Development and initial validation of an MDMA/Ecstasy motives assessment.

OBJECTIVE: MDMA/Ecstasy motives differ from those of other substances such as alcohol, cannabis, and methamphetamine. Previous literature on alcohol and cannabis use identified social, expansion, enhancement, coping, and conformism as primary motives for use. MDMA/Ecstasy users also report using the drug for increases in self-awareness and energy. The development of an MDMA/Ecstasy use motives assessment has potential to inform treatment interventions and public policy on harm reduction. METHOD: An MDMA/Ecstasy use motives assessment was developed from alcohol and cannabis motives measures and qualitative feedback from MDMA/Ecstasy users. Participants included an international sample of adults (N = 1754) who completed an online questionnaire regarding their motives for using recreational MDMA/Ecstasy. RESULTS: Exploratory and confirmatory factor analysis supported a 4-factor MDMA/Ecstasy motives scale. The four motive scales showed good internal consistency reliabilitySocial (α = 0.88) Expansion (α = 0.81), Coping (α = 0.82), and Energy (α = 0.75). Conformity and Enhancement did not emerge as significant factors. Analyses demonstrated convergent and discriminant validity with relevant constructs including quantity/frequency of use, MDMA use disorder, sensation seeking personality, and positive and negative consequences of use. CONCLUSIONS: MDMA/Ecstasy use motives differ from those of other substances due to the distinctly stimulating, emotional, and empathic effects sought by users. By identifying salient MDMA/Ecstasy motives, this study highlights the unique aspects of recreational MDMA/Ecstasy use. This research has utility for informing clinical practice and contributing to public health harm reduction efforts.

Relative reinforcing effects of dibutylone, ethylone, and N-ethylpentylone: self-administration and behavioral economics analysis in rats.

RATIONALE: Following the emergence of methylone as one of the most popular synthetic cathinones, this group of novel psychoactive substance with names ending in "-lone," such as dibutylone, ethylone, and N-ethylpentylone, appeared on the recreational drug market. The pharmacological mechanisms of dibutylone, ethylone, and N-ethylpentylone are well understood; however, to date, the reinforcing effects of dibutylone, ethylone, and N-ethylpentylone are still unclear. OBJECTIVES: This study aimed to examine the self-administration of dibutylone, ethylone, and N-ethylpentylone relative to methamphetamine (METH) and to quantify their relative reinforcing effectiveness using behavioral economic analysis. METHODS: Male Sprague-Dawley rats were trained to self-administer METH (0.05 mg/kg) under a fixed-ratio 1 (FR1) schedule. Following the training, dose substitution was used to generate full dose-response curves for METH and the three synthetic cathinones. According to the first doses on the descending limb of the dose-response curves, rats were trained to self-administer METH (0.05 mg/kg), dibutylone (0.1 mg·kg-1·infusion-1), ethylone (0.4 mg·kg-1·infusion-1), or N-ethylpentylone (0.1 mg·kg-1·infusion-1) under an FR1 schedule, and a behavioral economic evaluation of their reinforcing effectiveness was then performed. RESULTS: Dibutylone, ethylone, and N-ethylpentylone functioned as reinforcers, and the inverted U-shaped dose-response curves were obtained. The rank order of reinforcing potency in this procedure was METH > N-ethylpentylone ≈ dibutylone > ethylone. In the economic analysis, the comparisons of the essential value (EV) transformed from demand elasticity (α) indicated that the rank order of efficacy as reinforcers was METH (EV = 7.93) ≈ dibutylone (EV = 7.81) > N-ethylpentylone (EV = 5.21) ≈ ethylone (EV = 4.19). CONCLUSIONS: These findings demonstrated that dibutylone, ethylone, and N-ethylpentylone function as reinforcers and have addictive potential, suggesting that the modification of α-alkyl and N-alkyl side chains may affect their reinforcing efficacy.

Rapid assessment of the dose-response relationship of methamphetamine using the progressive-dosing procedure.

