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NATURE MEDICINE • VOLUME 7 • NUMBER 10 • OCTOBER 2001

NEWS & VIEWS

Cannabinoid activity curtails cocaine cravingBehavioral studies demonstrate that the central mechanism involved in cocaine relapse is closely linked to the sites where mari-juana has its effect, suggesting that cannabinoid receptor antagonists may be used as anti-craving agents. (pages 1151–1154)

Although drugs begins the use of as a voluntary psychoactive

behav-DANIELEior, in addicted individuals it becomes asuncontrollable as the compulsive, ritual-ized acts that afflict obsessive-compul-sive disorder patients. The overpoweringnature of drug addiction and the associ-ated changes in brain structure andfunction have led to conceptualizationof this condition as a chronic disease ofthe central nervous system. Like otherchronic brain diseases, drug addictiongoes through recurrent cycles of re-mission and relapse, which can bereadily triggered when abstinentaddicts are confronted with re-minders of their drug habit (‘condi-tioned cues’) or with emotionaldistress. The prevention of such re-lapses is thus one of the primarygoals of addiction treatment1.Relapse to drug taking can bemodeled in laboratory animals. Inone such model, the ‘reinstate-ment paradigm’, cocaine self-ad-ministration is first induced in ratsand then extinguished by subject-ing the animals to a period of ab-stinence. After drug taking hasstopped, exposure to stress, admin-istration of low doses of cocaine orpresentation of cocaine-associatedcues will cause the behavior toreappear. Regardless of the stimu-lus, relapses are accompanied byincreased activity of the mesolim-bic dopamine system—a neuralpathway comprising a small groupof dopamine-releasing cells in themidbrain connected to a much largerfield of dopamine-responsive neuronsin the forebrain’s nucleus accumbensand prefrontal cortex (Fig. 1). This path-

way is thought to be activated in behav-iors such as eating and mating, and tounderlie the rewarding properties ofmany psychoactive drugs, but its exactrole in drug craving and relapse is onlypartially understood. One key questionis what neurotransmitter systems inter-act with this mesolimbic dopaminepathway during relapse. In this issue, astudy by De Vries et al. may provide ananswer2. In doing so, the study opens upan unexpected avenue for the preven-tive therapy of cocaine relapse2.type, although evidence for the exis-PIOMELLItence of other subtypes is accumulat-ing4. CB1 receptors are coupled to Gi/oDe Vries et al. used the rat reinstate-proteins and are normally activated byment model to test whether cannabi-a small group of endogenous lipidsnoid receptors—the target of thecalled endocannabinoids, of whichmarijuana constituent ∆9-tetrahydro-anandamide and 2-arachidonylglycerolcannabinol—have a role in cocaine re-are two well-studied examples. Unlikelapse. They show that the cannabinoidneurotransmitters and neuropeptides,agonist HU-210 precipitates relapse,endo-cannabinoids are not stored inwhereas the cannabinoid antagonistsynaptic vesicles but are produced onSR141716A prevents relapse induceddemand and released from neurons5.Two neurotransmitter systemshave been linked to the genera-tion of endocannabinoids:dopamine elicits anandamide re-lease in the dorsal striatum bystimulating D2by cocaine or cocaine-associated cues,but not relapse induced by stress.Because SR141716A has no effect oncocaine self-administration3, thesefindings suggest that cannabinoid re-ceptors may be selectively involved intriggering cocaine craving during absti-nence, rather than in mediating theprimary effects of the drug. Thatcannabinoid receptors should be impli-

