THURSDAY PM DRUGS OF ABUSE: THC, PCP, AND (5261-5266) 1059

5261 5262 GC/MS ANALYSIS OF PIPERIDINOCYCLOHEXANECARBONlTRILE(PCC) STEREOSELECTIVEEFFECTS OF lIDlIA ON INHIBITION OF MONOAMINE SMOKINGPRODUCTS. L.P. Lue, J.A. Scimeca, B.F. Thomas and UPTAKE. T.D. ~ ~ Nichols-L and G.K.W. Yim. B.R. Martin. Department of Pharmacology/Toxicology, Dept. Pharmacol. & Toxicol. and Dept. Med. Chem. & Medical College of Virginia, Virginia Commonwealth Pharmacognosy) Sc'h. Pharm. & Pharm. Sei., Purdue Univ., University, Richmond, VA 23298-000l. West Lafayette, IN 47907. Piperidinocyclohexanecarbonitrile (PCC), an intermediate The R(-)-isomers of hallucinogenic phenylisopropylamines in (PCP) synthesis, is a major contaminant of are most active, whereas the S(+)-enantiomers of illicit PCP. Due to the frequent abuse of PCP by smoking, amphetamine (AMPH)and methylenedioxymethamphetamine (MDIIA) this study was conducted to determine the PCC pyrolysis are more potent centrally. To determine if lIDlIA exhibits products delivered in ~oke. Marihu1~a placebo cigarettes stereoselective effects at the biochemical level that were impregnated with H-piperidino- C-cyano-PCC (synthe- resemble either those of amphetamine or the potent sized in our lab and recrystallized twice, m.p. 67°C) and hallucinogen 2,S-dimethoxy-4-methylamphetamine (DOM), the burned under conditions which simulated smoking. Main- abilit.y of the isomers of MDIIA.AMPHand DOMto inhibit stream smoke was passed through ~!ass wool filters and uptake of radiolabelled monoamines into 8ynaptosomes was H SO and NaOH traps. Tritium and C were recoved as 83%, measured. f.lIPH was more potent than MDIIAin inhibiting a~d %6%, respectively, of the starting material. Seventy- uptake of H-nore~inephrine (NE) into hypothalamic .six percent of the recoved tritrium was found in the glass synaptosomes and H-dopamine (DA) into striatal synap- wool trap followed by 13, 7 and 4% in the acid trap, base tosomes. The S(+)-isomer was more active in each csse. trap and in the ash/unburned bu\~, respectively. Seventy- ~MA was more potent than AMPHin inhibiting uptake of three percent of the recovered e was found in the gl ass H-serotonin (S-HT) into hippocampal synaptosomes and ex- wooI fil ter and 16 and 8% were found in the aci d and base hibited a high degree of stereoselectivity, in favor of the traps, respectively. GC/MS analysis revealed the presence S(+)-isomer. DOMshowed only minima1 activity in inhibit- 5 of 1-piperidinocyclohexene (30%), pce (24%), piperidine ing uptake of any monoamine (ICSO>IO- M). These results (7%), and I-acetyl-piperidine (5%). (Supported by NIDA suggest that MDIIAexhibits stereoselective effects similar grant DA-02396). to those of amphetamine on monoamine uptake Lnhib i t Lon, a parameter that is unrelated to the mechanism 6f action of the hallucinogen DOM. (Supported by USPHS Grant DA02189 from NIDA and USPHS/BRSG 5S86).