This paper describes a new method to rapidly obtain dose-response curves for a drug with rewarding properties using the conditioned place preference protocol. In the usual single-dosing procedure, different animals receive single, varying doses. Thus, a large number of animals are required to generate a curve. A new procedure, known as progressive dosing, alternates increasing drug doses with saline. In this way, the same animal can receive multiple tests. The dose-response curves of the rewarding effect of methamphetamine in mice were obtained using both single-dosing and progressive-dosing procedures. Although the progressive-dosing curves were not identical to the single-dosing curves, they showed a similar pattern. The progressive-dosing procedure was replicated with a new set of mice to confirm the reliability of the method and a dose-response curve similar to the previous one was obtained. This new method can reduce the number of animals required and shorten the duration of the experiment.

Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB.

Novel psychoactive substances (NPS) are increasingly prevalent world-wide although their pharmacological characteristics are largely unknown; those with stimulant properties, due to interactions with the dopamine transporter (DAT), have addictive potential which their users may not realise. We evaluated the binding of 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB) to rat striatal DAT by means of quantitative autoradiography with [125I]RTI-121, and the effects of 5-MAPB on electrically-evoked dopamine efflux by fast-cyclic voltammetry in rat brain slices. 5-MAPB displaced [125I]RTI-121 in a concentration-dependent manner, with significant effects at 10 and 30µM. The voltammetry data suggest that 5-MAPB reduces the rate of dopamine reuptake; while the peak dopamine efflux was not increased, the area under the curve was augmented. 5-MAPB can also cause reverse dopamine transport consistent with stimulant properties, more similar to amphetamine than cocaine. Molecular modelling and docking studies compared the binding site of DAT in complex with 5-MAPB to dopamine, amphetamine, 5-APB, MDMA, cocaine and RTI-121. This structural comparison reveals a binding mode for 5-MAPB found in the primary binding (S1) site, central to transmembrane domains 1, 3, 6 and 8, which overlaps with the binding modes of dopamine, cocaine and its analogues. Atomistic molecular dynamics simulations further show that, when in complex with 5-MAPB, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into inward-facing state, similarly to that observed in dopamine-bound DAT. These novel insights, offered by the combination of computational methods of biophysics with neurobiological procedures, provide structural context for NPS at DAT and relate them with their functional properties at DAT as the molecular target of stimulants.

Orexinergic neurotransmission in temperature responses to methamphetamine and stress: mathematical modeling as a data assimilation approach.

EXPERIMENTAL DATA: Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t > 60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t < 60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. MATHEMATICAL MODELING: We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods.

Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature.

BACKGROUND: Despite initial reports of a decline in use in the early 2000s, methamphetamine remains a significant public health concern with known neurotoxic and neurocognitive effects to the user. The goal of this review is to update the literature on methamphetamine use and addiction since its assent to peak popularity in 1990s. METHODS: We first review recent epidemiological reports with a focus on methamphetamine accessibility, changes in use and disorder prevalence rates over time, and accurate estimates of the associated burden of care to the individual and society. Second, we review methamphetamine pharmacology literature with emphasis on the structural and functional neurotoxic effects associated with repeated use of the drug. Third, we briefly outline the findings on methamphetamine-related neurocognitive deficits as assessed via behavioral and neuroimaging paradigms. Lastly, we review the clinical presentation of methamphetamine addiction and the evidence supporting the available psychosocial and pharmacological treatments within the context of an addiction biology framework. CONCLUSION: Taken together, this review provides a broad-based update of the available literature covering methamphetamine research over the past two decades and concludes with recommendations for future research.

Pharmacological assessment of methamphetamine-induced behavioral hyperactivity mediated by dopaminergic transmission in planarian Dugesia japonica.

The freshwater planarian Dugesia japonica has a simple central nervous system (CNS) and can regenerate complete organs, even a functional brain. Recent studies demonstrated that there is a great variety of neuronal-related genes, specifically expressed in several domains of the planarian brain. We identified a planarian dat gene, named it D. japonica dopamine transporter (Djdat), and analyzed its expression and function. Both in situ hybridization and immunofluorescence revealed that localization of Djdat mRNA and protein was the same as that of D. japonica tyrosine hydroxylase (DjTH). Although, dopamine (DA) content in Djdat(RNAi) planarians was not altered, Djdat(RNAi) planarians showed increased spontaneous locomotion. The hyperactivity in the Djdat(RNAi) planarians was significantly suppressed by SCH23390 or sulpiride pretreatment, which are D1 or D2 receptor antagonists, respectively. These results suggest that planarians have a Djdat ortholog and the ability to regulate dopaminergic neurotransmission and association with spontaneous locomotion.

