pathway (ventral tegmental area to nucleus accumbens) are involved in reward and motivation and are activated by these drugs of abuse. Additionally, psychostimulant-induced increases in DA in the nigrostriatal pathway (substantia nigra to corpus striatum) lead to increases in locomotor behavior. However, the majority of preclinical investigations have only assessed the effects of individual bath salt constituents and have provided little information regarding the possibility of significant drug interactions with the co-exposure of MDPV, mephedrone, and methylone. This study sought to evaluate and compare the effects of individual versus combined MDPV, mephedrone, and methylone on dopamine (DA) levels in discrete brain regions as well as motor stimulant responses in mice. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline, MDPV, mephedrone, methylone (1.0 or 10.0 mg/kg), or the cathinone cocktail (MDPV + mephedrone + methylone at 1.0, 3.3, or 10 mg/kg). The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure utilizing high pressure liquid chromatography with electrochemical detection (HPLC-ECD). Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. The results demonstrate that MDPV, mephedrone, and methylone produce dose-related increases in the mesolimbic and nigrostriatal DA levels that are significantly enhanced following their co-administration. Additionally, a decrease in locomotor activity on day 1 that was exacerbated by day 7 was noted in mice treated with the cathinone cocktail and was not observed with any of the single agents. The decrease in locomotor activity was accompanied by an increase in stereotypic-like behavior including excessive grooming and even self-mutilation. Our findings demonstrate a significantly enhanced effect of MDPV, mephedrone, and methylone on both DA and its metabolites resulting in significant alterations in locomotor activity. This work provides insight into the potential enhanced risk of the use of these combination synthetic cathinone products.

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Apr 12th, 9:00 AM Apr 12th, 2:30 PM

Dopaminergic Effects of major Bath Salt Constituents 3, 4-methylenedioxypyrovalerone (MDPV), Mephedrone, and Methylone are Enhanced Following Co-exposure

Clinch Mtn

An unprecedented rise in the availability of new synthetic drugs of abuse has been observed in the recent years. One of the most noted cases is that of a popularized designer drug mixture known as ‘bath salts’. Commonly obtained from various shops and on the internet, “bath salts” often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in diverse combinations. Individually, the synthetic cathinones are known to have similar pharmacology to controlled psychostimulants such as cocaine and the amphetamines, increasing the levels of dopamine (DA) in the synaptic cleft. DA is an important neurotransmitter that regulates a variety of behaviors and functions; neurons within the mesolimbic DA pathway (ventral tegmental area to nucleus accumbens) are involved in reward and motivation and are activated by these drugs of abuse. Additionally, psychostimulant-induced increases in DA in the nigrostriatal pathway (substantia nigra to corpus striatum) lead to increases in locomotor behavior. However, the majority of preclinical investigations have only assessed the effects of individual bath salt constituents and have provided little information regarding the possibility of significant drug interactions with the co-exposure of MDPV, mephedrone, and methylone. This study sought to evaluate and compare the effects of individual versus combined MDPV, mephedrone, and methylone on dopamine (DA) levels in discrete brain regions as well as motor stimulant responses in mice. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline, MDPV, mephedrone, methylone (1.0 or 10.0 mg/kg), or the cathinone cocktail (MDPV + mephedrone + methylone at 1.0, 3.3, or 10 mg/kg). The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure utilizing high pressure liquid chromatography with electrochemical detection (HPLC-ECD). Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. The results demonstrate that MDPV, mephedrone, and methylone produce dose-related increases in the mesolimbic and nigrostriatal DA levels that are significantly enhanced following their co-administration. Additionally, a decrease in locomotor activity on day 1 that was exacerbated by day 7 was noted in mice treated with the cathinone cocktail and was not observed with any of the single agents. The decrease in locomotor activity was accompanied by an increase in stereotypic-like behavior including excessive grooming and even self-mutilation. Our findings demonstrate a significantly enhanced effect of MDPV, mephedrone, and methylone on both DA and its metabolites resulting in significant alterations in locomotor activity. This work provides insight into the potential enhanced risk of the use of these combination synthetic cathinone products.