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Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions—the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500–1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase. [ABSTRACT FROM AUTHOR]

• MDPV increases dopamine- and glutamatergic- neurotransmission within VTA. • MDPV promotes dopaminergic signaling within PFC; reduces such signaling within NAc. • MDPV impairs novel object recognition. 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. [ABSTRACT FROM AUTHOR]

Designer drug mixtures popularized as "bath salts" often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in various combinations. However, most preclinical investigations have only assessed the effects of individual bath salt constituents, and little is known about whether co-exposure to MDPV, mephedrone, and methylone produces significant neuropharmacological interactions. This study evaluated and compared how MDPV, mephedrone, and methylone influence discrete brain tissue dopamine (DA) levels and motor stimulant responses in mice when administered alone and as a ternary mixture. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline or 1 or 10 mg/kg doses of MDPV, mephedrone, or methylone, or a cocktail of all three cathinones at doses of 1, 3.3, or 10 mg/kg each. 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 using HPLC-ECD. Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. MDPV, mephedrone, and methylone produced dose-related increases in mesolimbic and nigrostriatal DA levels that were significantly enhanced following their co-administration. In addition, mice treated with the cathinone cocktail displayed decreased locomotor activity on day 1 that was exacerbated by day 7 and not observed with any of the drugs alone. Our findings demonstrate a significant enhanced effect of MDPV, mephedrone, and methylone on both DA, and these effects on DA result in significant alterations in locomotor activity. [ABSTRACT FROM AUTHOR]

Studies using 224 blood samples as examples showed that the use of solid-phase extraction and gas chromatography with mass spectrometric detection for screening blood provides reliable identification of a wide range of narcotic and pharmaceutical substances of forensic medical interest, including 'designer' synthetic narcotics - methylenedioxypyrovalerone (MDPV), pyrrolidinovalerophenone (PVP), and their metabolites; cannabimimetic metabolites N-(1-carbamoyl-2-methylpropyl)-1-pentyl-1 H-indazole-3-carboxamide (ABPINACA) and/or N-[(1-pentyl-1 H-indazol-3-yl)carbonyl]valine methyl ester (AMB). The distribution of substances in different elusion fractions is given and dissociation constants (pK) and coefficients of distribution in an octanol-water system (log P) are calculated. [ABSTRACT FROM AUTHOR]

Methylenedioxypyrovalerone (MDPV) has emerged in recent years as a recreational substance with psychostimulant properties. In this study, in vitro metabolites of MDPV were characterized based on liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC/QTOF MS). MDPV was incubated with human liver microsomes, human recombinant cDNA-expressed cytochrome P450 enzymes and flavin monooxygenase (FMO). MDPV was metabolized to yield eight metabolites (M1-M8) with major metabolic reactions such as demethylenation and oxidation. Among them, M6 was assigned as an N- oxide metabolite. FMO was found to be a principal enzyme responsible for the formation of M6; FMO1 and FMO3 were the main enzymes involved in N- oxidation of MDPV. [ABSTRACT FROM AUTHOR]

Background: Synthetic cathinones, 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxypyrovalerone (MDPV), serve as a substrate or blocker at monoaminergic transporters, respectively, and produce locomotor stimulant effects in rodents. The present study investigated in rats the effects of repeated exposure to 4-MMC, MDPV, or mixtures of the two on the induction of locomotor sensitization and expression of cross-sensitization to cocaine.Methods: Seventy-two male Sprague-Dawley rats received daily intraperitoneal injections of saline, MDPV (0.5mg/kg), 4-MMC (0.5, 1.0, or 2.0mg/kg) or mixtures of 0.5mg/kg MDPV+4-MMC (0.5, 1.0, or 2.0mg/kg) for seven consecutive days. Locomotor activity was recorded on days 1 and 7 and again after an acute injection of 5mg/kg cocaine following a 10day drug washout period.Results: Rats injected with 0.5mg/kg MDPV, 0.5, 1.0, or 2.0mg/kg 4-MMC, or 2.0mg/kg 4-MMC+0.5mg/kg MDPV displayed time-dependent increases in horizontal activity that were augmented on day 7 compared to day 1. In addition, rats pretreated with 0.5mg/kg MDPV, 2.0mg/kg 4-MMC, or mixtures of 4-MMC+MDPV displayed an enhanced response to cocaine.Conclusions: Locomotor responses sensitize to MDPV and to certain mixtures of MDPV and 4-MMC following repeated dosing. Furthermore, previous exposure to these substances may produce cross-sensitization to the locomotor stimulant effects of cocaine. Considered together with recent findings that 4-MMC and MDPV have different sites of action, but both influence monoaminergic functioning, further investigations utilizing a variety of behavioral assays may prove informative regarding the abuse liability of synthetic cathinone mixtures. [ABSTRACT FROM AUTHOR]

Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague–Dawley rats ( n =12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0–10 mg/kg) and MDPV (3.2 mg/kg) facilitated ICSS. RTI-118 (3.2–32 mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25–0.5 mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32 mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV. [ABSTRACT FROM AUTHOR]

Abstract: Background: Synthetic cathinones or “bath salts” are an increasing problem in the United States. Their adverse effects are related to sympathomimetic toxicity and seizures have been listed among the side effects. This study details the seizures that occur after synthetic cathinone exposure in the pediatric population. Methods: We used the American Association of Poison Control Centers database to capture all known synthetic cathinone exposures in children <20 years of age from January 1, 2010 through January 31, 2013. Demographic data along with signs of fever, acidosis, hallucinations and/or delusions, hypertension, tachycardia, electrolyte abnormalities, and coingested substances were collected for all synthetic cathinone users and compared with those users who experienced seizure activity. Results: Over the specified time period, there were 1328 pediatric synthetic cathinone exposures. Seizures complicated 73 (5.5%) of the cases, with 37 (50.7%) of those cases experiencing a single seizure, 29 (39.7%) multiple seizures, and seven (9.6%) status epilepticus. Fever and acidosis were associated with single seizures, multiple seizures, and status epilepticus. There was no correlation found between any seizure activity and electrolyte abnormalities, hallucinations and/or delusions, tachycardia, or hypertension. Coingestants were present in 33 (45%) of the seizure cases. The most commonly coingested substances were tetrahydrocannabinol, alcohol, and opioids. Conclusions: Seizures complicated 5.5% of synthetic cathinone exposures in the pediatric population. Fever and acidosis were associated with seizure activity. The presence of fever after a synthetic cathinone exposure may warrant more aggressive monitoring and treatment. [Copyright &y& Elsevier]

Rationale: Abuse of synthetic cathinones, popularized as 'bath salts,' has increased dramatically in the USA since their debut in 2010. Preclinical behavioral studies may clarify determinants of the abuse-related effects produced by these compounds. Objectives: This study examined behavioral effects of (±)-methcathinone, (±)-3,4-methylenedioxypyrovalerone (MDPV), (±)-3,4-methylenedioxymethcathinone (methylone), and (±)-4-methylmethcathinone (mephedrone) in rats using intracranial self-stimulation (ICSS). Methods: Male Sprague-Dawley rats ( n = 18) with electrodes targeting the medial forebrain bundle responded for multiple frequencies of brain stimulation and were tested in two phases. First, dose-effect curves for methcathinone (0.1-1.0 mg/kg), MDPV (0.32-3.2 mg/kg), methylone (1.0-10 mg/kg), and mephedrone (1.0-10 mg/kg) were determined. Second, time courses were determined for effects produced by the highest dose of each compound. Results: Methcathinone produced dose- and time-dependent facilitation of ICSS. MDPV, methylone, and mephedrone produced dose- and time-dependent increases in low rates of ICSS maintained by low brain stimulation frequencies, but also produced abuse-limiting depression of high ICSS rates maintained by high brain stimulation frequencies. Efficacies to facilitate ICSS were methcathinone ≥ MDPV ≥ methylone > mephedrone. Methcathinone was the most potent compound, and MDPV was the longest acting compound. Conclusions: All compounds facilitated ICSS at some doses and pretreatment times, which is consistent with abuse liability for each of these compounds. However, efficacies of compounds to facilitate ICSS varied, with methcathinone displaying the highest efficacy and mephedrone displaying the lowest efficacy to facilitate ICSS. [ABSTRACT FROM AUTHOR]

