Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats

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1 BJP British Journl of Phrmcology DOI: /j x RESEARCH PAPERbph_1499 Mephedrone, compred with MDMA (ecstsy) nd mphetmine, rpidly increses both dopmine nd 5-HT levels in nucleus ccumbens of wke rts J Kehr 1,2, F Ichinose 2, S Yoshitke 2, M Goiny 1,2, T Sievertsson 2, F Nyberg 3 nd T Yoshitke 1 Correspondence Dr Jn Kehr, Pronexus Anlyticl AB, Krolinsk Institutet Science Prk, Fogdevreten 2, Stockholm, Sweden. E-mil: Keywords 4-methylmethcthinone; cthinones; phenethylmines; 3,4-methylenedioxymethmphetmine; microdilysis; dopmine; 5-HT; serotonin; legl highs; psychostimulnts Received 18 Jnury 2011 Revised 23 April 2011 Accepted 8 My Deprtment of Physiology nd Phrmcology, Krolinsk Institutet, Stockholm, Sweden, 2 Pronexus Anlyticl AB, Krolinsk Institutet Science Prk, Stockholm, Sweden, nd 3 Deprtment of Phrmceuticl Biosciences, Division of Biologicl Reserch on Drug Dependence, Uppsl University, Uppsl, Sweden BACKGROUND AND PURPOSE The designer drug 1-(4-methylphenyl)-2-methylminopropn-1-one (4-methylmethcthinone, mephedrone) is reported to possess psychostimulnt, entctogenic nd hllucinogenic effects. The purpose of this study ws to exmine the effects of cute dministrtion of mephedrone on extrcellulr levels of dopmine (DA) nd 5-HT in the nucleus ccumbens of wke rts nd compre these effects with those induced by 3,4-methylenedioxymethmphetmine (MDMA, ecstsy) nd mphetmine. EXPERIMENTAL APPROACH Microdilysis smpling ws performed while simultneously recording locomotor ctivity in rts nd the monomines were determined by HPLC with electrochemicl detection. KEY RESULTS Mephedrone (3 mg kg -1 s.c.) nd (+)-mphetmine (1 mg kg -1 s.c.) cused rpid increses in extrcellulr DA levels of 496% nd 412%, respectively, wheres MDMA (3 mg kg -1 s.c.) showed only moderte effect (235%). The corresponding 5-HT levels incresed to 941% (mephedrone) nd 911% (MDMA), but only to 165% following mphetmine. The clculted t 1/2 vlues for elimintion rte of mephedrone, MDMA nd mphetmine-induced increses in extrcellulr DA levels were 25, 303 nd 51 min, the corresponding t 1/2 vlues for 5-HT were 26, 48 nd 84 min, respectively. Locomotor ctivity ws incresed most by mphetmine, wheres both mephedrone nd MDMA showed bout three times lower nd shorter-lsting effects. CONCLUSIONS AND IMPLICATIONS The neurochemicl nd functionl properties of mephedrone resemble those of MDMA, but it lso shows n mphetmine-like effect in tht it evokes rpid relese nd elimintion of DA in the brin rewrd system, feture tht my contribute to its potent re-inforcing properties. Abbrevitions 5-HIAA, 5-hydroxyindolcetic cid; DA, dopmine; DOPAC, 3,4-dihydroxyphenylcetic cid; MDMA, ( )-3,4-methylenedioxymethmphetmine hydrochloride; NA, nordrenline; NAcc, nucleus ccumbens 2011 The Authors British Journl of Phrmcology 2011 The British Phrmcologicl Society British Journl of Phrmcology (2011)

2 BJP J Kehr et l. Introduction Mephedrone (1-(4-methylphenyl)-2-methylminopropn-1- one, 4-methylmethcthinone, 4-MMC) is substituted phenethylmine, structurlly cthinone derivtive tht possesses powerful psychostimulnt, entctogenic nd hllucinogenic effects (see Europol EMCDDA, 2010; Schifno et l., 2011). Recently, mephedrone hs gined growing populrity s designer drug or reserch compound offered for sle under vrious nmes vi Internet sites, hed shops nd recently, by street delers (Schifno et l., 2011; Winstock et l., 2010,b; 2011). During the lst 2 yers, mephedrone hs been bnned in most of the EU countries. However, the unified interntionl legisltion nd control of mephedrone s substnce of buse is still missing. The users of mephedrone hve described its psychomimetic effects being comprble to mphetmine, cocine nd 3,4-methylenedioxymethmphetmine (MDMA, ecstsy) cusing euphori, elevted mood, stimultion, enhnced pprecition for music, decresed hostility, improved mentl function nd mild sexul stimultion (Europol EMCDDA, 2010). A recent web-bsed survey from 1006 responders reveled tht mephedrone users consider its effects best compred with those of MDMA (Crhrt-Hrris et l., 2011). However, mephedrone is ssocited with high risk of triggering repetitive nd uncontrolled drug intke subsequent to its initil dministrtion. Excessive intke of mephedrone leds to cute intoxiction, displying the clinicl fetures of cute sympthomimetic toxidrome (Wood et l., 2010,b); this hs been linked to n incresing number of ftlities in Europen countries s reported recently (Gustvsson nd Escher, 2009; Dickson et l., 2010; Winstock et l., 2010; Lusthof et l., 2011). Bsed on the spectrum of psychostimulnt effects described by the drug users nd the chemicl similrity of mephedrone to substituted methcthinone nd methmphetmine it hs been speculted tht mephedrone my ct vi incresed relese nd re-uptke inhibition of 5-HT (serotonin) nd dopmine (DA) (Schifno et l., 2011). However, there re no dt vilble to provide neurochemicl evidence for the in vivo effects of mephedrone on DA nd 5-HT trnsmission in the brin res implicted in drug reinforcement. The chemicl structure of mephedrone, being b-ketomphetmine, indictes tht it is closely relted to cthinone, the ctive constituent of kht known for its psychostimulnt properties (see Klix, 1994). Indeed, cthinone ws shown to exert similr effects to mphetmine, incresing locomotor ctivity (Klix, 1992) nd extrcellulr DA levels in the nucleus ccumbens (NAcc) nd cudteputmen of rts (Pehek et l., 1990). These findings offer n initil hypothesis tht mephedrone, besides its similrity to MDMA tht ffects mostly 5-HT relese nd 5-HT 2 receptors (see Gudelsky nd Ymmoto, 2008), my lso ct by incresing the relese of DA nd/or inhibiting its re-uptke in the mesolimbic structures including the NAcc. Both niml