cated in reward is intuitive—millionsof marijuana users can testify to that—but that these receptors should alsogate cocaine relapse is more surprising.How might it occur?Cannabinoid receptors present in thebrain belong largely to the CB1 sub--type receptors6,while glutamate causes 2-arachi-donylglycerol formation in thecortex by engaging NMDA (N-methyl-D-aspartate) receptors6,7.To explain their results, DeVries et al. outline two possiblescenarios that are based on adopamine–endocannabinoid con-nection. In one model, elevateddopamine levels produced by co-caine or cocaine-associated cueselicit the release of endocannabi-noids, which cause relapse.Alternatively, cocaine or cocaine-associated cues elevate endo-cannabinoid levels, which causerelapse by enhancing dopaminerelease. Because the brain’scannabinergic pathways are stilluncharted, we lack hard evidenceto support either scenario. Yet,the latter hypothesis—that of a disin-hibitory role for the endocannabinoidson dopamine transmission—is sup-ported by three observations: CB1 re-ceptors are found in high numbers onaxon terminals of γ-aminobutyric acid(GABA)-ergic interneurons throughoutthe central nervous system; activationof these receptors inhibits GABA re-lease8; and GABA-ergic interneuronsstrongly influence the activity ofdopaminergic projection neurons.Irrespective of the cellular mechanism,the finding that blockade of cannabinoidreceptors prevents cue-mediated relapsesto cocaine seeking is of obvious thera-peutic significance. There is no pharma-

PrefrontalcortexNucleusaccumbensVentricle

tegmentalareaFig. 1 Cocaine craving is thought to be associated with acti-vation of the mesolimbic dopamine system. This neuromodu-latory pathway projects from the ventral tegmental area (VTA)in the midbrain to the nucleus accumbens and the prefrontalcortex. Stress and drug-associated cues may activate themesolimbic dopamine system by engaging two distinct brainregions, the prefrontal cortex and the amygdala, respectively,that send excitatory projections to the VTA. Presynapticcannabinoid receptors are present in these brain areas, wheretheir primary role may be to modulate γ-aminobutyric acid(GABA) and glutamate release.

© 2001 Nature Publishing Group http://medicine.nature.com

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NEWS & VIEWS

cological treatment for cocaine relapse atpresent, and even though there are manysocial and psychological factors that canfacilitate relapse, an agent that ‘takes theedge off’ craving would provide an in-valuable complement to behavioral ther-apy and psychotherapy. Moreover, ascommonality emerges in the mechanismby which these drugs are addictive, thetherapeutic range of cannabinoid antag-onists may be expanded to include otherabused substances, such as opiates andalcohol. Animal studies suggest thatcannabinoid receptor blockade may alle-viate both heroin and alcohol crav-ing2,9,10. One possible reservation to theuse of cannabinoid antagonists in relapsetherapy is that these molecules may notbe able to prevent stress-induced relapse,as shown by De Vries et al. However,other agents such as non-peptide antago-nists of corticotropin-releasing factor re-ceptors may adequately control this con-dition11. As with other chronic diseases,it is reasonable to expect that treatmentof drug craving and relapse will involvethe use of more than one drug.1. O’Brien, C.P. A range of research based pharma-cotherapies for addiction. Science 278, 66–70(1997).2. De Vries, T.C. et al. A cannabinoid mechanism inrelapse to cocaine seeking. Nature Med. 7,1151–1154 (2001).3. Fattore, L., Martellotta, M.C., Cossu, G., Mascia,M.S. & Fratta, W. CB1 cannabinoid receptor ago-nist WIN 55,212-2 decreases intravenous cocaineself-administration in rats. Behav. Brain Res. 104,141–146 (1999).4. Hajos, N., Ledent, C. & Freund, T.F. Novelcannabinoid-sensitive receptor mediates inhibi-tion of glutamatergic synaptic transmission in thehippocampus. Neuroscience (in press).5. Piomelli, D., Giuffrida, A., Rodríguez de Fonseca,F. & Calignano, A. The endocannabinoid systemas a target for therapeutic drugs. TrendsPharmacol. Sci. 21, 218–224 (2000).6. Giuffrida, A. et al. Dopamine activation of en-dogenous cannabinoid signaling in dorsal stria-tum. Nature Neurosci. 2, 358–363 (1999).7. Stella, N. & Piomelli, D. Receptor-dependent for-mation of endogenous cannabinoids in corticalneurons. Eur. J. Pharmacol. 425, 189–196 (2001).8. Kátona, I. et al. Presynaptically located CB1cannabinoid receptors regulate GABA release

from axon terminals of specific hippocampal in-terneurons. J. Neurosci. 19, 4544–4558 (1999).9. Gallate, J.E. & McGregor, I.S. The motivation forbeer in rats: effects of ritanserin, naloxone andSR141716. Psychopharmacology 142, 302–308(1997).10. Colombo, G. et al. Reduction of voluntary ethanolintake in ethanol-preferring SP rats by thecannabinoid antagonist SR-141716. AlcoholAlcohol. 33, 126–130 (1998).11. Shaham, Y., Erb, S. & Stewart, J. Stress-inducedrelapse to heroin and cocaine seeking in rats: Areview. Brain Res. Rev. 33, 13–33 (2000).Department of PharmacologyUniversity of California, IrvineIrvine, California, USAE-mail: piomelli@uci.edu