Cathinone derivatives (bath salts) have emerged as the latest drugs of abuse. 3,4-methylenedioxypyrovalerone ( MDPV) is the primary active ingredient in bath salts used in this country. This article presents the second reported cause of death by MDPV intoxication alone. In April 2011, a delusional man was emergently brought to a hospital, where he self-reported bath salt usage. He became agitated, developed ventricular tachycardia, hyperthermia, and died. Comprehensive alcohol and drug testing was performed. Using the alkaline drug screen, heart blood contained 0.7 mg/L MDPV and peripheral blood contained 1.0 mg/L MDPV. His bizarre behavior with life-threatening hyperthermia was consistent with an MDPV-induced excited delirium state. MDPV is not yet found by routine immunoassay toxicology screens. Testing for MDPV should be considered in cases with a history of polysubstance abuse with stimulant type drugs, report of acute onset of psychogenic symptoms, excited delirium syndrome, or presentation in a hyperthermic state. [ABSTRACT FROM AUTHOR]

Introduction and Aims Novel psychoactive substances are increasingly available, both in traditional storefronts and via the Internet. While some use of such substances has been captured in Australian consumer surveys and wastewater analyses, there is little information about the products that are available to Australia via the Internet. Design and Methods Systematic monthly Internet monitoring for emerging psychoactive substances was conducted between July 2011 and July 2012. Webstores identified through searches were examined to determine if they sold stimulant or psychedelic emerging psychoactive substances to Australia. Internet search numbers for these products were examined over time using commercial tools. Results In 12 months, 43 unique webstores were identified selling to Australia, averaging two new webstores per month; however, two-fifths had closed within six months. Over 200 unique chemically unspecified products sold by purported effect (e.g. 'charge') were identified over 12 months, averaging 10 new products per month. Almost half of these products had disappeared from the market within six months. Eighty-six unique chemically specified products (e.g. methylenedioxypyrovalerone) were identified over 12 months, averaging four new novel substances per month. Once released, these products typically remained available, with almost 90% still available for purchase over a 6-month period. Almost 40 000 searches for these products emanated from Australia per month. Discussion and Conclusion This market is fast paced as retailers strive to beat both regulatory processes and competitors. Ongoing attention to these markets, incorporating surveillance of both Internet and traditional storefronts, is crucial as several of the substances identified have demonstrated potential for health and neurological harm. [Bruno R, Poesiat R, Matthews AJ. Monitoring the Internet for emerging psychoactive substances available to Australia. Drug Alcohol Rev 2013;32:541-544] [ABSTRACT FROM AUTHOR]

A new group of recreational drugs, popularly known as ''bath salts'', ''plant feeders'' or ''plant food'', has recently emerged in numerous countries. Although various products are labeled with warnings ''not for human consumption'' or ''not tested for hazards or toxicity'', they are intended to produce a high similar to that obtained with illegal stimulants, such as MDMA, methamphetamine or cocaine. The active compounds in ''bath salts'' are cathinone derivatives continuously developed and modified by drug designers to avoid detection or legal scrutiny. Around 2010 the most prevalent were mephedrone (4- methylmethcathinone) and MDPV (3,4-methylenedioxypyrovalerone). This review surveys the current state of knowledge regarding the pharmacotoxicological properties of synthetic cathinones, the prevalence and pattern of their use. Special emphasis is given to the negative consequences of using these products including, among others, cardiovascular, psychiatric and neurologic symptoms, dehydration, rhambdomyolysis, renal and liver failure. Case reports on synthetic cathinones-related fatalities are also presented. [ABSTRACT FROM AUTHOR]

Rationale: Psychoactive 'bath salts' represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated. Materials and methods: Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes. Results: Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine. Conclusions: Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine. [ABSTRACT FROM AUTHOR]