nd humn studies reveled tht the cute re-inforcing effects of drugs, s well s their incentive nd rewrd seeking behviour, re ntomiclly linked to the NAcc nd mesolimbic DA system (see Koob nd Volkow, 2010). Further, the buse potentil of drug is believed to be governed primrily by its t 1/2, nd the potency nd the kinetics of the phrmcodynmic responses induced (see Nutt et l., 2007). The rtionle behind this study ws to exmine, by use of in vivo microdilysis nd simultneous recordings of locomotor ctivity, the effects of cute dministrtion of mephedrone on extrcellulr levels of DA nd 5-HT nd their metbolites 3,4-dihydroxyphenylcetic cid (DOPAC) nd 5-hydroxyindole-3-cetic cid (5-HIAA) in the NAcc of wke rts nd compre these effects with those induced by single dose of ( )-3,4-methylenedioxymethmphetmine (MDMA) nd (+)-mphetmine. Methods Chemicls nd test substnces Dopmine.HCl (DA), 5-HT, the metbolites DOPAC, 5-HIAA nd MDMA, s well s chemicls for mobile phse nd perfusion medium preprtions including sodium dihydrogen phosphte monohydrte, disodium hydrogen phosphte, sodium chloride, potssium chloride, clcium chloride, citric cid, sodium cette nd methnol were purchsed from Sigm-Aldrich (St. Louis, MO, USA). EDTA-2N ws obtined from Dojindo (Kummoto, Jpn). (+)-Amphetmine sulphte slt ws purchsed from Apoteket AB (Stockholm, Sweden), mephedrone.hcl (illicit formultion, purity >95%) ws kindly provided by Swedish Ntionl Lbortory of Forensic Science (Linköping, Sweden). De-ionized wter ws obtined from MilliQ wter purifiction system (Millipore, MA, USA). Stndrd solutions of monomines, metbolites nd drugs were prepred in wter nd kept frozen (-20 C) in mber-coloured test tubes. All drugs were dissolved in sline nd dministered s.c. in volume of 1 ml kg -1 in the scruff of the neck t the following doses (ll in the respective slt form): mephedrone (1 or 3 mg kg -1 ), MDMA (3 mg kg -1 ) nd (+)-mphetmine (1 mg kg -1 ). The nomenclture of drugs nd moleculr trgets conforms to Guide to Receptors nd Chnnels (Alexnder et l., 2008). Surgery nd microdilysis experiments Mle Sprgue-Dwley rts (weighing g) were used in the study. The microdilysis experiments were crried out on wke rts following the protocol described elsewhere (Kehr, 1999; Kehr nd Yoshitke, 2006). All niml cre nd experimentl procedures were pproved by the locl ethicl committee nd complied with the guidelines of the Principles of Lbortory Animl Cre (NIH publiction no. 8023) nd the Council of the Europen Communities (86/809/EEC). The rts (three nimls per cge) were mintined on 12 h light-drk cycle (light t 7:00 h), room temperture 22 2 C nd humidity 50 55%. All efforts were mde to minimize niml suffering nd the number of nimls used for the study. Rts were nesthetized with isoflurne (Forene, Abbott Lbortories, Abbott Prk, IL, USA) using Univentor 400 nesthesi unit (AgnThos, Lidingö, Sweden). The rt ws plced in stereotxic frme (Dvid Kopf Instruments, CA, USA) in flt skull position with the incisor br set to -3.2 mm. The isoflurne nesthesi ws mintined t 2% in the mixture of ir, the ir flow ws 500 ml min -1, the body temperture of the rt ws controlled by rectl thermometer nd mintined t +37 C using CMA/150 temperture controller (CMA/Microdilysis, Stockholm, Sweden). The middle 1950 British Journl of Phrmcology (2011)

3 Mephedrone increses both DA nd 5-HT in rt brin BJP sclp incision of 2 3 cm ws mde nd the flps were kept side using the homeosttic forceps. After exposure of the skull, hole for probe nd two holes for the fixing screws were drilled using fine trephine drill. The guide cnnul for microdilysis probe (Eicom Corp., Kyoto, Jpn) ws implnted into the NAcc (AP +2.2 mm, L +1.1 mm, V -5.3 mm; from bregm nd the durl surfce, ccording to the stereotxic tls of Pxinos nd Wtson (2007). The guide cnnul ws fixed firmly to the skull surfce using dentl cement. Following 5 7 dys of recovery, microdilysis probe (Eicom CX-I; 0.22 mm outside dimeter, 2 mm membrne length with D cut-off) ws inserted into the guide cnnul of the wke rt. The probe ws perfused with Ringer s solution (NCl, 147 mm; KCl, 4 mm; CCl 2, 2.3 mm) t flow rte of 1 ml min -1. After the initil stbiliztion period of 2 3 h, the microdilysis smples were collected in 20 min intervls. The first three smples were used for estimtion of bsl levels of DA, 5-HT, nd DOPAC, homovnillic cid (HVA) nd 5-HIAA. Therefter, mephedrone (1 or 3 mg kg -1 ), MDMA (3 mg kg -1 )(+)-mphetmine (1 mg kg -1 ) or vehicle were injected s.c. to seprte groups of rts nd the frctions were collected for 180 min. At the end of the experiment, the nimls were killed by n overdose of isoflurne nd disloction of the neck. The brins were removed nd exmined for correct plcement of the probe (the probe trck) in the rt brin. Locomotor ctivity test Locomotor ctivity ws monitored by use of single-bem ctivity frme (44 30 cm ACTIMO 10, Shintechno, Jpn) plced round the lower prt of the Mcrolon III cge. This rrngement llowed for simultneous recordings of locomotor ctivity nd microdilysis smpling. The dt were collected by counting nd summrizing the overll ctivity (number of bem crossings) in 5 min intervls nd further pooled into 20 min bins, thereby mtching the frequency of microdilysis smpling. HPLC determintion of monomines nd cidic metbolites Concentrtions of DA nd 5-HT in the brin microdilysis smples were determined by HPLC with electrochemicl detection s described elsewhere (Kehr nd Yoshitke, 2006). Briefly, the HPLC system consisted of HTEC500 unit (Eicom, Kyoto, Jpn), nd CMA/200 Refrigerted Microsmpler (CMA Microdilysis, Stockholm, Sweden) equipped with 20 ml loop nd operting t +4 C. The potentil of the glssy crbon working electrode ws +450 mv versus the Ag/AgCl reference electrode. The seprtion ws chieved on (inside dimeter) mm Eicompk CAX column (Eicom) protected with gurd column CAX-GC2/20 (Eicom). The mobile phse ws mixture of methnol nd 0.1 M phosphte buffer (ph 6.0) (30:70, v v -1 ) contining 40 mm potssium chloride nd 0.13 mm EDTA-2N. The chromtogrms were recorded nd integrted by use of computerized dt cquisition system Clrity (DtApex, Prgue, Czech Republic). The detection limit (signl-to-noise rtio = 3) for DA nd 5-HT ws 0.05 nm, tht is, 0.75 fmol in 15 ml injected onto the column respectively. Concentrtions of DOPAC, HVA nd 5-HIAA in the brin microdilysis smples were determined by seprte HPLC system with electrochemicl detection (HTEC500). The potentil of the glssy crbon working electrode ws +750 mv versus the Ag/AgCl reference electrode. The seprtion ws chieved on (inside dimeter) mm Eicompk SC-5ODS column (Eicom) protected with the gurd column OPTI-GUARD C18 (Optimize Technologies, Oregon, OR, USA). The mobile phse ws mixture of methnol nd 0.1 M citrte/0.1 M sodium cette buffer solution (ph 3.5) (16:84, v v -1 ) nd contined 210 mg L -1 octnesulphonic cid sodium slt nd 5 mg L -1 EDTA-2N. The detection limit (signl-to-noise rtio = 3) for DOPAC nd 5-HIAA ws 2 nm, tht is, 10 fmol in 5 ml injected onto the column. The chromtogrms were recorded nd integrted by use of the computerized dt cquisition system Clrity (DtApex). Dt presenttion nd sttisticl nlysis The bsl concentrtions of monomines nd metbolites were clculted from the men vlues of three frctions collected from ech individul niml during the pre-drug period (-60 to 0 min) nd then expressed s men SEM, n = 4 rts for ech treted group. The men concentrtions were tken s 100% nd ll vlues were reclculted s percentge of these bsl levels. The overll effects of drug tretments on DA nd 5-HT levels, s well s on the levels of metbolites DOPAC nd 5-HIAA were expressed for ech nlyte s the re under the curve (AUC (0 180 min)) clculted s the sum of reltive chnges in extrcellulr levels of DA, 5-HT, DOPAC nd 5-HIAA over the 180 min post-tretment period (nine smples) nd subtrcted from the men reltive AUC (0 180 min) vlue of the vehicle-treted group. Sttisticl nlysis ws performed using Prism 5 (GrphPd Softwre, Sn Diego, CA, USA) sttisticl softwre. Men bsl levels were compred by use of one-wy ANOVA followed by Newmn Keuls multiple comprison test. Differences between the groups of tretment nd interction of tretment nd time were nlysed by repeted mesures two-wy repeted mesures ANOVA followed by Bonferroni s post-test. Differences between the AUC (0 180 min) vlues of DA, 5-HT, DOPAC, 5-HIAA nd the rtio 5-HT : DA of the vehicle- nd drug-treted groups were nlysed by one-wy ANOVA followed by Newmn Keuls multiple comprison test. Elimintion rtes expressed s the t 1/2 of the decys in drug-induced increses in extrcellulr DA nd 5-HT levels nd locomotor ctivity were clculted by use of non-liner fit to the one phse exponentil decy curve. Results Bsl extrcellulr levels of DA, 5-HT, DOPAC nd 5-HIAA in the rt NAcc A typicl plcement of the guide cnnul nd the microdilysis probe in the NAcc is illustrted in Figure 1. As seen, the membrne of the microdilysis probe ws positioned preferentilly in the NAcc shell but protruded lso to the core prt of the nucleus. The bsl concentrtions (expressed in nm) of DA, 5-HT nd metbolites DOPAC nd 5-HIAA in the rt NAcc re summrized in Tble 1. The bsl levels of monomines nd metbolites did not significntly differ within the respective treted groups. British Journl of Phrmcology (2011)

4 BJP J Kehr et l. Tble 1 Bsl levels of DA, 5-HT, DOPAC nd 5-HIAA Vehicle Mephedrone (1 mg kg -1 ) Mephedrone (3 mg kg -1 ) MDMA (3 mg kg -1 ) Amphetmine (1 mg kg -1 ) DA HT DOPAC HIAA The results were clculted s nm nd expressed s men SEM, n = 4, in the microdilystes from rt nucleus ccumbens The bsl levels of monomines nd metbolites did not differ significntly within the respective tretment groups. NAcc shell NAcc core Bregm 2.16 mm Figure 1 A representtive plcement of the microdilysis probe in the nucleus ccumbens. The membrne of the microdilysis probe is trgeting preferentilly the shell but protruded lso to the core prt of the nucleus. Adpted from Pxinos nd Wtson (2007). Effects of mephedrone, MDMA nd mphetmine on DA nd 5-HT levels Administrtion of mephedrone t dose of 3 mg kg -1 s.c. cused rpid increse in extrcellulr levels of DA reching the pek levels of % (P < 0.001) for DA t 40 min (Figure 2A) nd % (P < 0.001) for 5-HT levels lredy t 20 min (Figure 2B) Mephedrone given t the lower (1 mg kg -1 ) dose cused reduced but still significnt increses in 5-HT levels to % (P < 0.001) nd DA levels to % (P < 0.05). The DA levels between the groups were significntly different both for the tretment [F (4,15) = 5.26; P < 0.01] nd the interction of time nd tretment [F (44,165) = 3.28; P < 0.001]. The corresponding vlues for the differences in 5-HT levels for the tretment were [F (4,15) = 9.45; P < 0.001] nd the interction of time nd tretment [F (44,165) = 11.89; P < 0.001]. The incresed concentrtions of DA nd 5-HT returned rpidly within the next min to the bsl levels. A single injection of MDMA (3 mg kg -1 s.c.) cused only moderte increse in DA levels to %, which ws not significnt (two-wy ANOVA) from the vehicle group (Figure 2A). However, MDMA cused mssive increse in extrcellulr 5-HT levels with pek vlue of % (P < 0.001) t 40 min s shown in Figure 2B. Lstly, single dose of mphetmine (1 mg kg -1 s.c.) incresed the DA levels to % (P < 0.001) t 40 min, nd the 5-HT levels to % (not significnt from the vehicle group) shown in Figure 2A nd B, respectively. Effects of mephedrone, MDMA nd mphetmine on DOPAC nd 5-HIAA levels The sme smples nlysed for DA nd 5-HT concentrtions were lso nlysed for the content of metbolites DOPAC nd 5-HIAA. The grph representing the overll effect on the metbolites DOPAC nd 5-HIAA following cute tretments with mephedrone t 1 nd 3 mg kg -1, MDMA (3 mg kg -1 ) nd mphetmine (1 mg kg -1 ), expressed s reltive AUC (0 180 min) vlues, is shown in Figure 3. Following dministrtion of mephedrone t the higher dose, the DOPAC levels were significntly reduced by % (P < 0.01) compred with the AUC (0 180 min) vlue of the control group. A similr decrese by % (P < 0.001) ws observed for the MDMA effect, wheres mphetmine cused the most significnt decrese of the DOPAC levels by % (P < 0.001) of the corresponding vlue of the vehicle-treted group. Mephedrone (3 mg kg -1 ) nd MDMA decresed non-significntly the AUC (0 180 min) vlues of 5-HIAA by % nd % respectively, wheres mphetmine cused significnt increse in 5-HIAA levels by % (P < 0.05) of the vehicle-treted group British Journl of Phrmcology (2011)