Rate-dependent effects of monoamine releasers on intracranial self-stimulation in rats: implications for abuse liability assessment.

'Rate dependency' in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, predrug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an intracranial self-stimulation assay. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in-vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (P<0.025, R=0.50). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (P<0.05, R=0.64). Overall, these results extend the rate-dependent effects of monoamine releasers to behavior maintained under intracranial self-stimulation and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate-dependency plots might be a useful metric of drug reward and predictor of drug self-administration measures of drug reinforcement.

Alternative reinforcer response cost impacts methamphetamine choice in humans.

Methamphetamine use disorders are a persistent public health concern. Behavioral treatments have demonstrated that providing access to non-drug alternative reinforcers reduces methamphetamine use. The purpose of this human laboratory experiment was to determine how changes in response cost for non-drug alternative reinforcers influenced methamphetamine choice. Seven subjects with past year histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 8 or 16 mg) and completed a battery of subject-rated and physiological measures. During subsequent sessions, subjects then made eight discrete choices between 1/8th of the sampled dose and an alternative reinforcer ($0.25). The response cost to earn a methamphetamine dose was always 500 responses (FR500). The response cost for the alternative reinforcer varied across sessions (FR500, FR1000, FR2000, FR3000). Methamphetamine functioned as a positive reinforcer and produced prototypical stimulant-like effects (e.g., elevated blood pressure, increased ratings of Stimulated). Choice for doses over money was sensitive to changes in response cost for alternative reinforcers in that more doses were taken at higher FR values than at lower FR values. Placebo choices changed as a function of alternative reinforcer response cost to a greater degree than active methamphetamine choices. These findings suggest that manipulating the effort necessary to earn alternative reinforcers could impact methamphetamine use.

A web-based survey on mephedrone.

BACKGROUND: This study sought to collect information on the former legal-high 'mephedrone' using a web-based survey targeted at mephedrone users. METHODS: The survey was advertised on websites frequented by drug users. Individuals were invited to complete the survey if they had taken mephedrone on at least one occasion in the past. RESULTS: One thousand and six completed forms were received from declared users, making this the largest survey on mephedrone to date. CONCLUSION: Results showed that mephedrone users consider its effects to compare best with those of MDMA, and while MDMA was considered marginally safer and its effects more pleasurable, mephedrone's appeal lay in its availability, low price and reliable purity.

MDMA and methamphetamine: some paradoxical negative and positive mood changes in an acute dose laboratory study.

RATIONALE: This study investigated the acute mood effects of oral MDMA, methamphetamine, and placebo in a double-blind laboratory study. METHODS: Fifty-two healthy participants comprised abstinent recreational users of stimulant drugs, 27 female and 25 male, mean age 24.8 years. Three test sessions involved acute 100 mg oral 3.4-methylendioxymethamphetamine (MDMA), 0.42 mg/kg oral methamphetamine, and matching placebo. Drug administration was counterbalanced, testing was double-blind, and medical supervision was present throughout. Car-driving performance on a laboratory simulator was assessed after 3 and 24 h, with the findings being presented elsewhere. Positive and negative moods (PANAS self-ratings) were completed before drug administration, 3, 4.5, and 24 h later. Blood samples were taken to monitor drug plasma levels. RESULTS: Following MDMA, there were no significant increases in positive moods, whereas negative moods were significantly higher than under placebo. Methamphetamine led to significant increases in both positive and negative moods. The MDMA findings contrast with the elated moods, typically noted by dance clubbers on Ecstasy. However, they are consistent with some previous laboratory findings, since a wide array of positive and negative mood changes have been demonstrated. One possible explanatory factor was the neutral environmental situation, particularly if a primary action of MDMA is to intensify ongoing psychological states. Other explanatory factors, such as dosage, gender, post-drug timing, neurohormonal aspects, and social factors, are also discussed. CONCLUSIONS: In the laboratory, acute methamphetamine led to significantly higher positive moods. However, against expectations, MDMA did not generate a significant increase in positive moods.

Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: assessment using biotelemetry.

The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40-140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.

Multitracer assessment of dopamine function after transplantation of embryonic stem cell-derived neural stem cells in a primate model of Parkinson's disease.

The ability of primate embryonic stem (ES) cells to differentiate into dopamine (DA)-synthesizing neurons has raised hopes of creating novel cell therapies for Parkinson's disease (PD). As the primary purpose of cell transplantation in PD is restoration of dopaminergic neurotransmission in the striatum, in vivo assessment of DA function after grafting is necessary to achieve better therapeutic effects. A chronic model of PD was produced in two cynomolgus monkeys (M-1 and M-2) by systemic administration of neurotoxin. Neural stem cells (NSCs) derived from cynomolgus ES cells were implanted unilaterally in the putamen. To evaluate DA-specific functions, we used multiple [(11)C]-labeled positron emission tomography (PET) tracers, including [beta-(11)C]L-3,4-dihydroxyphenylalanine (L-[beta-(11)C]DOPA, DA precursor ligand), [(11)C]-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([(11)C]beta-CFT, DA transporter ligand) and [(11)C]raclopride (D(2) receptor ligand). At 12 weeks after grafting NSCs, PET demonstrated significantly increased uptake of L-[beta-(11)C]DOPA (M-1:41%, M-2:61%) and [(11)C]beta-CFT (M-1:31%, M-2:36%) uptake in the grafted putamen. In addition, methamphetamine challenge in M-2 induced reduced [(11)C]raclopride binding (16%) in the transplanted putamen, suggesting release of DA. These results show that transplantation of NSCs derived from cynomolgus monkey ES cells can restore DA function in the putamen of a primate model of PD. PET with multitracers is useful for functional studies in developing cell-based therapies against PD.

l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine.

This study evaluated whether the caudate-putamen dopamine response that has been observed after deprenyl administration could be attributed exclusively to metabolically generated l-methamphetamine (l-MeAmp). Brain and plasma levels of deprenyl and l-MeAmp were measured after deprenyl (10 mg/kg s.c.) from 10 to 60 min in conscious rats. Peak caudate-putamen levels were observed for deprenyl (15 nmol/g) at 10 min and for l-MeAmp (3 nmol/g) at 30 min. In a parallel study, l-MeAmp metabolism was evaluated. After l-MeAmp (20 mg/kg s.c.), metabolite levels remained low relative to those of the parent compound: l-amphetamine, approximately 5 to 12%; and para-hydroxy-l-methamphetamine (OH-MeAmp), approximately 0.25%. Accordingly, l-MeAmp was considered to be the primary pharmacologically active deprenyl metabolite. A pharmacokinetic-pharmacodynamic analysis was then used to relate these pharmacokinetic data to the results of previous microdialysis studies in which increases in extracellular dopamine were measured in the caudate-putamen after l-MeAmp (3-18 mg/kg) and after deprenyl (10 mg/kg). Dopamine response-area under curve versus dose plots were generated and used to show that an administered dose of 4 mg/kg l-MeAmp would be necessary to effect a dopamine response-area under curve comparable to that observed after the deprenyl dose. However, the present pharmacokinetic results indicated that l-MeAmp brain levels after deprenyl corresponded to those that would be obtained from 0.4 mg/kg l-MeAmp (i.e., one tenth of the required dose). Collectively, these results suggest that the acute increases in extracellular dopamine observed after deprenyl are not due uniquely to metabolically generated l-MeAmp but also to other actions of deprenyl at the dopamine terminal.

Microdialysis assessment of methamphetamine-induced changes in extracellular neurotensin in the striatum and nucleus accumbens.

