From: "J-P" <[t--um--n] at [citi2.fr]> Newsgroups: alt.drugs.pot,alt.drugs.pot.cultivation,rec.drugs.cannabis,rec.drugs.psychedelic,talk.politics.drugs Subject: Re: So called "gateway drug" study Date: 9 Jul 1997 16:09:17 GMT For those that are interested in the recent reports of cannabis as a potential 'gateway drug', I've written down my thoughts on these articles (yes, it's a bit long !), and include the original two abstracts that were published in Science (you may access Science Online at this address : http://www.sciencemag.org). The first study injected 150 - 300µg/kg of THC into the femoral vein of mice (apparently a small sample size was used, but I can't find the exact number in the paper !). They then measured the amount of mesolimbic dopamine (DA) in the brain, by the insertion of probes. Something addictive raises DA levels in the brain (e.g. heroin, cocaine, nicotine). They found that DA increased with either THC or heroin, and that DA increase due to THC was reduced when a cannabinoid inhibitor (anti-CB1) was used. Surprisingly, an opiate inhibitor decreased DA in both heroin and THC stimulated mice. The authors suggest that the increase in DA must be an indirect effect of THC stimulation. The authors also suggest that THC should be classed alongside morphine, cocaine, amphetamine and nicotine. While more physiological, and personally I believe this study to be better than the second, it must be pointed out that other groups, using different types of rats and different doses, have found, at best, small increases in DA (for example, one group used 1 to 10 mg/kg through an oral route and found no difference - Castaneda et al., THC does not affect striatal dopamine release: microdialysis in freely moving rats. Pharmacol Biochem Behav 40 (3): 587-591 (Nov 1991)). Another study found that the strain of rat was important to dopamine levels and THC (Chen JP et al., Strain-specific facilitation of dopamine efflux by delta 9-tetrahydrocannabinol in the nucleus accumbens of rat: an in vivo microdialysis study. Neurosci Lett 129 (1): 136-180 (Aug 5 1991)). Therefore, the effect may not be a general one, or that the strain of rat used in the first study may have been more susceptible to DA changes due to THC administration. This would mirror humans, where the majority have no adverse effects due to pot smoking, but a few do. Studying just those few addicted to cannabis only tells you about their condition, and nothing on the majority who have no problems. Weiss's group in the second study injected 50 rats daily with 100µg/kg of HU-210, a synthetic analogue of THC, which is supposed to bind to the cannabinoid receptors in the brain with a higher avidity than THC. They then blocked the effect of HU-210 with a cannabis receptor (CB1) blocker. At first, the amount of HU-210 doesn't seem too high, at least it's still in the realms of acceptable. However, the potency of HU-210 compared with THC is very high, and is just not the same molecule ! The brain has two types of cannabis receptors, called CB1 and CB2. Real cannabis binds to the two equally well, while HU-210 binds strongest to CB1 (Felder CC et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol 48 (3): 443-450 (Sep 1995)). Remember, the study used a CB1 blocker, therefore not all the receptors were blocked. This in itself doesn't mean that HU-210 is an unrealistic model of THC, but shows that people must use caution in interpreting the results. Furthermore, HU-210 is structurally pure, in the sense that all it's molecules are built the same way. Usually, molecules come in two forms or enantiomers, which have identical compositions except that one is the mirror image of the other. This can increase, decrease or even change the action of that molecule in the body. Cannabis has both forms, HU-210 has only one form. It's partner (or mirror image), HU-211, has strange effects on cells, which cannabis nor HU-210 exhibit (Wilson RG Jr et al. Cannabinoid enantiomer action on the cytoarchitecture. Cell Biol Int 20 (2): 147-157 (Feb 1996)). Therefore, HU-210 is NOT exactly like THC, therefore a direct comparison is useless. Cannabinoid and Heroin Activation of Mesolimbic Dopamine Transmission by a Common µ1 Opioid Receptor Mechanism Gianluigi Tanda, Francesco E. Pontieri, * Gaetano Di Chiara The effects of the active ingredient of Cannabis, D9-tetrahydrocannabinol (D9-THC), and of the highly addictive drug heroin on in vivo dopamine transmission in the nucleus accumbens were compared in Sprague-Dawley rats by brain microdialysis. D9-THC and heroin increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2. SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of D9-THC but not those of heroin. Naloxone, a generic opioid antagonist, administered systemically, or naloxonazine, an antagonist of µ1 opioid receptors, infused into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopamine transmission. Thus, D9-THC and heroin exert similar effects on mesolimbic dopamine transmission through a common µ1 opioid receptor mechanism located in the ventral mesencephalic tegmentum. Department of Toxicology and Consiglio Nazionale delle Ricerche (CNR), Center for Neuropharmacology, University of Cagliari, Viale A. Diaz 182, 09126 Cagliari, Italy. * Present address: Department of Neuroscience, University "La Sapienza," Viale dell'Universitá 30, 00185 Roma, Italy. ------------------------------------------------------------------------ Volume 276, Number 5321, Issue of 27 June 1997, pp. 2048-2050 ©1997 by The American Association for the Advancement of Science Activation of Corticotropin-Releasing Factor in the Limbic System During Cannabinoid Withdrawal Fernando Rodríguez de Fonseca, * M. Rocío A. Carrera, Miguel Navarro, * George F. Koob, Friedbert Weiss Corticotropin-releasing factor (CRF) has been implicated in the mediation of the stress-like and negative affective consequences of withdrawal from drugs of abuse, such as alcohol, cocaine, and opiates. This study sought to determine whether brain CRF systems also have a role in cannabinoid dependence. Rats were treated daily for 2 weeks with the potent synthetic cannabinoid HU-210. Withdrawal, induced by the cannabinoid antagonist SR 141716A, was accompanied by a marked elevation in extracellular CRF concentration and a distinct pattern of Fos activation in the central nucleus of the amygdala. Maximal increases in CRF corresponded to the time when behavioral signs resulting from cannabinoid withdrawal were at a maximum. These data suggest that long-term cannabinoid administration alters CRF function in the limbic system of the brain, in a manner similar to that observed with other drugs of abuse, and also induces neuroadaptive processes that may result in future vulnerability to drug dependence. F. Rodríguez de Fonseca and M. Navarro, Instituto Complutense de Drogodependencias, Departamento de Psicobiología, Facultad de Psicología, Universidad Complutense de Madrid, 28223 Madrid, Spain. M. R. A. Carrera, G. F. Koob, F. Weiss, Department of Neuropharmacology, Scripps Research Institute, La Jolla, CA 92037, USA. ------------------------------------------------------------------------ Volume 276, Number 5321, Issue of 27 June 1997, pp. 2050-2054 ©1997 by The American Association for the Advancement of Science.