5 Mephedrone increses both DA nd 5-HT in rt brin BJP eee c eee ee sme dose of MDMA incresed the 5-HT vlue up to % (P < 0.001) of the vehicle group. The AUC (0 180 min) rtios of the 5-HT nd DA vlues, clculted s men SEM for ech tretment group were: (vehicle), (mephedrone 1 mg kg -1 ), (mephedrone 3 mg kg -1 ), (MDMA 3 mg kg -1 ) nd for mphetmine (1 mg kg -1 ). As seen, the 5-HT : DA vlues for mephedrone, nd MDMA, indicte tht these drugs re preferentil relesers of 5-HT, wheres the 5-HT : DA rtio for mphetmine confirms its preferentil effect on DA relese. Time (min) 5-HT ddd eee eee ccc dd ccc Elimintion rte of DA nd 5-HT relese induced by mephedrone, MDMA or mphetmine The elimintion rtes of drug-induced increses in extrcellulr DA nd 5-HT levels in the rt NAcc were clculted by use of one-phse exponentil decy curve fit to the experimentl dt nd clculting the respective t 1/2 vlues for DA nd 5-HT. The clculted t 1/2 vlues for the elimintion rtes of mephedrone-induced relese of DA nd 5-HT were 24.5 min nd 25.5 min, respectively, for the dose of 3 mg kg -1. The corresponding vlues for 1 mg kg -1 mephedrone were 37.4 min nd 24.8 min; for MDMA min nd 47.9 min, respectively, nd for elimintion of mphetmine-induced DA nd 5-HT relese, their respective t 1/2 vlues were 51 min nd 84.1 min. The clculted correltion fctors (r 2 ) for the curve fit of the DA nd 5-HT decys for the mephedrone, MDMA nd mphetmine-treted groups were for the DA curves: 0.595, nd 0.438, nd for the 5-HT curves: 0.898, 0.664, 0.254, respectively. Figure 2 Time (min) Effects of single s.c. dministrtion of mephedrone (1 nd 3 mg kg -1 ), MDMA (3 mg kg -1 ) nd mphetmine (1 mg kg -1 )on (A) extrcellulr levels of DA nd (B) extrcellulr levels of 5-HT in the NAcc of wke rts. The rrow indictes the time of drug or vehicle dministrtion. Repeted mesures two-wy ANOVA followed by Bonferroni post-test; the drug-treted groups were compred with the vehicle group: mephedrone (1 mg kg -1 ) ccc P < 0.001, c P < 0.05; mephedrone (3 mg kg -1 ) eee P < 0.001, ee P < 0.01; MDMA ddd P < 0.001, dd P < 0.01; mphetmine P < 0.001, P < 0.05; men SEM, n = 4. The overll effects of mephedrone, MDMA nd mphetmine on DA nd 5-HT levels The overll effects of mephedrone, MDMA nd mphetmine on the reltive AUC (0 180 min) vlues of DA nd 5-HT re depicted in Figure 4. Mephedrone (3 mg kg -1 ) cused mrked nd significnt increse in the AUC (0 180 min) vlue of DA by % (P < 0.01), which ws similr to tht induced by mphetmine: % (P < 0.01). Further, mephedrone t 3 mg kg -1 cused mrked increse in the AUC (0 180 min) of 5-HT by % (P < 0.05), wheres the Effects of mephedrone, MDMA nd mphetmine on locomotor ctivity Locomotor ctivity of vehicle- nd drug-treted rts ws monitored simultneously during the microdilysis smpling period (Figure 5). The mephedrone-induced motor ctivtion showed pek level of counts in 20 min nd returned to bsl levels during the following 40 min. MDMA cused similr, not significnt motor ctivtion ( bem crossings) in 40 min. Amphetmine induced robust nd long-lsting locomotor ctivtion with mximum of counts (P < 0.001) in the min bin nd the ctivtion remined significntly elevted during the following 60 min, nd, therefter, slowly decresed until the end of the smpling period. Two-wy repeted mesures ANOVA followed by Bonferroni multiple comprison test reveled significnt differences for the tretment (F (4,15) = 6.04; P < 0.01) nd the interction of time nd tretment (F (44,165) = 4.69; P < 0.001). The overll vlue of locomotor ctivtion (AUC (0 180 min)) by mphetmine ws 4.47 nd 5.37 times lrger thn the corresponding AUC (0 180 min) vlues of MDMA nd mephedrone, respectively. The rte of decline of drug-induced motor ctivtion expressed s the t 1/2 of ech exponentil curve clculted by the nonliner regression nlysis of the experimentl dt reveled t 1/2 of 7.3 min (r ) for mephedrone, 23.6 min (r ) for MDMA nd 43.9 min (r ) for mphetmine. British Journl of Phrmcology (2011)

6 BJP J Kehr et l. e e d d d Figure 3 Overll effects of mephedrone (1 nd 3 mg kg -1 ), MDMA (3 mg kg -1 ) nd mphetmine (1 mg kg -1 ) on DOPAC, nd 5-HIAA levels in the NAcc of wke rts. The columns represent the AUC (0 180 min) vlues clculted s the differences in reltive chnges in DOPAC nd 5-HIAA levels over 3 h period between the drug- nd vehicle-treted groups. One-wy ANOVA followed by Newmn Keuls multiple comprison test; drug-treted groups were compred with the vehicle group: mephedrone (3 mg kg -1 ) ee P < 0.01; MDMA ddd P < 0.001; mphetmine P < 0.001; P < 0.05; men SEM, n = 4. ddd e e e Figure 4 Overll effects of mephedrone (1 nd 3 mg kg -1 ), MDMA (3 mg kg -1 ) nd mphetmine (1 mg kg -1 ) on DA, nd 5-HT levels in the NAcc of wke rts. The columns represent the AUC (0 180 min) vlues clculted s the differences in reltive chnges in DA nd 5-HT over 3 h period between the drug- nd vehicle-treted groups. One-wy ANOVA followed by Newmn Keuls multiple comprison test; drug-treted groups were compred with the vehicle group: mephedrone (3 mg kg -1 ) ee P < 0.01, e P < 0.05; MDMA ddd P < 0.001; mphetmine P < 0.01; men SEM, n = 4. Discussion Recently, numerous reports, comments nd correspondence in medicl literture hve discussed nd pointed out the helth problems ssocited with growing use of novel synthetic stimulnt drugs, so-clled legl highs, which re reltively chep nd distributed under vrious nmes mostly vi the Internet. Cthinone derivtives nd, in prticulr, mephedrone hs gined wide populrity s reserch chemicl nd prty drug in severl Europen countries (see Europol EMCDDA, 2010) including Sweden (Gustvsson nd Escher, 2009), Englnd (Brndt et l., 2010,b,c; Drgn et l., 2010; Schifno et l., 2011; Winstock et l., 2010,b; 2011), Frnce (Debruyne et l., 2010), Irelnd (McNmr et l., 2010; Nicholson et l., 2010), Scotlnd (Torrnce nd Cooper, 2010) nd the Netherlnds (Brunt et l., 2010). The users of mephedrone hve compred its powerful psychostimulnt, entctogenic nd hllucinogenic properties to other buse substnces of this clss including mphetmine, methmphetmine, cocine nd ecstsy (Europol EMCDDA, 2010; Winstock et l., 2010,b; 2011). In survey mong dnce drug users in the UK (Winstock et l., 2011), mephedrone ws the sixth most frequently used drug fter tobcco, lcohol, cnnbis, cocine nd MDMA. However, the use of mephedrone is ssocited 1954 British Journl of Phrmcology (2011)

7 Mephedrone increses both DA nd 5-HT in rt brin BJP Counts per 20 min Figure 5 Time (min) Effects of mephedrone (1 nd 3 mg kg -1 ), MDMA (3 mg kg -1 )nd mphetmine (1 mg kg -1 ) on locomotor ctivity recorded simultneously with microdilysis smpling. The drug or vehicle ws dministered t time 0 min (rrow). Repeted mesures two-wy ANOVA followed by Bonferroni post-test; the drug-treted groups were compred with the vehicle group: mphetmine: P < 0.001, P < 0.05; men SEM, n = 4. with high risk of overdose, leding to uncontrolled nd often ftl drug intoxiction (Gustvsson nd Escher, 2009; Dickson et l., 2010; Jmes et l., 2010; Regn et l., 2010; Wood et l., 2010,b; 2011; Lusthof et l., 2011). Mephedrone s substituted b-ketomphetmine is expected to ct primrily by incresing the relese of monomines nd possibly vi inhibition of their re-uptke (Schifno et l., 2011). The mjor finding of the present study is tht mephedrone cuses significnt, rpid nd dosedependent increses in both 5-HT nd DA levels in the NAcc. The overll effects of mephedrone injected t higher dose on the 5-HT levels were comprble to the effects induced by the sme dose of MDMA. Both mephedrone nd MDMA preferentilly incresed 5-HT over the DA levels; however, the proportion of 5-HT increse (rtio 5-HT : DA) ws t lest two times higher for MDMA thn for mephedrone. In ddition, mephedrone but not MDMA, still potently incresed the ccumbl DA relese to level tht ws comprble to the effect induced by mphetmine. Amphetmine hd only minor effect on extrcellulr 5-HT concentrtions. The effects of MDMA nd mphetmine on the relese of DA nd 5-HT in the rt NAcc observed in this study re in good greement with erlier reports on the effects of these two drugs given t similr doses. Thus, single i.p. injection of MDMA (2.5 or 3 mg kg -1 ) incresed ccumbl DA to bout 200 to 250% (Knknpää et l., 1998; O She et l., 2005; Pnos nd Bker, 2010) nd 5-HT levels only to bout 350% (Knknpää et l., 1998) nd 200% (O She et l., 2005) of the bseline. However, in nother pper, Kurling et l. (2008) reported tht MDMA (5 mg kg -1 free bse, i.p.) incresed the DA levels to bout 700% nd 5-HT levels to more thn 1400% in NAcc of wke rts. Amphetmine sulphte incresed ccumbl DA to bout 250% following dose of 0.75 mg kg -1 i.p. (Auclir et l., 2004) nd to bout 300% t s.c. dose of 0.63 mg kg -1 free bse (Milln et l., 1999), to 650% following n i.p. injection of 1.6 mg kg -1 sulphte slt (Pehek et l., 1990), to % in the Lewis nd Fisher rts, respectively, following s.c. dose of 1 mg kg -1 sulphte slt (Cdoni nd Di Chir, 2007) nd up to 700% t the sme dose but clculted s free bse (Knknpää et l., 1998). The effects of mphetmine on ccumbl 5-HT levels re negligible (Knknpää et l., 1998) or only moderte, incresing the 5-HT levels to bout 130% of control vlues (Milln et l., 1999). The differences between the reported effects of systemic mphetmine on ccumbl DA levels cn be explined by the different routes of dministrtion, doses given s slts or free bses, rcemic or (+)-form of mphetmine nd vritions in the microdilysis protocols used by different investigtors. Microdilysis dt provide vluble informtion on the in vivo phrmcodynmics of neurotrnsmitter relese; however, the dt do not llow direct evlution of potentil mechnism of ction of drugs such s mephedrone. Mephedrone cused only minor nd temporl decreses in the DOPAC levels, wheres the vlues of 5-HIAA were not significntly ffected. These effects re similr to those induced by MDMA, wheres mphetmine significntly decresed the DOPAC levels, while the 5-HIAA levels significntly incresed. Thus, the modertely reduced levels of DOPAC nd 5-HIAA further indicte tht the effect of mephedrone resembles tht of MDMA, tht is, it cts preferentilly s releser of 5-HT, NA nd DA, s reported for MDMA using in vitro methods (Rothmn et l., 2001). Addition of substituents to the ring of phenethylmine nd its relted derivtives t the ethylmine moiety including mphetmine cuses shift in the psychostimulnt properties of these gents from cting s preferentil relesers of NA nd DA to relese lso 5-HT nd/or exhibit binding ffinity to 5-HT 2 receptors, the fetures responsible for incresed hllucinogenic effects of such compounds (Shulgin nd Shulgin, 2007). Strtegies bsed on incresed 5-HT trnsmission, for exmple, by use of mphetmine nlogues tht relese both DA nd 5-HT (Rothmn et l., 2001; Rothmn nd Bumnn, 2006; Bumnn et l., 2011), co-dministrtion of 5-HT relesing drug fenflurmine (Wee nd Woolverton, 2006) or co-dministrtion of 5-HT 2A ntgonits or 5-HT 2C receptors gonists (Bubr nd Cunninghm, 2008; Fletcher et l., 2011) were proposed to counterct self-dministrtion of psychostimulnt drugs in niml models. In recent study, Bumnn nd collegues (Bumnn et l., 2011) compred four mphetmine nlogues displying similr in vitro potency s DA relesers but mrked differences s 5-HT relesers. Although the microdilysis dt on DA relese in NAcc did not correlte with the in vitro predictions, the uthors found good correltions between extrcellulr DA levels nd locomotor ctivity. The increses in 5-HT relese in NAcc were proportionl to the decresed DA relese nd decresed locomotion, the most significnt effect ws observed for the p-methylmphetmine (PAL-313) nlogue (Bumnn et l., 2011). These dt support the findings in our study, demonstrting tht substituted phenethylmines mephedrone nd MDMA mrkedly increse 5-HT relese, but lower DA relese nd reduce locomotor ctivity when compred with the effects of mphetmine. In this respect, it could be predicted tht mephedrone nd MDMA re weker re-inforcers thn mphetmine or cocine. British Journl of Phrmcology (2011)

8 BJP J Kehr et l. This conclusion is in line with current report on mephedrone nd cocine users in the UK where bout 56% of 947 responders (dnce drug users) evluted mephedrone s less ddictive but giving better high thn cocine, wheres 30% nd 14% reported tht it ws eqully or more ddictive thn cocine (Winstock et l., 2011). On the other hnd, it ws reported tht some users compulsively redose mephedrone, consuming their whole supply during session (Europol EMCDDA, 2010). One possible explntion for this behviour could be short durtion (2 3 h) of the mephedrone effects (Europol EMCDDA, 2010). This conclusion is in greement with our dt showing tht mephedrone, given t sme dose s MDMA, is more potent DA releser thn MDMA, wheres the elimintion rte of mephedrone-induced DA relese in the NAcc ws lmost 10 times fster thn tht of induced by MDMA nd two times fster thn tht induced by mphetmine. The clculted elimintion rtes of extrcellulr DA nd 5-HT levels correlte well with the phrmcokinetic profiles of MDMA nd mphetmine reported elsewhere. Thus, the estimted t 1/2 of MDMA ws 47.4 min following s.c. injection of 2 mg kg -1 MDMA in the rt (Bumnn et l., 2009). This vlue is in good greement with the t 1/2 of 48 min reflecting the rte of elimintion of MDMA-induced 5-HT efflux but does not gree with the t 1/2 of 303 min for decy of MDMAinduced DA relese. This discrepncy cn be due to lrge stndrd error in estimted t 1/2 for elimintion rte of MDMAinduced DA, lterntively, the slow elimintion rte of DA my imply the effects of MDMA re evoked by its ctive metbolites such s 3,4-methylenedioxymphetmine (MDA) (Bumnn et l., 2009). The estimted t 1/2 of (+)-mphetmine following n i.v. bolus injection in the rt ws 67 min (Hutchleelh et l., 1994). This cn be compred with the phrmcodynmic effects of mphetmine expressed s t 1/2 of elimintion rtes of extrcellulr levels of DA (51 min) nd 5-HT (84 min) reported in this study. There re no phrmcokinetic dt vilble on mephedrone. Six mephedrone (phse I) metbolites hve been identified in rt urine nd seven in humn urine (Meyer et l., 2010). The initil metbolic step for both species is N-demethyltion of mephedrone to normephedrone. It is not known whether normephedrone possesses ny psychomimetic properties. This possibility cnnot be excluded, prticulrly when considering n nlogous N-demethyltion of methmphetmine to its ctive metbolite mphetmine (see Schep et l., 2010) nd N-demethyltion of MDMA to its ctive metbolite MDA (Bumnn nd Rothmn, 2009). Interestingly, the clculted t 1/2 for (+)-methmphetmine nd its metbolite (+)- mphetmine in the mle rt following i.v. dministrtion of 1 mg kg -1 (+)-methmphetmine were 73 min nd 93 min, respectively (Milesi-Hllé et l., 2005), nd in nother study (Rivière et l., 1999), 63 min nd 98 min, respectively. The estimted t 1/2 of the crdiotoxic metbolite MDA formed from MDMA ws 175 min, which is lmost four times lower thn the t 1/2 vlue for MDMA (Bumnn et l., 2009). In conclusion, by referring to metbolism of methmphetmine (Rivière et l., 1999) nd MDMA (Bumnn et l., 2009), it cn be hypothesized tht potentil ccumultion of mephedrone metbolites including normephedrone could contribute to the cliniclly-reported, toxicity of mephedrone binges. The pek effect of mephedrone on DA relese ws similr to the effect of 1 mg kg -1 s.c. dose of mphetmine, which in turn, could be compred with the i.v. dose of 0.1 mg kg -1 inducing self-dministrtion in rts (Di Cino et l., 1995). Here, the rts self-dministered t bout 0.7 mg mphetmine within the first 30 min of the session, which ws ccompnied by n increse in ccumbl DA to the pek level of 550% in the min frction (Di Cino et l., 1995), levels similr to those observed for the mphetmine nd mephedrone doses in our study. However, further studies re necessry to demonstrte whether mephedrone cn induce self-dministrtion in rts. From comprison of the time courses of locomotor ctivtion induced by mephedrone, MDMA nd mphetmine it ws concluded tht the overll effect of mephedrone ws equipotent to MDMA; however, the mephedroneinduced motor ctivtion diminished bout three, nd six times fster thn tht induced by MDMA nd mphetmine, respectively. Amphetmine cused mrked increse in locomotor ctivity tht lsted for bout 120 min; this finding is in good greement with dt reported elsewhere (Cdoni nd Di Chir, 2007; Kurling et l., 2008). Compred to its bility to relese of DA, (+)-mphetmine is n even more potent t inducing the relese of NA, while possessing similr efficcies for inhibition of DA nd NA uptke (Rothmn et l., 2001). This suggests tht the differences in locomotor ctivtion observed between (+)-mphetmine