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Dependence Liability of Halazepam May Be Due to Its Metabolite Naloxone Antagonism of the Effects of Mdma 'Estasy' on Nordiazepam

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Dependence Liability of Halazepam May Be Due to Its Metabolite Naloxone Antagonism of the Effects of Mdma 'Estasy' on Nordiazepam 31 314 34 317 PREPARATION OF L~,.9-TETRAHYDROCANNABINOL SUCCINATE PERIPHERAL COCAINE HECEPTOR. !l_I!!.:i:!!~~~_~_!~~!,__8!l_~_~!tx.~~ AFFINITY COLUMN. Thomas J. Martin David R. Compton. Everette _~_~l_ _~_fE'!w._~'Dept. of Pharmacol. & Exp. Ther., Univ. of Md. L. May and Billy R. Martin, Department of Pharmacology and Sch. of Med., Baltimore, MD, 21201. Toxicology, Medical College of Virginia, Virginia Commonwealth [3H]Cocaine at 2 riM bound most to liver, less to diaphragm University, Richmond, VA 23298 and ileum and least to heart, lung and kidney of rats. Identification of specific cannabinoid binding sites in brain has been [3H]Cocaine bound to a P2 membrane preparation from liver hampered by the large degree nonspecific binding of 3H_f,9_ THC. with high affinity (Kd = 2 riM). The concentration of binding Therefore, efforts were undertaken to isolate specific binding sites using sites (Bmax) was 15.3 pmol/mg protein. It was eliminated by affinity column chromatography. ~9-THC succinate was prepared from 95°C for 5 min and was sensitive to trypsin and detergents. ~9-THC and succinic anhydride in THF and triethylamine under reflux. Binding was stable at pH 6.5-8.5 and was higher at 210C than The succinate derivative was approximately one half as potent as f,9-THC at 4°C or 370C. [3H)Cocaine binding to liver membranes was in that it produced hypoactivity (EDso ~ 10 mg/kg), hypothermia (1.8· @ fairly slow (Tl/2 9 min), and only 70% of the bound. 10 mg/kg) and antinociception (EDso ~ 3 mg/kg) in mice. ~9 -THC [3H)cocaine dissociated in 60 min. However, TLC chromatog- succinate (250 mg in ethylene glycol/ ethanol/water) was added to 50 m1 raphy of the membrane-bound [3H]cocaine extracted by ethanol of Affi-Gel 102 suspension followed by the gradual addition of 0.831 g showed that >90% of the radioactivity was [3H]cocaine. of dicyclohexylcarbodiimide while maintaining pH at 4.7. The reaction (-)Norcocaine, which was almost equally potent to cocaine in was allowed to proceed overnight at room temperature. Basic hydrolysis inhibiting [3H]cocaine binding to the brain receptor, was the of an aliquot of the suspension revealed the presence of ~9-THC thus least potent of the analogs on these peripheral cocaine confirming the success of the preparation. The fact that an affinity receptors (ICso = 3 JJM). On the other hand, (-) trans- column can be prepared with ~ 9-THC succinate which retains cinnamoyl cocaine had a very high potency on these peripheral cannabinoid activity suggests that this may be a useful technique for receptors (ICso = 8 riM). The peripheral cocaine receptors isolation of specific binding sites for cannabinoids. Supported by NIDA had affinities for imipramine 20 times higher than the brain grant DA 03672. receptors, but similar affinities for benztropine and desipramine. (Supported in part by NIDA grant 03680) 32 315 35 318 PHARMACOLOGICAL AND RADIOLIGAND BINDING STUDIES EFFECT OF 3,4-METHYLENEDIOXYMETHAMPHETAMINE (MDMA) OF TETRAMETHYLAMMONIUM-~8_TETRAHYDROCANNABINOL ON CONTRACTILE RESPO~SES IN THE G.PIG ILEUM. (TMA). David R. Compton and Billy R. Martin. Deptartment of Gerald Frye & Robert I'atthews. Texas A&~l Univ. Pharmacology and Toxicology, Med. Coil. of V A, V A Commonwealth ColI. of Medicine, College Station, TX 77843 Univ., Richmond, VA 23298. The "deSigner drug", MDMA binds specifically to The possibility that THC might exert its effects by interacting with a rat brain (Gehlert et al., Eur. J. Pharmacol., specific receptor has recently gained partial support from the finding that 1985) and may act on serotonin (5-HT) neuro- 3H_TMA labels a stereoselective, saturable, high affinity binding site transmission. The present study examined effects (Nye et al. JPET 234: 784, 1985). Pharmacological comparison reveals of MDMA on 5-HT and other neurogenic responses of that both f,8_THC and TMA induce hypothermia (2.6· and 3.0·, resp.) at the longitudinal