The alternative to penicillinsMethicillin-resistant Staphylococcus aureus infections have become a major problem worldwide. The findingthat two bacterial enzymes, one native and one acquired, cooperate to build cell walls in the presence ofmethicillin has drawn attention to an as yet unutilized target for new antibiotics.

The to the widespread cure of infections use of antibiotics but also led

toJOACHIMthe rise of resistant—even multiply re-sistant—bacterial strains. The continu-ing and increasing threat of drug-resistant bacterial pathogens, particu-larly ones that emerge in hospitals,must be met by developing new antibi-otics. In a recent publication1, Tomaszand colleagues demonstrate the impor-tance of a crucial enzymatic reactioninvolved in cell-wall metabolism tomethicillin resistance in Staphylococcusaureus. The report supports the viewthat one of the most promising bio-chemical pathways in which to iden-tify new antibiotic targets is themetabolism of the bacterial exoskele-ton, or the peptidoglycan (murein)layer—the target of the β-lactams,which are the most important currentantibiotics. There are two main reasonsfor this: peptidoglycan is found only inbacteria, and the pathway is extracellu-lar, therefore easily available to drugs.The bacterial cell wall has to with-stand an intracellular osmotic pressureof several atmospheres and is rein-

forced by a kind of exoskeleton madeof peptidoglycan (murein). The chemi-cal design of murein—a cross-linkedpolymer in which sugar strands are in-terlinked by peptide bridges—makes it-VOLKERHÖLTJEperfections in the murein polymer.Penicillin and the entire β-lactamfamily of compounds are among theideally suited to act as a cell-wall scaf-most efficient antibiotics; they act byfold2. Moreover, the murein nettinginhibiting the transpeptidation reac-forms a covalently closed hollow bodytions that lead to cross-linking of thethat completely envelopes the bac-murein strands. Penicillin is struc-terium, much like a string bag. Just asturally similar to theDthe strength and tightness of a stringbag depend on every single mesh inthe netting, so do those of the bag-shaped murein sacculus. The mureinsacculus is formed by the polymeriza-tion of a peptidyl-disaccharide precur-sor in two directions: peptidyl moietiesare hooked to one another bytranspeptidation reactions and disac-charides are polymerized to long gly-can chains by transglycosylationreactions (Fig. 1)3–5. The mechanicalstrength of the murein fabric criticallydepends on perfect coordination of thetwo different polymerization reactions.Interfering with either transglycosyla-tion or transpeptidation results in afragile murein sacculus that can even-tually rupture. Interestingly, nature de-signed bifunctional enzymes con-sisting of a transglycosylase and atranspeptidase domain6,7. With suchenzymes, the two polymerizing reac-tions are automatically coordinated,thereby minimizing the chance of im--alanyl-D-alanylmoiety of the murein precursor that isrecognized by the transpeptidases.Thus, in the presence of penicillin, a

stable penicilloyl–enzyme complex isformed that irreversibly blocks the en-zyme6,7 Most bacteria are equippedwith several transpeptidases, both bi-functional and monofunctional, thatare specifically involved in differentgrowth processes, such as cell enlarge-ment and cell division8. Because peni-cillin binds covalently to the trans-peptidation site of these enzymes, theyare known collectively as penicillin-binding proteins (PBPs). Along withthe murein-synthesizing D.D-transpep-tidases, this family includes the mureinmodifying D.D-endopeptidases and theD.D-carboxypeptidases6,7.Bacterial resistance to β-lactamsevolved mainly through three mecha-nisms9: (i) synthesis of β-lactamasesthat degrade penicillin; (ii) in Gram-negative bacteria, decreases in the per-meability of the outer membrane,

1100NATURE MEDICINE • VOLUME 7 • NUMBER 10 • OCTOBER 2001

© 2001 Nature Publishing Group http://medicine.nature.com