nd mephedrone or MDMA could lso ccount for the differences in ctivtion of the nordrenergic system. Indeed, it ws demonstrted tht (+)-mphetmine-induced locomotor hyperctivity is mrkedly reduced in mice lcking 1B-drenoceptors (Drouin et l., 2002). On the other hnd, the mphetmine-induced locomotion could be lmost completely bolished by the blockde of 5-HT 2A receptors in the ventrl tegmentl re of the rt (Auclir et l., 2004). These dt indicte complex interply between NA nd 5-HT nd their respective receptors in controlling the relese of DA in the NAcc induced by vrious psychostimulnt drugs. In conclusion, the present dt demonstrte for the first time tht cute dministrtion of mephedrone induces rpid relese of both 5-HT nd DA in the NAcc of wke rts nd this effect is ccompnied by short-lsting increse in locomotor ctivity. These results support the notion tht mephedrone resembles the key neurochemicl nd functionl properties of MDMA, confirming the similrities between mephedrone nd MDMA effects reported by drug users. In ddition, mephedrone-induced relese nd rpid elimintion of DA in the NAcc were similr to the effect of mphetmine given t dose relevnt to its ddictive properties. However, further studies re needed to elucidte the detiled mechnisms behind the reported risk of compulsive binge intke of mephedrone nd the risk for tolernce development. Acknowledgements The study ws supported by the Swedish Ntionl Institute of Public Helth nd the Swedish Reserch Council (Grnt 9459). The uthors thnk Ann Zckrisson from Swedish 1956 British Journl of Phrmcology (2011)

9 Mephedrone increses both DA nd 5-HT in rt brin BJP Ntionl Lbortory of Forensic Science, Linköping, Sweden for kind supply of mephedrone. Conflict of interest The uthors declre no conflict of interest. References Alexnder SPH, Mthie A, Peters JA (2008). Guide to Receptors nd Chnnels (GRAC), 3rd edition. Br J Phrmcol 153 (Suppl. 2): S1 S209. Auclir A, Blnc G, Glowinski J, Tssin JP (2004). Role of serotonin 2A receptors in the d-mphetmine-induced relese of dopmine: comprison with previous dt on lph1b-drenergic receptors. J Neurochem 91: Bumnn MH, Rothmn RB (2009). Neurl nd crdic toxicities ssocited with 3,4-methylenedioxymethmphetmine (MDMA). Int Rev Neurobiol 88: Bumnn MH, Zolkowsk D, Kim I, Scheidweiler KB, Rothmn RB, Huestis MA (2009). Effects of dose nd route of dministrtion on phrmcokinetics of (+ or -)-3,4-methylenedioxymethmphetmine in the rt. Drug Metb Dispos 37: Bumnn MH, Clrk RD, Woolverton WL, Wee S, Blough BE, Rothmn RB (2011). In vivo effects of mphetmine nlogs revel evidence for serotonergic inhibition of mesolimbic dopmine trnsmission in the rt. J Phrmcol Exp Ther 337: Brndt SD, Freemn S, Sumnll HR, Meshm F, Cole J (2010). Anlysis of NRG legl highs in the UK: identifiction nd formtion of novel cthinones. Drug Test Anl ccessed on 29 December 2010 [Epub hed of print] PMID: Brndt SD, Sumnll HR, Meshm F, Cole J (2010b). Anlyses of second-genertion legl highs in the UK: initil findings. Drug Test Anl 2: Brndt SD, Sumnll HR, Meshm F, Cole J (2010c). Second genertion mephedrone. The confusing cse of NRG-1. BMJ 341: c3564. Brunt TM, Poortmn A, Niesink RJ, vn den Brink W (2010). Instbility of the ecstsy mrket nd new kid on the block: mephedrone. J Psychophrmcol ccessed on 8 September 2010 [Epub hed of print] PMID: Bubr MJ, Cunninghm KA (2008). Prospects for serotonin 5-HT2R phrmcotherpy in psychostimulnt buse. Prog Brin Res 172: Cdoni C, Di Chir G (2007). Differences in dopmine responsiveness to drugs of buse in the nucleus ccumbens shell nd core of Lewis nd Fischer 344 rts. J Neurochem 103: Crhrt-Hrris RL, King LA, Nutt DJ (2011). A web-bsed survey on mephedrone. Drug Alcohol Depend ccessed on 21 Mrch 2011 [Epub hed of print]. Drgn PI, Albert S, Wood DM (2010). Mephedrone use nd ssocited dverse effects in school nd college/university students before the UK legisltion chnge. QJM 103: Debruyne D, Courné MA, Le Boisselier R, Djezzr S, Gérrdin M, Boucher A et l. (2010). Mephedrone: designer drug of recent use in Frnce. Therpie 65: (French). Di Cino P, Coury A, Depoortere RY, Egilmez Y, Lne JD, Emmett-Oglesby MW et l. (1995). Comprison of chnges in extrcellulr dopmine concentrtions in the nucleus ccumbens during intrvenous self-dministrtion of cocine or d-mphetmine. Behv Phrmcol 6: Dickson AJ, Vorce SP, Levine B, Pst MR (2010). Multiple-drug toxicity cused by the codministrtion of 4-methylmethcthinone (mephedrone) nd heroin. J Anl Toxicol 34: Drouin C, Drrcq L, Trovero F, Blnc G, Glowinski J, Cotecchi S et l. (2002). Alph1b-drenergic receptors control locomotor nd rewrding effects of psychostimulnts nd opites. J Neurosci 22: Europol EMCDDA Joint report on new psychoctive substnce: 4-methylmethcthinone (mephedrone). Europen Monitoring Centre for Drugs nd Drug Addiction (EMCDDA), Lisbon, Portugl. September Fletcher PJ, Rizos Z, Noble K, Higgins GA (2011). Impulsive ction induced by mphetmine, cocine nd MK801 is reduced by 5-HT(2C) receptor stimultion nd 5-HT(2A) receptor blockde. Neurophrmcology 61: Gudelsky GA, Ymmoto BK (2008). Actions of 3,4-methylenedioxymethmphetmine (MDMA) on cerebrl dopminergic, serotonergic nd cholinergic neurons. Phrmcol Biochem Behv 90: Gustvsson D, Escher C (2009). Mephedrone Internet drug which seems to hve come nd sty. Ftl cses in Sweden hve drwn ttention to previously unknown substnce. Lkrtidningen 106: Hutchleelh A, Sukbuntherng J, Chow HH, Myersohn M (1994). Disposition kinetics of d- nd l-mphetmine following intrvenous dministrtion of rcemic mphetmine to rts. Drug Metb Dispos 22: Jmes D, Adms RD, Spers R, Cooper G, Lupton DJ, Thompson JP et l. (2010). Clinicl chrcteristics of mephedrone toxicity reported to the UK Ntionl Poisons Informtion Service. Emerg Med J 28: Klix P (1992). Cthinone, nturl mphetmine. Phrmcol Toxicol 70: Klix P (1994). Kht, n mphetmine-like stimulnt. J Psychoctive Drugs 26: Knknpää A, Meririnne E, Lillsunde P, Seppälä T (1998). The cute effects of mphetmine derivtives on extrcellulr serotonin nd dopmine levels in rt nucleus ccumbens. Phrmcol Biochem Behv 59: Kehr J (1999). Monitoring chemistry of brin microenvironment: biosensors, microdilysis nd relted techniques. Chpter 41. In: Windhorst U, Johnsson H (eds). Modern Techniques in Neuroscience Reserch. Springer-Verlg GmbH: Heidelberg, pp Kehr J, Yoshitke T (2006). Monitoring brin chemicl signls by microdilysis. In: Grimes CA, Dickey EC, Pishko MV (eds). Encyclopedi of Sensors, Vol. 6. Americn Scientific Publishers: Vlenci, CA, pp Koob GF, Volkow ND (2010). Neurocircuitry of ddiction. Neuropsychophrmcology 35: British Journl of Phrmcology (2011)