muscle of the G. pig ileum in 5 mg/kg and decrease spontaneous activity (ED50 = 10 and 2.1 mg/kg, vitro. MDMA (1-100uM) evoked dose-related transi- resp.) in the mouse after iv administration. ~ 8_THC and TMA also ent"l1 m i n ) contractions equal to 31% of maximal induce hypothermia (4.4· and 5.0·, resp.) as well as hypoactivity (ED5o ~ 5-HT (1 OuM) responses. MDMA contractions wer e 46 and 133 ug, resp.) after icv administration in the mouse. In the dog, blocked by atropine (10uM) but unaltered by pyril- both drugs produce mild sedation, but only ~8-THC produces static ataxia amine (O.luM), bicuculline (10uM), or desensitiza- (at 0.2 mg/kg, iv) while TMA is inactive at doses up to 1.0 mg/kg (iv). tion with 5-HT (3uM) or GABA (10uM). MDMA (50u:~) Although TMA exhibits CNS depressant properties, it probably lacks failed to reduce contractions due to 5-HT typical cannabinoid psychoactivity. The specific binding of 75 pM (O.OluM), ACh (O.luM) or GABA (10uM). These 3H-TMA (measured in the presence of 10 ~M unlabelled ligand) to results indicate that MDMA exerts a weak atropine freshly prepared rat brain homogenates (20 ug protein per 5 m1 of 25 mM sensitive excitatory action on the g.pig ileum TES, pH 6.8) after a 3 hr, 37 C incubation is not different from that myenteric plexus prep~ration, but this action does observed with heat-denatured tissue. Therefore, it is unlikely that these not appear to involve 5-HT receptors. (Supported binding sites mediate the psychoactive effects of cannabinoids. by PHS AA06322 & MH40774). (Supported by NIDA Grants DA-03672 and DA-07027). 33 316 36 319 DEPENDENCE LIABILITY OF HALAZEPAM MAY BE DUE TO ITS METABOLITE NALOXONE ANTAGONISM OF THE EFFECTS OF MDMA 'ESTASY' ON NORDIAZEPAM. G.A.Patrick, G.J.Yutrzenka and W.Rosenberger, REWARDING BRAIN STIMULATION. Michae 1 Bird and Conan Med. College of Virginia, V.C.U., Richmond, VA. 23298. Kornetsky. Boston University School of Medicine, Boston, It has been suggested that the benzodiazepine halazepam MA 02118. (HZM) does not produce physical dependence itself, but rather Methylenedioxymethamphetamine (MDMA) is a psychoactive that its active metabolite nordiazepam (NDZ) accounts for its compound having structural similarities to both amphetamine dependence-producing properties. The present data tend to sup- related sympathomimetics and hallucinogens like mescaline. port that contention. Male Sprague-Dawley rats were made phys- Since naloxone will attenuate the threshold lowering effect ically dependent upon pentobarbital (PB) by chronic intra- of d-amphetamine or cocaine on rewarding electrical brain peritoneal infusion of the drug for 12 days on an escalating stimulation (REBS), and since MDMA also lowers the threshold dosage schedule, culminating in a final daily dosage of 950 for REBS, the present study tested the hypothesis that MDMA's mg/kg. HZM and NDZ, both unidentified at the time of the mechanism of action may be similar to that of d-amphetamine experiments, were substituted for PB in the infusion at daily or cocaine in this reward system. dosages of 30 and 60 mg/kg; and their ability to suppress Electrodes were implanted into the medial forebrain bundle signs of abstinence was assessed in the PB-dependent rats. of male CDF rats (Charles River Laboratories). Thresholds Neither dose of HZM suppressed overt behavioral signs of were determined using a modification of the psychophysical abstinence in the rat, and HZM produced only a modest method of limits. Racemic 3,4-MDHA (,5-2.0 mg/kg s ,c) suppression of weight loss during withdrawal.· NDZ, an active significantly lowered the reward threshold and naloxone metabolite of HZM that is formed poorly by the rat, did mark- b locked this effect. These resu Its suggest that MDMA effects edly suppress the overt signs of abstinence and, at the higher the same dopaminerg ic and opioid substrates invo 1ved in dose, significantly suppressed the weight loss. These findings. cocaine and d-amphetamine reward. (Supported in part by suggest that NDZ is more likely than HZM to produce sedatlve- NIDA grant DA 02326 and NIDA Research Scientist Award (CK) like dependence. (Supported in part by the CPOD and NIDA grant DA 00099). DA 00490). 149 -----_. ---.---------- " ~".
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