Stimulants of abuse such as cocaine and methamphetamine (METH) have dramatic effects on tissue neurotensin (NT) levels in the striatum and nucleus accumbens. Presumably these effects are due to the ability of such drugs to increase dopamine transmission. Because changes in dopamine activity appear to influence NT systems, we examined the effects of increasing doses of METH on extracellular NT levels in the medial striatum and nucleus accumbens using in vivo microdialysis in conscious rats. At the lowest dose tested (0.5 mg/kg), METH almost doubled the extracellular concentration of NT in both regions. When the dose of METH was increased to 5.0 mg/kg, extracellular NT concentration was elevated, but only to approximately 150% of control. At the highest dose examined (15.0 mg/kg), extracellular NT was not altered compared to pretreatment control levels. The role of DA D-1 and D-2 receptors in mediating these effects was determined by combining specific antagonists with the low dose of METH. The D-1 antagonist SCH 23390 blocked the METH-induced increase in extracellular NT levels in the striatum, but not in the nucleus accumbens. Pretreatment with the D-2 antagonist, eticlopride, blocked the increase in extracellular NT in both regions. Changes in striatal NT extracellular levels after a single METH injection were compared to the alterations in tissue NT levels following multiple administrations of the same doses of METH. Tissue levels were significantly elevated with 5 or 15 mg/kg METH in the medial, but not the lateral, striatum. There was not a clear correlation observed between the METH effects on striatal NT tissue levels and extracellular NT concentration.

SCH 23390 equivalently, but YM-09151-2 differentially reduces the stimulant effects of methamphetamine, MK-801 and ketamine: assessment by discrete shuttle avoidance in mice.

The inhibitory actions of the selective dopamine D1-and D2-antagonists SCH 23390 and YM-09151-2, respectively, on the mouse's discrete shuttle avoidance were almost equipotent at doses ranging from 0.01-0.1 mg/kg. SCH 23390 reduced the stimulant action of methamphetamine (0.5 mg/kg), MK-801 (0.1 mg/kg) and ketamine (10 mg/kg) with a similar potency. YM-09151-2 also antagonized the actions of these drugs, with the following order of effectiveness: ketamine > MK-801 > methamphetamine. The present results indicate that methamphetamine, MK-801 and ketamine have different characteristics of CNS stimulant action through dopamine D2-receptors.

Assessment of the ambulation-increasing effect of ketamine by coadministration with central-acting drugs in mice.

The coadministration of ketamine (12.5 mg/kg, but not 3.1 mg/kg, s.c.) with methamphetamine (2 mg/kg, s.c.), cocaine (10 mg/kg, s.c.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) and MK-801 (0.1 mg/kg, i.p.) significantly enhanced the ambulation-increasing effects. Furthermore, in the coadministration with morphine (10 mg/kg, s.c.) and GBR-12909 (10 mg/kg, i.p.), not only 12.5 mg/kg but also 3.1 mg/kg of ketamine produced a significant enhancement. On the other hand, the ambulation-increasing effect of ketamine (12.5 mg/kg, s.c.) was significantly suppressed by ceruletide (0.01 mg/kg, i.p.), alpha-methyl-p-tyrosine (100 and 300 mg/kg, i.p. x 2), nimodipine (1 and 3 mg/kg, i.p.), haloperidol (0.03 and 0.1 mg/kg, s.c.), a low dose of apomorphine (0.1 mg/kg, s.c.), physostigmine (0.1 mg/kg, s.c.) and N6-(L-2-phenylisopropyl)-adenosine (0.1 mg/kg, s.c.). However, imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (100 mg/kg, s.c.), a high dose of apomorphine (0.5 mg/kg), reserpine (0.3 and 1 mg/kg, s.c.), propranolol (0.3 and 1 mg/kg, s.c.), phenoxybenzamine (3 and 10 mg/kg, s.c.) and naloxone (0.3 and 1 mg/kg, s.c.) scarcely interacted with ketamine. These results suggest that ketamine increases the ambulatory activity in mice by facilitating dopamine release from a newly synthesized pool at the presynaptic level, which is affected by a calcium-dependent mechanism.