10 BJP J Kehr et l. Kurling S, Knknpää A, Seppälä T (2008). Sub-chronic nndrolone tretment modifies neurochemicl nd behviorl effects of mphetmine nd 3,4-methylenedioxymethmphetmine (MDMA) in rts. Behv Brin Res 189: Lusthof KJ, Oosting R, Mes A, Verschrgen M, Dijkhuizen A, Sprong AG (2011). A cse of extreme gittion nd deth fter the use of mephedrone in the Netherlnds. Forensic Sci Int 206: e93 e95. McNmr S, Stokes S, Colemn N (2010). Hed shop compound buse mongst ttendees of the Drug Tretment Centre Bord. Ir Med J 103: 134, Meyer MR, Wilhelm J, Peters FT, Murer HH (2010). Bet-keto mphetmines: studies on the metbolism of the designer drug mephedrone nd toxicologicl detection of mephedrone, butylone, nd methylone in urine using gs chromtogrphy-mss spectrometry. Anl Bionl Chem 397: Milesi-Hllé A, Hendrickson HP, Lurenzn EM, Gentry WB, Owens SM (2005). Sex- nd dose-dependency in the phrmcokinetics nd phrmcodynmics of (+)-methmphetmine nd its metbolite (+)-mphetmine in rts. Toxicol Appl Phrmcol 209: Milln MJ, Brocco M, Gobert A, Joly F, Bervoets K, Rivet J et l. (1999). Contrsting mechnisms of ction nd sensitivity to ntipsychotics of phencyclidine versus mphetmine: importnce of nucleus ccumbens 5-HT2A sites for PCP-induced locomotion in the rt. Eur J Neurosci 11: Nicholson PJ, Quinn MJ, Dodd JD (2010). Hedshop hertche: cute mephedrone meow myocrditis. Hert 96: Nutt D, King LA, Sulsbury W, Blkemore C (2007). Development of rtionl scle to ssess the hrm of drugs of potentil misuse. Lncet 369: O She E, Escobedo I, Orio L, Snchez V, Nvrro M, Green AR et l. (2005). Elevtion of mbient room temperture hs differentil effects on MDMA-induced 5-HT nd dopmine relese in stritum nd nucleus ccumbens of rts. Neuropsychophrmcology 30: Pnos JJ, Bker LE (2010). An in vivo microdilysis ssessment of concurrent MDMA nd cocine dministrtion in Sprgue-Dwley rts. Psychophrmcology (Berl) 209: Pxinos G, Wtson C (2007). The Rt Brin in Sterotxic Coordintes, 6th edn. Elsevier, Acdemic Press: Amsterdm. Pehek EA, Schechter MD, Ymmoto BK (1990). Effects of cthinone nd mphetmine on the neurochemistry of dopmine in vivo. Neurophrmcology 29: Regn L, Mitchelson M, Mcdonld C (2010). Mephedrone toxicity in Scottish emergency deprtment. Emerg Med J ccessed on 23 December 2010 [Epub hed of print] PMID: Rivière GJ, Byrnes KA, Gentry WB, Owens SM (1999). Spontneous locomotor ctivity nd phrmcokinetics of intrvenous methmphetmine nd its metbolite mphetmine in the rt. J Phrmcol Exp Ther 291: Rothmn RB, Bumnn MH (2006). Blnce between dopmine nd serotonin relese modultes behviorl effects of mphetmine-type drugs. Ann N Y Acd Sci 1074: Rothmn RB, Bumnn MH, Dersch CM, Romero DV, Rice KC, Crroll FI et l. (2001). Amphetmine-type centrl nervous system stimulnts relese norepinephrine more potently thn they relese dopmine nd serotonin. Synpse 39: Schep LJ, Slughter RJ, Besley DM (2010). The clinicl toxicology of metmfetmine. Clin Toxicol (Phil) 48: Schifno F, Albnese A, Fergus S, Stir JL, Deluc P, Corzz O et l. (2011). Mephedrone (4-methylmethcthinone; meow meow ): chemicl, phrmcologicl nd clinicl issues. Psychophrmcology (Berl) 214: Shulgin A, Shulgin A (2007). PiHKAL Phenethylmines I Hve Known nd Loved: A Chemicl Love Story. Trnsform Press: Berkeley, CA. Torrnce H, Cooper G (2010). The detection of mephedrone (4-methylmethcthinone) in 4 ftlities in Scotlnd. Forensic Sci Int 202: e62 e63. Wee S, Woolverton WL (2006). Self-dministrtion of mixtures of fenflurmine nd mphetmine by rhesus monkeys. Phrmcol Biochem Behv 84: Winstock AR, Mrsden J, Mitcheson L (2010). Wht should be done bout mephedrone? BMJ 340: c1605. Winstock A, Mitcheson L, Mrsden J (2010b). Mephedrone: still vilble nd twice the price. Lncet 376: Winstock AR, Mitcheson LR, Deluc P, Dvey Z, Corzz O, Schifno F (2011). Mephedrone, new kid for the chop? Addiction 106: Wood DM, Dvies S, Greene SL, Button J, Holt DW, Rmsey J et l. (2010). Cse series of individuls with nlyticlly confirmed cute mephedrone toxicity. Clin Toxicol (Phil) 48: Wood DM, Dvies S, Puchnrewicz M, Button J, Archer R, Ovsk H et l. (2010b). Recretionl use of mephedrone (4-methylmethcthinone, 4-MMC) with ssocited sympthomimetic toxicity. J Med Toxicol 6: Wood DM, Greene SL, Drgn PI (2011). Clinicl pttern of toxicity ssocited with the novel synthetic cthinone mephedrone. Emerg Med J 28: British Journl of Phrmcology (2011)

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Treatment Spring Late Summer Fall 0.10 5.56 3.85 0.61 6.97 3.01 1.91 3.01 2.13 2.99 5.33 2.50 1.06 3.53 6.10 Mean = 1.33 Mean = 4.88 Mean = 3.

Treatment Spring Late Summer Fall 0.10 5.56 3.85 0.61 6.97 3.01 1.91 3.01 2.13 2.99 5.33 2.50 1.06 3.53 6.10 Mean = 1.33 Mean = 4.88 Mean = 3. The nlysis of vrince (ANOVA) Although the t-test is one of the most commonly used sttisticl hypothesis tests, it hs limittions. The mjor limittion is tht the t-test cn be used to compre the mens of only

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