Among the legal high drugs easily obtained by internet, 3,4-methylenedioxypyrovalerone (MDPV) and methoxetamine (MXE) were observed in 8 patients who needed hospitalization after ingestion for an isolated experience (n = 4) or collective recreational use (n = 4). Clinical symptoms were hypertension, tachycardia, agitation, hallucinations, and coma for 2 patients. Methods: Plasma and urine analyses were performed by classical HPLC/UV-DAD and GC/MS screening approaches, both with quantitative measurements by either HPLC/UV after back-extraction at acidic pH and/or UPLC/MS/MS after single protein-precipitation purification. Results: MDPV levels (n = 2) were 45 µg/L and below the limit of quantification for plasma, and 2.3 and 0.3 mg/L for urine samples. MXE plasma levels were between 122 and 366 µg/L for 6 patients and below the limit of quantification for one patient. Urine levels (n = 6) were between 2 and 165 mg/L. Two supposed metabolites of MXE were identified as N-desethyl-MXE and O-demethyl- N-desethyl-MXE. Conclusion: While MDPV is now a controlled substance in France, MXE has no status. These observations should be taken into account for a possible future registration. [ABSTRACT FROM AUTHOR]

Bath salts are new designer drugs with stimulant effects on the central nervous system. White or brown powder sold online and in mini-marts under different brand names, bath salts can be used by injecting, snorting, smoking, or ingesting with food or drink. The case of a 30-year-old Caucasian male who developed acute psychosis within a few hours of injecting himself with bath salts is described. The patient was hospitalized with a complaint of hearing voices. The drug also induced in the patient a state of euphoria, increased energy level, along with decreased need for sleep and decreased appetite. The psychological effects of the bath salts subsided within a few hours of injection and his reality testing remained consistently intact over the next 3 days of hospitalization. This case brings to attention the fact that bath salts were legal throughout the United States until recently and is still not completely controlled. This report informs clinicians of harmful effects of bath salts, including severe agitation with possible rhabdomyolysis, psychosis, suicidal ideation, hypertension, tachycardia, and death. [ABSTRACT FROM AUTHOR]

Synthetic psychoactive cathinones (SPCs) are drugs with psychostimulant and entactogenic properties like methamphetamine (MA) and 3,4-methylenedioxymethamphetamine (MDMA). Despite clinical reports of human overdose, it remains to be determined if SPCs have greater propensity for adverse effects than MA or MDMA. To determine whether the SPCs cathinone (CAT), methcathinone (MCAT), mephedrone (MMC), and methylenedioxypyrovalerone (MDPV) have lower LD50 values than MA or MDMA. Male and female C57Bl/6J mice received single injections of one of 6 doses of a test drug (0–160 mg/kg IP). Temperature and behavioral observations were taken every 20 min for 2 h followed by euthanasia of surviving mice. Organs were weighed and evaluated for histopathological changes. LD50 values for MA and MDMA, 84.5 and 100.9 mg/kg respectively, were similar to previous observations. The LD50 for MMC was 118.8 mg/kg, but limited lethality was observed for other SPCs (CAT, MCAT, MDPV), so LD50 values could not be calculated. For all drugs, death was associated with seizure, when it was observed. Rather than hyperthermia, dose-dependent hypothermia was observed for MMC, MDPV, CAT, and MCAT. Contrary to initial expectations, none of the SPCs studied here had LD50 values lower than MA or MDMA. These data indicate that, under the conditions studied here: (1) SPCs exhibit less lethality than MA and MDMA; (2) SPCs impair thermoregulation; (3) effects of SPCs on temperature appear to be independent of effects on lethality. [ABSTRACT FROM AUTHOR]

Abstract: Of growing concern has been the phenomenon of psychoactive chemicals legally marketed as a variety of products such as “bath salts” or “herbal incense.” There is little in the formal literature about actual adverse effects of such chemicals. We have two cases of a paranoid psychosis in individuals consuming methylenedioxypyrovalerone. A discussion of this chemical and its abuse follows. [Copyright &y& Elsevier]