5263 5264 MDMA INDUCED BEHAVIORAL CHANGES IN MEMBERS OF (+ )MEIHYLENEDIOXYMETHAMPHETAMlNE(HOMA): A POTENTIALLY PRIMATE SOCIAL COLONIES. R.F. Schlemmer, Jr.*, S.E. NEUROTOXIC AMPHETAMINE ANALOGUE. .;;C.:..J~._-:;S;;ch;;:m=;;i"d",t,-;",aOin;=-d Montell*, J.M. Davis*. (SPON: J.I. Javaid). Coli. of Pharmacy, U. II. Lovenbe rg , Sec. Biochemical Pharmacol. NHLBI, NIH, of lll. at Chicago & Ill, State Psychiatric Inst., Chicago, IL 60612. Bethesda, MD20892 3,4-Methylenedioxymethamphetamine (MDMA) is a psycho- MDIIA is a novel psychotomimetic agent with behavioral active drug which has recently achieved popularity under the effects and a chemical structure placing .it somewhere between street name "Ecstas y". Although little is known about the the amphetaminesand phenylethylamlne hallucinogens pharmacology of MDMA, some have reported that MDMA may such as mescaline. At high doses many aubat t t ut ed amphet- promote interaction between individuals and have suggested its have been shown to -p r oduce degenerative changes in use as an adjunct to psychotherapy. Conversely, adverse reac- various monoaminergic systems of the rat brain. To determine tions to MDMA have led to strict regulation of this drug. The if MDMAexhibited similar effects male Sprague-Dawley rats present study sought to determine the behavioral effects of (200-250 g) were administered MDMA-HCl ( s , c.) at various MDMA in primates in a social setting. In the Ist expt., 4 members doses and sacrificed 3 h later. Brain concentrations of of a stable, social colony of adult Stumptail macaques (Macaca dopamine (DA) , serotonin (SHT) and their major metabolites arctoides) received 4 acute doses of MDMA (0.3-10 mg(b)/kg) i.m. were measured by HPLC-EC. At doses of 2.S, 5, 10 and 20 in a la tin square design. Then a 2nd colony of 4 monkeys each mg!kg MDMAreduced striatal SHT concentrations to 97, 40, 25 received the highest MDMA dose (to mg/kg). Pre-drug (Base) and and 25% of control, respectively. Similar results were drug Tx observation of colony behavior was conducted by a "blind" observed in the hippocampus and cerebral cortex. Although observer for 60 min daily beginning 15 min after injection. the greatest reduction in SHTconcentration WaS observed at Significant behavioral changes induced by MDMA included: an 3 h. striatal SHT levels were still significantly depressed 1 increase In checking; decreases In locomotion, self-grooming, and week after a single injection of MDMA(10 mg/kg). Coadmini- food foraging behaviors; and increased staring. The predominant stration of the SHT uptake inhibitor. cHalopram completely affillative behavior social grooming was reduced or eliminated. blocked the MDIIA-induced decline in striatal SRT concentra- The hallucinogen-related behavior limb jerks was only induced in 2 tions. The results indicate that MDIIAmay be neurotoxic of 8 monkeys. The results of' this study suggest that MDMA has a toward SHT neurons while the blockade of this effect by behavioral profile in primates which is different from hallucino- citalopram suggests a mechanism of toxicity similar to ·that gens and other psychotomimetics. In addition, MDMA appeared to of the better known serotonergic neurotoxin p-chko rcaaphet+ disrupt rather than facilitate social Interaction. .

5265 5266 RELEASE OF [3H)-MONOAMINESFROM SUPERPUSED RAT STRIATAL Effects of methylenedioxymethamphetamine. (MDMA)on dopamine SLICES BY METHYLENEDIOXYMETHAMPHETAMINE(MDMA). J .A. Levin, (DA) and serotonin (S-HT) efflux in the rat neostriatum. C.J. Schmidt, and W. Lovenberg. Sec. Biochem. Pharmacal., H. Takeda, R.A. Gazzara, S.G. Howard and A.K. Cho NHLBI, NIH, Bethesda, MD 20892 Methylenedioxymethamphetamine (MDMA)has recently been the MDMAis a phenylisopropylamine which is reported to have subject of public discussion because of its use as an adjunct unique behavioral effects in man. Because of its structural to psychotherapy and its hazard as an hallucinogenic agent. similarities to the amphetamines we have compared the effect. The effects of MDMAand methylenedioxyamphetamine (MDA) on of MDMAand two related amphetamines on the spontaneous DAand 5-HT release were examined using in vivo voltammetry. release of tritiated dopamine (DA) and serotonin (5HT) from Rats were anesthetized with chloral hydrate (400mg/kg i.p.) superfused rat striatal slices. At concentrations of 10-7 - and stearic-acid modified electrodes implanted into the neo- IO-5M MDMAand the serotonergic neurotoxin, p-chloroamphet- striatum. Semidifferential voltammetric measurements were amine, were equipotent releasers of [3H) SHT being approxi- performed by scanning from -0.1 to +O.3SV (S-HT) vs Ag/AgCl mately lOx more potent than . However, meth- and the peak currents measured at +0.12 (DA) and +O.27V. amphetamine was the more potent releaser of [3H)DA by a MDMA(10 and lmg!kg i.p.) produced a biphasic effec; on DA factor of approximately lOx. MDMA-induced release of both efflux. The slight increase in DA efflux lasted for 40 min [3H)5HT and [3H)DA was Ca2+-independent and inhibited by and was followed by a significant decrease in DAefflux. selective monoamine uptake blockers suggesting a 5-HT efflux was Significantly increased by MDMAand returned carrier-dependent release mechanism. Synaptosomal uptake to control values within 3 hrs. MDA(lmg/kg i.p.) produced experiments with (+)[3H)MDMA indicated no specific uptake of a rapid decrease in DAefflux and an increase in S-HT efflux. the drug further s~ggesting the effect of uptake blockers may These data suggest that the effect of MDMAon DA efflux be to inhibit the carrier-mediated export of amines displaced may be metabolism dependent and modifying DA activity through by MDMA. 5-HT release. (Supported by USPHS Grant DA 02411)

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